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Objective: The purpose of this article was to determine the relationships among total body fat, visceral adipose tissue (VAT), fat cell size (FCS), ectopic fat deposition in liver (intrahepatic lipid [IHL]) and muscle (intramyocellular lipid [IMCL]), and insulin sensitivity index (S(i)) in healthy overweight, glucose-tolerant subjects and the effects of calorie restriction by diet alone or in conjunction with exercise on these variables.Research Design and Methods: Forty-eight overweight volunteers were randomly assigned to four groups: control (100% of energy requirements), 25% calorie restriction (CR), 12.5% calorie restriction +12.5% energy expenditure through structured exercise (CREX), or 15% weight loss by a low-calorie diet followed by weight maintenance for 6 months (LCD). Weight, percent body fat, VAT, IMCL, IHL, FCS, and S(i) were assessed at baseline and month 6.Results: At baseline, FCS was related to VAT and IHL (P < 0.05) but not to IMCL. FCS was also the strongest determinant of S(i) (P < 0.01). Weight loss at month 6 was 1 +/- 1% (control, mean +/- SE), 10 +/- 1% (CR), 10 +/- 1% (CREX), and 14 +/- 1% (LCD). VAT, FCS, percent body fat, and IHL were reduced in the three intervention groups (P < 0.01), but IMCL was unchanged. S(i) was increased at month 6 (P = 0.05) in the CREX (37 +/- 18%) and LCD (70 +/- 34%) groups (P < 0.05) and tended to increase in the CR group (40 +/- 20%, P = 0.08). Together the improvements in S(i) were related to loss in weight, fat mass, and VAT, but not IHL, IMCL, or FCS.Conclusions: Large adipocytes lead to lipid deposition in visceral and hepatic tissues, promoting insulin resistance. Calorie restriction by diet alone or with exercise reverses this trend. [ABSTRACT FROM AUTHOR]

Objective: 31P magnetic resonance spectroscopy (MRS) was used to document long lasting losses in muscle oxidative capacity after bouts of intense endurance exercise.Methods: The subject was a 34 year old highly fit female cyclist (VO2MAX = 53.3 ml/kg/min). Over a five month period, she participated in three separate intense bouts of acute unaccustomed exercise. 31P MRS measurements were performed seven weeks after the first bout and every two weeks for 14 more weeks. In all cases, 31P MRS measurements followed three days after each bout.Results: The subject showed a decreased ability to generate ATP from oxidative phosphorylation and an increased reliance on anaerobic ATP production during the 70% and 100% maximal voluntary contractions after the exercise bouts. Increased rates of fatigue and increased indicators of exercise difficulty also accompanied these reductions in muscle oxidative capacity. Increased oxidative and anaerobic ATP production were needed to maintain the work level during a submaximal 45% maximal voluntary contraction exercise.Conclusions: Acute increases in intensity accompanied by a change in exercise mode can influence the ability of muscle to generate ATP. The muscles were less economical and required more ATP to generate force during the submaximal exercises. During the maximal exercises, the muscle's mitochondria showed a reduced oxidative capacity. However, these reductions in oxidative capacity at the muscle level were not associated with changes in whole body maximal oxygen uptake. Finally, these reductions in muscular oxidative capacity were accompanied by increased rates of anaerobic ATP production, fatigue, and indicators of exercise difficulty. [ABSTRACT FROM AUTHOR]

Background: The prevalence of obesity is higher in black than in white women. Differences in energy economy and physical activity may contribute to this difference. Objective: The objective of this study was to compare free-living energy expenditure and physical activity in black and white women before and after weight loss. Design: Participants were 18 white and 14 black women with body mass indexes (in kg/m2) between 27 and 30. Diet, without exercise, was used to achieve a weight loss of 10 kg and a body mass index <25. After 4 wk of energy balance in overweight and normal-weight states, body composition was assessed by using a 4-compartment model, sleeping and resting energy expenditures were assessed by using a chamber calorimeter, physiologic stress of exercise and exercise economy were measured by using standardized exercise tasks, and daily energy expenditure was assessed by using doubly labeled water. Results: Weight loss averaged 12.8 kg. Sleeping and resting energy expenditures decreased in proportion to changes in body composition. Weight reduction significantly improved physiologic capacity for exercise in both groups of women, making it easier for them to be physically active. Black women had lower body composition-adjusted energy requirements than did white women-both before and after weight loss-during sleep (9% lower, 519 kJ/d; P < 0.001), at rest (14% lower, 879 kJ/d; P < 0.001), during exercise (6% lower; P < 0.05), and as a daily total (9% lower, 862 kJ/d; P < 0.06). By contrast, free-living physical activity was similar between the groups. Conclusions: Weight-reduced women had metabolic rates appropriate for their body sizes. Black women had lower resting and nonresting energy requirements in both overweight and normal-weight states than did white women and did not compensate with greater physical activity, potentially predisposing them to greater weight regain. Copyright © 2000 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

Abstract Background Insulin resistance is often associated with increased levels of intracellular triglycerides, diacylglycerol and decreased fat β-oxidation. It was unknown if this relationship was present in patients with acute insulin resistance induced by trauma. Methods A double blind placebo controlled trial was conducted in 18 children with severe burn injury. Metabolic studies to assess whole body palmitate oxidation and insulin sensitivity, muscle biopsies for mitochondrial palmitate oxidation, diacylglycerol, fatty acyl Co-A and fatty acyl carnitine concentrations, and magnetic resonance spectroscopy for muscle and liver triglycerides were compared before and after two weeks of placebo or PPAR-α agonist treatment. Results Insulin sensitivity and basal whole body palmitate oxidation as measured with an isotope tracer increased significantly (P = 0.003 and P = 0.004, respectively) after PPAR-α agonist treatment compared to placebo. Mitochondrial palmitate oxidation rates in muscle samples increased significantly after PPAR-α treatment (P = 0.002). However, the concentrations of muscle triglyceride, diacylglycerol, fatty acyl CoA, fatty acyl carnitine, and liver triglycerides did not change with either treatment. PKC-θ activation during hyper-insulinemia decreased significantly following PPAR-α treatment. Conclusion PPAR-α agonist treatment increases palmitate oxidation and decreases PKC activity along with reduced insulin sensitivity in acute trauma, However, a direct link between these responses cannot be attributed to alterations in intracellular lipid concentrations.

Background: Older adults are threatened by the risk of muscle atrophy and excess accumulation of adipose tissue. The objective of this study was to determine whether an essential amino acid enriched meal replacement would reduce excess fat and foster skeletal muscle retention, potentially improving physical function in this cohort., Methods: Using a double blind, randomized controlled trial, we compared the influence of an experimental meal replacement enriched with essential amino acids (EMR) to a commercially available, widely used meal replacement (Optifast®) provided once/day (q.d.) for four weeks on body composition, skeletal muscle and physical function in obese older participants. Twenty-eight individuals completed either EMR (n = 13) or Optifast® (n = 15) supplementation protocols. Measurements of body composition, thigh skeletal muscle cross-sectional area (CSA), blood panels, intrahepatic lipid, and physical function were completed pre- and post-supplementation., Results: Body fat mass, visceral fat mass and volume, and intrahepatic lipid were reduced with EMR but not with Optifast®. Thigh muscle CSA increased (Δ 2.4 ± 3.0 cm 2 ) with EMR but not Optifast® (Δ -1.8 ± 6.0 cm 2 ). There was a significant increase in the distance covered during the 6-min walk test with EMR (Δ 23 ± 27 m) but no change in Optifast® (Δ 11 ± 37 m)., Conclusions: Beneficial alterations in fat and muscle support the use of EMR-based meal replacements in obese older adults., Clinical Trial Registration: ISRCTN registry under Reference Number ISRCTN15814848., Competing Interests: Conflict of Interest R. Coker and R. Wolfe are Managing Partners and Co-Owners of Essential Blends, LLC that have received funding through the Small Business Innovations in Research from the National Institutes of Health to develop clinical nutrition products. We declare that the results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

We have previously reported negative energy balance and health benefits during an Alaska backcountry expeditionary hunting (ABEH) immersion in two males. The purpose of our present study was to increase the number of participants, include females, and evaluate macronutrient intake and serum lipids. Four men (age: 46 ± 6 year, BMI: 26 ± 1 kg/m 2 ) and three women (age: 46 ± 11 year, BMI: 25 ± 3 kg/m 2 ) were recruited. Doubly labeled water methodology and dietary recall were utilized to assess energy expenditure and energy intake, respectively. Data were collected during pre- and post-ABEH visits. Body composition was measured using dual-energy x-ray absorptiometry and the cross-sectional area of skeletal muscle in the upper leg (XT), and intrahepatic lipid (IHL) was determined using magnetic resonance imaging and/or spectroscopy (MRI/MRS). Blood parameters were measured by LabCorp. Paired T-tests were used for statistical analysis. Data are reported as mean ± SD and considered significant at p < 0.05. Total energy intake was 7.7 ± 3.4 MJ/day and total energy expenditure was 17.4 ± 2.6 MJ/day, resulting in a negative energy balance of -9.7 ± 3.4 MJ/day. Protein intake(grams)/body weight(kilograms)/day was 1.0 ± 0.4. There were reductions in body weight (Δ-1.5 ± 0.7 kg), BMI (Δ-0.3 ± 0.2 kg/m 2 ), fat mass (Δ-1.7 ± 0.9 kg), and IHL (Δ-0.3 ± 0.3% water peak). There were no changes in lean tissue mass (Δ0.6 ± 1.4 kg) or XT (Δ-1.3 ± 3.3 cm 2 ). There were significant reductions in total cholesterol (Δ-44 ± 35 mg/dl), LDL-cholesterol (Δ-25 ± 14 mg/dl), VLDL-cholesterol (Δ-7 ± 7 mg/dl), and triglycerides (Δ-35 ± 33 mg/dl). The ABEH immersion resulted in considerable negative energy balance and provided comprehensive benefits in metabolic health without any reduction in skeletal muscle., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Excess alcohol consumption is a top risk factor for death and disability. Fatty liver will likely develop and the risk of liver disease increases. We have previously demonstrated that an essential amino acid supplement (EAAS) improved protein synthesis and reduced intrahepatic lipid in the elderly. The purpose of this exploratory pilot study was to initiate the evaluation of EAAS on intrahepatic lipid (IHL), body composition, and blood lipids in individuals with mild to moderate alcohol use disorder (AUD). Following consent, determination of eligibility, and medical screening, 25 participants (18 males at 38 ± 15 years/age and 7 females at 34 ± 18 years/age) were enrolled and randomly assigned to one of two dosages: a low dose (LD: 8 g of EAAS twice/day (BID)) or high dose (HD: 13 g of EAAS BID). Five of the twenty-five enrolled participants dropped out of the intervention. Both groups consumed the supplement BID for 4 weeks. Pre- and post-EAAS administration, IHL was determined using magnetic resonance imaging/spectroscopy, body composition was analyzed using dual-energy X-ray absorptiometry, and blood parameters were measured by LabCorp. T-tests were used for statistical analysis and considered significant at p < 0.05. While there was no significant change in IHL in the LD group, there was a significant 23% reduction in IHL in the HD group ( p = 0.02). Fat mass, lean tissue mass, bone mineral content, and blood lipids were not altered. Post-EAAS phosphatidylethanol was elevated and remained unchanged in LD at 407 ± 141 ng/mL and HD at 429 ± 196 ng/mL, indicating chronic and excess alcohol consumption. The HD of the proprietary EAAS formulation consumed BID seemed to lower IHL in individuals with mild to moderate AUD. We suggest that further studies in a larger cohort be conducted to more completely address this important area of investigation.

Type 2 diabetes is associated with impaired exercise capacity. Alterations in both muscle perfusion and mitochondrial function can contribute to exercise impairment. We hypothesized that impaired muscle mitochondrial function in type 2 diabetes is mediated, in part, by decreased tissue oxygen delivery and would improve with oxygen supplementation. Ex vivo muscle mitochondrial content and respiration assessed from biopsy samples demonstrated expected differences in obese individuals with ( n = 18) and without ( n = 17) diabetes. Similarly, in vivo mitochondrial oxidative phosphorylation capacity measured in the gastrocnemius muscle via 31 P-MRS indicated an impairment in the rate of ADP depletion with rest (27 ± 6 s [diabetes], 21 ± 7 s [control subjects]; P = 0.008) and oxidative phosphorylation ( P = 0.046) in type 2 diabetes after isometric calf exercise compared with control subjects. Importantly, the in vivo impairment in oxidative capacity resolved with oxygen supplementation in adults with diabetes (ADP depletion rate 5.0 s faster, P = 0.012; oxidative phosphorylation 0.046 ± 0.079 mmol/L/s faster, P = 0.027). Multiple in vivo mitochondrial measures related to HbA 1c These data suggest that oxygen availability is rate limiting for in vivo mitochondrial oxidative exercise recovery measured with 31 P-MRS in individuals with uncomplicated diabetes. Targeting muscle oxygenation could improve exercise function in type 2 diabetes., (© 2018 by the American Diabetes Association.)

Objective: Obese girls with polycystic ovarian syndrome (PCOS) have decreased insulin sensitivity (IS), muscle mitochondrial dysfunction and increased liver fat, which may contribute to their increased risk for type 2 diabetes. Less is known regarding normal-weight girls with PCOS., Methods: Normal-weight girls with PCOS [n =18, age 15.9 ± 1.8 years, body mass index (BMI) percentile 68 ± 18] and normal-weight controls (NWC; n = 20; age 15.0 ± 2.1 years, BMI percentile 60 ± 21) were studied. Tissue-specific IS was assessed with a four-phase hyperinsulinemic-euglycemic clamp with isotope tracers and a 2-hour oral glucose tolerance test (OGTT). Hepatic fat was determined using magnetic resonance imaging. Postexercise muscle mitochondrial function was assessed with 31 P MR spectroscopy., Results: Both groups had similar demographics, anthropomorphics, physical attributes, habitual physical activity levels and fasting laboratory values, except for increased total testosterone and DHEAS in PCOS. Clamp-assessed peripheral IS was lower in PCOS (10.4 ± 2.4 mg/kg/min vs 12.7 ± 2.1; P = 0.024). The 120-minute OGTT insulin and glucose concentrations were higher in PCOS (114 IU/mL ± 26 vs 41 ± 25, P = <0.001 and 119 ± 22 mg/dL vs 85 ± 23, P = 0.01, respectively). Muscle mitochondrial ADP and phosphocreatine time constants were slower in PCOS. Despite a higher percentage liver fat in PCOS, hepatic IS was similar between groups, as was adipose IS., Conclusions: Normal-weight girls with PCOS have decreased peripheral IS and muscle mitochondrial dysfunction, abnormal glucose disposal, relative postprandial hyperinsulinemia, and increased hepatic fat compared to NWC. Despite a normal BMI, multiple aspects of metabolism appear altered in normal-weight girls with PCOS.

Context: Obesity, insulin resistance (IR), and diabetes are increasing in youth, especially in girls. IR is associated with muscle mitochondrial dysfunction in youth and adults with diabetes. However, it is unknown whether this relationship is present in youth prior to development of diabetes., Objective: Assess IR and mitochondrial function, including sex differences, in nondiabetic youth., Design: Cross-sectional study of youth in the Exploring Perinatal Outcomes among Children, Resistance to InSulin in Type 1 And Type 2 diabetes, and Androgens and Insulin Resistance Study cohorts., Setting: Academic medical university., Participants: Two hundred seventy-five youth, 13 to 19 years old [43% males: 17.1 (16.52, 17.63) years, body mass index z-score (BMI-Z) 0.36, 64.7% Tanner 5; 57% females: 17.2 (16.43, 17.67) years, BMI-Z 0.72, 78.9% Tanner 5]., Interventions: Fasting laboratories, oral glucose tolerance test, and 31P magnetic resonance spectroscopy., Main Outcome Measures: IR [triglyceride:high-density lipoprotein (HDL) ratio, Matsuda index, and homeostasis model for insulin resistance (HOMA-IR)] and muscle mitochondrial function (adenosine 5'-diphosphate time constant and oxidative phosphorylation rate)., Results: Compared with males, females were more insulin resistant, with higher triglyceride:HDL ratio [1.95 (1.30, 2.79) vs 1.69 (1.21, 2.23), P = 0.042], HOMA-IR [3.18 (2.42, 4.39) vs 2.76 (2.02, 4.08), P = 0.035], and fasting free fatty acids (FFAs) and lower Matsuda score [3.98 (2.71, 5.96) vs 5.39 (3.43, 7.57), P < 0.001]. After adjustment for the higher BMI and Tanner stage and lower physical activity levels seen in females, there were no sex differences in mitochondrial function nor in any IR measure except FFAs. We did not find an association between measures of IR and mitochondrial function., Conclusions: The greater IR seen in adolescent girls vs boys is mostly explained by differences in BMI and physical activity. Mitochondrial function does not appear to be related to IR in a large cohort of nondiabetic youth., (Copyright © 2017 Endocrine Society)

Aims: Pioglitazone (Pio) is known to improve insulin sensitivity in skeletal muscle. However, the role of Pio in skeletal muscle lipid metabolism and skeletal muscle oxidative capacity is not clear. The aim of this study was to determine the effects of chronic Pio treatment on skeletal muscle mitochondrial activity in individuals with type 2 diabetes (T2D)., Materials and Methods: Twenty-four participants with T2D (13M/11F 53.38±2.1years; BMI 36.47±1.1kg/m 2 ) were randomized to either a placebo (CON, n=8) or a pioglitazone (PIO, n=16) group. Following 12weeks of treatment, we measured insulin sensitivity by hyperinsulinemic-euglycemic clamp (clamp), metabolic flexibility by calculating the change in respiratory quotient (ΔRQ) during the steady state of the clamp, intra- and extra-myocellular lipid content (IMCL and EMCL, respectively) by 1 H magnetic resonance spectroscopy ( 1 H-MRS) and muscle maximal ATP synthetic capacity (ATPmax) by 31 P-MRS., Results: Following 12weeks of PIO treatment, insulin sensitivity (p<0.0005 vs. baseline) and metabolic flexibility (p<0.05 vs. CON) significantly increased. PIO treatment significantly decreased IMCL content and increased EMCL content in gastrocnemius, soleus and tibialis anterior muscles. ATPmax was unaffected by PIO treatment., Conclusions: These results suggest that 12weeks of pioglitazone treatment improves insulin sensitivity, metabolic flexibility and myocellular lipid distribution without any effect on maximal ATP synthetic capacity in skeletal muscle. Consequently, pioglitazone-induced enhancements in insulin responsiveness and fuel utilization are independent of mitochondrial function., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: Insulin resistance (IR) correlates with mitochondrial dysfunction, free fatty acids (FFAs), and intramyocellular lipid (IMCL) in adults with type 2 diabetes (T2D). We hypothesized that muscle IR would relate to similar factors in T2D youth., Methods: Participants included 17 youth with T2D, 23 normal weight controls (LCs), and 26 obese controls (OBs) of similar pubertal stage and activity level., Results: T2D and OB groups were of similar BMI. T2D youth were significantly more IR and had higher calf IMCL and serum FFA concentrations during hyperinsulinemia. ADP time constant (ADPTC), a blood-flow dependent mitochondrial function measure, was slowed and oxidative phosphorylation rates lower in T2D. In multiple linear regression of the entire cohort, lack of FFA suppression and longer ADPTC, but not IMCL or HbA1c, were independently associated with IR., Conclusion: We found that elevated FFAs and mitochondrial dysfunction are early abnormalities in relatively well-controlled youth with T2D. Further, post-exercise oxidative metabolism appears affected by reduced blood flow, and is not solely an inherent mitochondrial defect. Thus, lowering FFAs and improving mitochondrial function and blood flow may be potential treatment targets in youth with T2D., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Hyperandrogenic syndrome (HAS) is associated with insulin resistance (IR) and type 2 diabetes. Muscle IR in type 2 diabetes is linked with defects in mitochondrial oxidative capacity. In vivo muscle mitochondrial function has not been studied in HAS, especially in youth, who are early in the disease process. Our goal was to measure muscle mitochondrial oxidative function and peripheral IR in obese youth with HAS. Obese girls without HAS [n = 22, age 15(13,17) yr, BMI Z-score 2.05 ± 0.37] and with HAS [n = 35, age 15(14,16) yr, BMI Z-score 2.18 ± 0.30] were enrolled. Mitochondrial function was assessed with (31)phosphorus MR spectroscopy before, during, and after near-maximal isometric calf exercise, and peripheral IR was assessed with an 80 mU·m(-2)·min(-1) hyperinsulinemic euglycemic clamp. Girls with HAS had higher androgens [free androgen index 7.9(6.6,15.5) vs. 3.5(3.0,4.0), P < 0.01] and more IR [glucose infusion rate 9.4(7.0, 12,2) vs. 14.5(13.2,15.8) mg·kg lean(-1)·min(-1), P < 0.01]. HAS girls also had increased markers of inflammation including CRP, platelets, and white blood cell count and higher serum free fatty acids during hyperinsulinemia. Mitochondrial oxidative phosphorylation was lower in HAS [0.11(0.06,0.19) vs. 0.18(0.12,0.23) mmol/s, P < 0.05], although other spectroscopy markers of mitochondrial function were similar between groups. In multivariate analysis of the entire cohort, IR related to androgens, oxidative phosphorylation, and free fatty acid concentrations during hyperinsulinemia. These relationships were present in just the HAS cohort as well. Obese girls with HAS have significant peripheral IR, which is related to elevated androgens and free fatty acids and decreased mitochondrial oxidative phosphorylation. These may provide future options as targets for therapeutic intervention.

The purpose of this investigation was to develop a potential model for how muscle fiber type, Achilles tendon length, stretch-shortening cycle potentiation (SSCP), and leg strength interact with running economy. Twenty trained male distance runners 24-40 years of age served as subjects. Running economy (net oxygen uptake) was measured while running on a treadmill. Leg press SSCP(force) and SSCP(velocity) were determined by measuring the difference in velocity between a static leg press throw and a countermovement leg press throw. Vertical jump SSCP was determined by measuring the difference in jump height between a static jump and a drop jump from a 20.3-cm bench. Tendon length was measured by magnetic resonance imaging, and muscle fiber type was made from a vastus lateralis muscle biopsy. Type IIx muscle fiber percent (r = 0.70, p < 0.001) and leg strength (r = 0.95, p < 0.001) were positively and independently related to late eccentric force development. Achilles tendon length (r = 0.42, p ≤ 0.05) and late eccentric force during stretch-shortening cycle (r = 0.76, p < 0.001) were independently related to SSCP(force). SSCP(force) was related to SSCP(velocity), which in turn was related to running economy (r = 0.61, p < 0.01). These results suggest that longer Achilles tendon length, type II fiber, and muscular leg strength may enhance the potential for SSCP, running economy, and physiological effort while running.

Insulin resistance (IR) increases cardiovascular morbidity and is associated with mitochondrial dysfunction. IR is now recognized to be present in type 1 diabetes; however, its relationship with mitochondrial function is unknown. We determined the relationship between IR and muscle mitochondrial function in type 1 diabetes using the hyperinsulinemic-euglycemic clamp and (31)P-MRS before, during, and after near-maximal isometric calf exercise. Volunteers included 21 nonobese adolescents with type 1 diabetes and 17 nondiabetic control subjects with similar age, sex, BMI, Tanner stage, and activity levels. We found that youths with type 1 diabetes were more insulin resistant (median glucose infusion rate 10.1 vs. 18.9 mg/kglean/min; P < 0.0001) and had a longer time constant of the curve of ADP conversion to ATP (23.4 ± 5.3 vs. 18.8 ± 3.9 s, P < 0.001) and a lower rate of oxidative phosphorylation (median 0.09 vs. 0.21 mmol/L/s, P < 0.001). The ADP time constant (β = -0.36, P = 0.026) and oxidative phosphorylation (β = 0.02, P < 0.038) were related to IR but not HbA1c. Normal-weight youths with type 1 diabetes demonstrated slowed postexercise ATP resynthesis and were more insulin resistant than control subjects. The correlation between skeletal muscle mitochondrial dysfunction in type 1 diabetes and IR suggests a relationship between mitochondrial dysfunction and IR in type 1 diabetes., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Unlabelled: Insulin resistance is increasingly prevalent in children and may be related to muscle mitochondrial dysfunction, necessitating development of mitochondrial assessment techniques. Recent studies used phosphorus magnetic resonance spectroscopy (P-MRS), a noninvasive technique appealing for clinical research. P-MRS requires exercise at a precise percentage of maximum volitional contraction (MVC). MVC measurement in children, particularly in those with a disease, is problematic because of variability in perception of effort and motivation. We therefore developed a method to predict MVC using maximal calf muscle cross-sectional area (MCSA) to assure controlled and reproducible muscle metabolic perturbations., Methods: Data were collected from 66 sedentary 12- to 20-yr-old participants. Plantarflexion MVC was assessed using an MRI-compatible exercise treadle device. MCSA of the calf muscles were measured from magnetic resonance images. Data from the first 26 participants were used to model the relation between MVC and MCSA (predicted MVC = 24.763 + 0.0047 MCSA). This model was then applied to the subsequent 40 participants., Results: MVC versus model-predicted mean MVC was 43.9 ± 0.8 kg versus 44.2 ± 1.81 (P = 0.90). P-MRS results when predicted and MVC were similar showed expected changes during MVC-based exercise. In contrast, MVC was markedly lower than predicted in four participants and produced minimal metabolic perturbation. Upon repeat testing, these individuals could perform their predicted MVC with coaching, which produced expected metabolic perturbations., Conclusions: Compared with using MVC testing alone, using magnetic resonance imaging to predict muscle strength allows for a more accurate and standardized P-MRS protocol during exercise in children. This method overcomes a major obstacle in assessing mitochondrial function in youths. These studies have importance as we seek to determine the role of mitochondrial function in youths with insulin resistance and diabetes and response to interventions.

Insulin sensitivity is impaired and ectopic fat (accretion of lipids outside of typical adipose tissue depots) increased in obese adults and adolescents. It is unknown how early in life this occurs; thus, it is important to evaluate young children to identify potential factors leading to the development of metabolic syndrome. We examined an ethnically diverse cohort of healthy, exclusively prepubertal children (N = 123; F = 57, M = 66; age 8.04 ± 0.77 years) to examine differences in insulin sensitivity and ectopic and visceral fat deposition between obese and nonobese youth. Obesity was categorized by age- and sex-adjusted BMI z-scores (nonobese = z-score <2 (N = 94) and obese = z-score ≥2 (N = 29)). Insulin sensitivity was assessed by both a frequently sampled intravenous glucose tolerance test (S(i)) and the homeostatic model assessment of insulin resistance (HOMA(IR)). Intramyocellular lipids (IMCLs) from soleus and intrahepatic lipids (IHLs) were assessed by magnetic resonance spectroscopy, visceral adipose tissue (VAT) by magnetic resonance imaging, and total body fat by dual-energy X-ray absorptiometry. We also examined serum lipids (total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol) and blood pressure (diastolic and systolic). Obese children exhibited significantly lower S(i) (5.9 ± 5.98 vs. 13.43 ± 8.18 (mµ/l)(-1)·min(-1), P = 0.01) and HDL-C and higher HOMA(IR) (1.68 ± 1.49 vs. 0.63 ± 0.47, P < 0.0001), IMCL (0.74 ± 0.39 vs. 0.44 ± 0.21% water peak, P < 0.0001), IHL (1.49 ± 1.13 vs. 0.54 ± 0.42% water peak, P < 0.0001), VAT (20.16 ± 8.01 vs. 10.62 ± 5.44 cm(2), P < 0.0001), total cholesterol, triglycerides, low-density lipoprotein cholesterol, and systolic blood pressure relative to nonobese children. These results confirm significantly increased ectopic fat and insulin resistance in healthy obese vs. nonobese children prior to puberty. Excessive adiposity during early development appears concomitant with precursors of type 2 diabetes and the metabolic syndrome.

Aims: Peak oxygen uptake (VO(2)) is diminished in patients with heart failure with preserved ejection fraction (HFpEF) suggesting impaired cardiac reserve. To test this hypothesis, we assessed the haemodynamic response to exercise in HFpEF patients., Methods and Results: Eleven HFpEF patients (73 ± 7 years, 7 females/4 males) and 13 healthy controls (70 ± 4 years, 6 females/7 males) were studied during submaximal and maximal exercise. The cardiac output (Q(c), acetylene rebreathing) response to exercise was determined from linear regression of Q(c) and VO(2) (Douglas bags) at rest, ∼30% and ∼60% of peak VO(2), and maximal exercise. Peak VO(2) was lower in HFpEF patients than in controls (13.7 ± 3.4 vs. 21.6 ± 3.6 mL/kg/min; P < 0.001), while indices of cardiac reserve were not statistically different: peak cardiac power output [CPO = Q(c) × mean arterial pressure (MAP); HFpEF 1790 ± 509 vs. controls 2119 ± 581 L/mmHg/min; P = 0.20]; peak stroke work [SW = stroke volume (SV) × MAP; HFpEF 13 429 ± 2269 vs. controls 13 200 ± 3610 mL/mmHg; P = 0.80]. The ΔQ(c)/ΔVO(2) slope was abnormally elevated in HFpEF patients vs. controls (11.2 ±3.6 vs. 8.3 ± 1.5; P = 0.015)., Conclusion: Contrary to our hypothesis, cardiac reserve is not significantly impaired in well-compensated outpatients with HFpEF. The abnormal haemodynamic response to exercise (decreased peak VO(2), increased ΔQ(c)/ΔVO(2) slope) is similar to that observed in patients with mitochondrial myopathies, suggesting an element of impaired skeletal muscle oxidative metabolism. This impairment may limit functional capacity by two mechanisms: (i) premature skeletal muscle fatigue and (ii) metabolic signals to increase the cardiac output response to exercise which may be poorly tolerated by a left ventricle with impaired diastolic function.

Purpose: The purpose of study was to determine whether quadriceps/patella and Achilles tendon length and flexibility of the knee extensors and plantar flexors are related to walking and running economy., Methods: Twenty-one male distance runners were subjects. Quadriceps/patella and Achilles tendon length were measured by magnetic resonance imaging; body composition was measured DXA; oxygen uptake at rest while seated, walking (3 mph), and running (6 and 7 mph) were measured by indirect calorimetry; knee and ankle joint flexibility were measured by goniometry; and leg lengths were measured by anthropometry while seated. Correlations were used to identify relationships between variables of interest., Results: Net VO2 (exercise VO2 - rest VO2) for walking (NVOWK) and running at 6 and 7 mph (NVO6 and NVO7, respectively) was significantly related to Achilles tendon length (r varying from -0.40 to -0.51, P all < 0.04). Achilles tendon cross section was not related to walking or running economy. Quadriceps/patella tendon length was significantly related to NVO7 (r = -0.43, P = 0.03) and approached significance for NVO6 (r = -0.36, P = 0.06). Flexibility of the plantar flexors was related to NVO7 (+0.38, P = 0.05). Multiple regression showed that Achilles tendon length was independently related to NVO6 and NVO7 (partial r varying from -0.53 to -0.64, all P < 0.02) independent of lower leg length, upper leg length, quadriceps/patella tendon length, knee extension flexibility, or plantarflexion flexibility., Conclusions: These data support the premise that longer lower limb tendons (especially Achilles tendon) and less flexible lower limb joints are associated with improved running economy.

We have previously shown that Achilles tendon length is related to walking economy on the flat, presumably because of increased stretch-shortening cycle elastic energy savings. In addition, greater walking economy in African American (AA) women compared to European American (EA) women is explained by longer Achilles tendons in AA women. The purposes of this study were to determine whether economy while walking up a grade and during isometric plantar flexion, two tasks expected to produce proportionately less energy savings from elastic savings are different between AA and EA women. We evaluated walking economy at 4.8 km/h at 0 and 2.5% grade in 48 AA and 48 EA premenopausal women. Plantar flexor muscle metabolic economy (force/ATP) was also evaluated using (31) phosphate magnetic resonance spectroscopy ((31)P-MRS). AA women walked on the flat more economically (net VO(2), AA 8.3 and EA 8.9 ml kg(-1) min(-1), P = 0.04). No significant ethnic differences were observed while walking up a 2.5% grade or in (31)P-MRS determined plantar flexor muscle metabolic economy. These data support our previous study's suggestion that AA women are more economical while walking on the flat. On the other hand, in activities in which stretch-shortening cycle elastic energy savings would be expected to be reduced (grade walking and isometric force production), no differences in economy during grade walking or isometric force production were observed suggesting that biomechanical, i.e. stretch-shortening cycle elastic energy savings differences rather biochemical differences contribute to the better flat walking economy observed in AA women.

Insulin resistance has been associated with the accumulation of fat within skeletal muscle fibers as intramyocellular lipid (IMCL). Here, we have examined in a cross-sectional study the interrelationships among IMCL, insulin sensitivity, and adiposity in European Americans (EAs) and African Americans (AAs). In 43 EA and 43 AA subjects, we measured soleus IMCL content with proton-magnetic resonance spectroscopy, insulin sensitivity with hyperinsulinemic-euglycemic clamp, and body composition with dual-energy X-ray absorptiometry. The AA and EA subgroups had similar IMCL content, insulin sensitivity, and percent fat, but only in EA was IMCL correlated with insulin sensitivity (r = -0.47, P < 0.01), BMI (r = 0.56, P < 0.01), percent fat (r = 0.35, P < 0.05), trunk fat (r = 0.47, P < 0.01), leg fat (r = 0.40, P < 0.05), and waist and hip circumferences (r = 0.54 and 0.55, respectively, P < 0.01). In a multiple regression model including IMCL, race, and a race by IMCL interaction, the interaction was found to be a significant predictor (t = 1.69, DF = 1, P = 0.0422). IMCL is related to insulin sensitivity and adiposity in EA but not in AA, suggesting that IMCL may not function as a pathophysiological factor in individuals of African descent. These results highlight ethnic differences in the determinants of insulin sensitivity and in the pathogenesis of the metabolic syndrome trait cluster.

Aims/hypothesis: We hypothesised that ectopic fat deposition is present in liver and skeletal muscle before puberty and that both are potentially important factors in the early pathogenesis of insulin resistance., Methods: Proton magnetic resonance spectroscopy was used to evaluate intramyocellular and intrahepatic lipids in 50 male and 42 female multi-ethnic, prepubertal (Tanner < 2) children (8.1 ± 0.8 years; 35.4 ± 10.7 kg; 27.9 ± 8.3% body fat; means ± SD). Intramyocellular lipid was measured in soleus muscle and intrahepatic lipid in the middle right lobe. Abdominal fat was measured by magnetic resonance imaging, body fat by dual energy X-ray absorptiometry, and insulin resistance using homeostatic model assessment., Results: Intrahepatic lipid ranged from 0.11% to 4.6% relative to the liver water signal (mean 0.79 ± 0.79%) whereas intramyocellular lipid ranged from 0.13% to 1.86% relative to the muscle water signal (mean 0.51 ± 0.28%). Intramyocellular and intrahepatic lipids were significantly correlated with total adiposity (r = 0.49 and 0.59), abdominal adiposity (r = 0.44 and 0.54), and each other (r = 0.39, p < 0.05, Spearman). Both intramyocellular and intrahepatic lipid were positively correlated with fasting insulin (r = 0.37 and 0.38 respectively) and insulin resistance (r = 0.37 and 0.37; p < 0.01). After adjustment for race and sex, the relations between ectopic fat and insulin resistance remained, whereas both disappeared when further adjusted for body fat or BMI z scores., Conclusions/interpretations: These results suggest that typical relations between body composition, ectopic fat and insulin resistance are present in children before puberty. Thus, interventions aimed at reducing adiposity have the potential to decrease ectopic fat accumulation, delay the onset of insulin resistance and decrease the risk for development of type 2 diabetes in children.

Aging is associated with loss of endurance; however, aging is also associated with decreased fatigue during maximal isometric contractions. The aims of this study were to examine the relationship between age and walking endurance (WE) and maximal isometric fatigue (MIF) and to determine which metabolic/fitness components explain the expected age effects on WE and MIF. Subjects were 96 pre-menopausal women. Oxygen uptake (walking economy) was assessed during a 3-mph walk; aerobic capacity and WE by progressive treadmill test; knee extension strength by isometric contractions, MIF during a 90-s isometric plantar flexion (muscle metabolism measured by (31)P MRS). Age was related to increased walking economy (low VO(2), r = -0.19, P < 0.03) and muscle metabolic economy (force/ATP, 0.34, P = 0.01), and reduced MIF (-0.26, P < 0.03). However, age was associated with reduced WE (-0.28, P < 0.01). Multiple regression showed that muscle metabolic economy explained the age-related decrease in MIF (partial r for MIF and age -0.13, P = 0.35) whereas walking economy did not explain the age-related decrease in WE (partial r for WE and age -0.25, P < 0.02). Inclusion of VO(2max) and knee endurance strength accounted for the age-related decreased WE (partial r for WE and age = 0.03, P > 0.80). In premenopausal women, age is related to WE and MIF. In addition, these results support the hypothesis that age-related increases in metabolic economy may decrease MIF. However, decreased muscle strength and oxidative capacity are related to WE.

The prevalence of type 2 diabetes is greater among African Americans (AA) vs. European Americans (EA), independent of obesity and lifestyle. We tested the hypothesis that intramyocellular lipid (IMCL) or extramycellular lipid (EMCL) would be associated with insulin sensitivity among healthy young women, and that the associations would differ with ethnic background. We also explored the hypothesis that adipokines and estradiol would be associated with muscle lipid content. Participants were 57 healthy, normoglycemic, women and girls mean age 26 (±10) years; mean BMI 27.3 (±4.8) kg/m²; 32 AA, 25 EA. Soleus IMCL and EMCL were assessed with ¹H magnetic resonance spectroscopy (MRS); insulin sensitivity with an insulin-modified frequently sampled intravenous glucose tolerance test and minimal modeling; body composition with dual-energy X-ray absorptiometry; and intra-abdominal adipose tissue (IAAT) with computed tomography. Adiponectin, leptin, and estradiol were assessed in fasting sera. Analyses indicated that EMCL, but not IMCL, was greater in AA vs. EA (2.55 ± 0.16 vs. 1.98 ± 0.18 arbitrary units, respectively, P < 0.05; adjusted for total body fat). IMCL was associated with insulin sensitivity in EA (r = -0.54, P < 0.05, adjusted for total fat, IAAT, and age), but not AA (r = 0.16, P = 0.424). IMCL was inversely associated with adiponectin (r = -0.31, P < 0.05, adjusted for ethnicity, age, total fat, and IAAT). In conclusion, IMCL was a significant determinant of insulin sensitivity among healthy, young, EA but not AA women. Further research is needed to determine whether the component lipids of IMCL (e.g., diacylglycerol (DAG) or ceramide) are associated with insulin sensitivity in an ethnicity specific manner.

Spaceflight represents a unique physiologic challenge to humans, altering hormonal profiles and tissue insulin sensitivity. Among these hormonal alterations, hypercortisolemia and insulin insensitivity are thought to negatively affect muscle mass and function with spaceflight. As insulin sensitivity influences the accumulation of muscle triglycerides, we examined this relationship during hypercortisolemia and inactivity. Six young healthy volunteers were confined to bed rest for 28 days. To mimic the stress response observed during spaceflight, hypercortisolemia (20-24 mg/dL) was induced and maintained by oral ingestion of hydrocortisone. On days 1 and 28 of bed rest, insulin sensitivity across the leg was assessed with a local (femoral arterial insulin infusion) 2-stage hyperinsulinemic-euglycemic clamp (stage 1, 35 microU/min per milliliter of leg; stage 2, 70 microU/min per milliliter of leg). Intramuscular lipid was measured with magnetic resonance spectroscopy. After bed rest, there was a decrease in insulin sensitivity, as assessed by glucose uptake during hyperinsulinemia (from 9.1 +/- 1.3 [mean +/- SEM] to 5.2 +/- 0.7 mg/kg of leg per minute [P = .015]). Intramuscular triglyceride increased from 0.077 +/- 0.011 to 0.136 +/- 0.018 (signal area of fat/signal area of standard, P = .009). Intramuscular lipid content correlated with the glucose uptake at day 28 (R = -0.85, P = .035). These data demonstrate that muscular inactivity and hypercortisolemia are associated with an increase in intramuscular triglyceride and skeletal muscle insulin resistance in previously healthy subjects.

Background: Intramyocellular and intrahepatic (IHL) lipids are significantly associated with insulin resistance in adults and adolescents and may represent an early marker for developing the metabolic syndrome or type 2 diabetes., Methods: During the pilot phase of a larger cross-sectional study, we used proton magnetic resonance spectroscopy ((1)H-MRS) to determine the feasibility of noninvasively evaluating IHL in 11 male (n = 4) and female (n = 7) prepubertal children using a standard clinical system and to determine whether IHL is correlated with adiposity, fasting insulin and glucose, and liver enzymes., Results: Body mass index (BMI) (range, 13.4-32.4 kg/m(2)) and IHL stores (range, 0.07-3.2% relative to an oil phantom) were variable. IHL was correlated with body mass (r = 0.66, P = 0.037), BMI (r = 0.73, P = 0.016), percentage body fat (r = 0.73, P = 0.01, n = 10), waist circumference (r = 0.85, P = 0.016), and serum lactate dehydrogenase concentration (r = 0.77, P = 0.03) but was not significantly correlated with other markers of liver damage, including aspartate aminotransferase activity (r = 0.59, P = 0.09, n = 9) and alkaline phosphatase concentrations (r = 0.60, P = 0.087). IHL was also (P < 0.01) correlated with fasting insulin concentration (r = 0.85, P = 0.03, n = 6) and insulin resistance (r = 0.94, P = 0.006, n = 6), but these correlations were driven by the results for one child., Conclusions: These preliminary data suggest that (1)H-MRS obtained in a standard pediatric clinical environment may be used to determine IHL in healthy normal and overweight prepubertal youth. This noninvasive technique may prove useful in identifying early markers of the metabolic syndrome in at-risk youth.

Intramyocellular lipid (IMCL) has been inversely associated with insulin sensitivity in some, but not all, studies. This study utilized fast, high-resolution, magnetic resonance spectroscopic imaging (MRSI) to: investigate relationships between muscle lipids (IMCL and extramyocellular lipid (EMCL)) and insulin sensitivity in muscles of varying oxidative capacity, explore ethnic differences in these relationships, and determine whether a eucaloric, low-fat dietary intervention would reduce IMCL and increase insulin sensitivity. Subjects were 30 healthy, African-American (AA; n=14) and European-American (EA; n=16) males, BMI 26.49 (±5.57) kg/m(2), age 21.80 (±7.84) yrs. Soleus and tibialis anterior muscle lipids were quantified using MRSI. Insulin sensitivity was assessed via intravenous glucose tolerance test. A 2-week, eucaloric, low-fat diet intervention was conducted in a sub-group (n=12) subjects with assessments at baseline and post-intervention. Neither IMCL nor EMCL levels differed between ethnicities. In the total group, and within EA (but not AA), both tibialis anterior IMCL and EMCL were inversely associated with insulin sensitivity (P<0.05 for both); soleus muscle lipids were not associated with insulin sensitivity. Soleus, but not tibialis anterior, IMCL declined in both ethnic groups (average 25.3%; p<0.01) following dietary intervention; insulin sensitivity was unchanged. Results suggest that an association of muscle lipids with insulin sensitivity may be influenced by the oxidative capacity of the muscle group studied and may vary with ethnicity.

This article addresses the emerging technology of PET coupled with MRI, or PET/MRI, which could become the technology of choice in the future for many reasons. Some of these reasons will be discussed, along with a historical account of the field of MRI and how this modality has evolved to include many aspects of molecular and functional imaging. After reading this article, nuclear medicine technologists should be able to provide an overview of the history of MRI, discuss PET and how it is mainly used today melded to CT as PET/CT, discuss how MRI is used diagnostically, explain how PET technology and MRI technology are able to function simultaneously together as PET/MRI, discuss some issues concerning who will operate these new units, and discuss the possibility that PET/MRI could be the blended technology of choice in the future.

Objective: Hypertriglyceridemia is a risk factor for coronary heart disease. The aim of this study was to determine the effect of amino acid (AA) supplementation on plasma, liver, and muscle lipid concentrations and insulin sensitivity in the elderly., Methods: Twelve impaired glucose tolerant elderly (mean +/- SD 67.0 +/- 5.6 y of age, seven women and five men) ingested 11 g of essential AAs plus arginine twice a day for 16 wk, after a 7-wk control run-in. Diet and activity were not otherwise modified. Plasma lipid concentrations and oral glucose tolerance were measured every fourth week and tissue lipid concentrations (magnetic resonance spectroscopy) every eighth week., Results: No changes in plasma lipids were observed during the control run-in. AA supplementation lowered plasma triacylglycerol (TG; P < 0.001), total cholesterol (P = 0.048), and very low-density lipoprotein cholesterol (P < 0.001) concentrations. Plasma TG decreased approximately 20% from the initial value of 1.45 +/- 0.18 mmol/L (mean +/- SE, 128 +/- 16 mg/dL), with the greatest decrease in the subjects starting out with the highest concentrations (r = -0.83). Similarly, liver fat content (liver TG/Intralipid standard) decreased approximately 50% from the initial value of 0.34 +/- 0.06 (P = 0.021, n = 8), with the greatest decrease in the subjects who initially had the highest values (r = -0.86). Intramuscular fat content and insulin sensitivity did not change., Conclusion: Diet supplementation with AAs lowers plasma TG, total cholesterol, and very low-density lipoprotein cholesterol concentrations and liver lipid content in impaired glucose tolerant elderly. AA supplementation may have a potential role in the treatment of hypertriglyceridemia or hepatic steatosis.

Objective: Nonalcoholic fatty liver disease (NAFLD) and its association with insulin resistance are increasingly recognized as major health burdens. The main objectives of this study were to assess the relation between liver lipid content and serum lipids, markers of liver function and inflammation in healthy overweight subjects, and to determine whether caloric restriction (CR) (which improves insulin resistance) reduces liver lipids in association with these same measures., Methods and Procedures: Forty-six white and black overweight men and women (BMI = 24.7-31.3 kg/m(2)) were randomized to "control (CO)" = 100% energy requirements; "CR" = 25%; "caloric restriction and increased structured exercise (CR+EX)"= 12.5% CR + 12.5% increase in energy expenditure through exercise; or "low-calorie diet (LCD)" = 15% weight loss by liquid diet followed by weight-maintenance, for 6 months. Liver lipid content was assessed by magnetic resonance spectroscopy (MRS) and computed tomography (CT). Lipid concentrations, markers of liver function (alanine aminotransferase (ALT), alkaline phosphatase (ALK)), and whole-body inflammation (tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP)) were measured in fasting blood., Results: At baseline, increased liver lipid content (by MRS) correlated (P < 0.05) with elevated fasting triglyceride (r = 0.52), ALT (r = 0.42), and hsCRP (r = 0.33) concentrations after adjusting for sex, race, and alcohol consumption. With CR, liver lipid content was significantly lowered by CR, CR+EX, and LCD (detected by MRS only). The reduction in liver lipid content, however, was not significantly correlated with the reduction in triglycerides (r = 0.26; P = 0.11) or with the changes in ALT, high-density lipoprotein (HDL)-cholesterol, or markers of whole-body inflammation., Discussion: CR may be beneficial for reducing liver lipid and lowering triglycerides in overweight subjects without known NAFLD.

The study aimed to analyze the effects of a short-term very low-calorie diet (VLCD) on intramyocellular lipid (IMCL), total body fat, and insulin sensitivity in a group of obese nondiabetic and type 2 diabetic subjects. Seven untreated type 2 diabetic and 5 obese nondiabetic individuals were studied before and after a 6-day VLCD using proton magnetic resonance spectroscopy to quantify IMCL, dual-energy x-ray absorptiometry to assess body fat, and hyperinsulinemic-euglycemic clamps to measure peripheral insulin sensitivity. In both groups, decrements in total body fat mass and body mass index were small but statistically significant. In contrast, the diet resulted in a pronounced reduction in IMCL compared with baseline values in nondiabetic subjects (56% decrease) and type 2 diabetic subjects (40% decrease) (P < .05), and this was accompanied by an overall 9.3% increase in maximally stimulated glucose disposal rate (P < .01). Intramyocellular lipid was significantly correlated with insulin sensitivity (r = -0.69, P < .01) and waist circumference (r = 0.72 and 0.83, baseline and postdiet, respectively; both P < .01), but neither IMCL nor insulin sensitivity was related to measures of general adiposity such as body mass index, percentage of body fat, or total body fat (P = not significant). In conclusion, short-term VLCD is accompanied by small decrements in general adiposity, marked decrease in IMCL, and an increase in insulin sensitivity in nondiabetic and type 2 diabetic subjects. Therefore, rapid amelioration of insulin resistance by VLCD can be partially explained by loss of IMCL both in nondiabetic and type 2 diabetic subjects in the absence of substantial changes in total body fat. These observations are consistent with the idea that insulin resistance is more directly related to IMCL rather than to body fat per se.

Background: Fat deposition in muscle has been found to be related to metabolic risk., Objective: This study compared soleus intramyocellular lipid (IMCL) concentrations after consumption of weight-maintaining, controlled diets differing in total fat and fat type., Design: This study consisted of 3 phases of 25 d each in a crossover, controlled feeding design. The low-fat (LF) diet provided 30.8% and 5.2% of energy from fat and polyunsaturated fat (PUFA), respectively. Two higher-fat diets were tested: the high-fat (HF) diet provided 37.9% and 5.8% of energy from fat and PUFA, respectively, and the high-PUFA (HPUFA) diet provided 36.3% and 9.7% of energy from fat and PUFA, respectively. Twenty-four men and women [age range: 19-65 y; body mass index (in kg/m(2)): 20-35] whose LDL and glucose concentrations were between 130 and 180 mg/dL and <126 mg/dL, respectively, completed all study phases., Results: IMCL content was 1.88 times as high after the HF diet (P = 0.005) and 1.71 times as high after the HPUFA diet (P = 0.002) as after the LF diet. There was no significant correlation between percentage fat mass or waist circumference and IMCL content. With pooled data from all diets, there was no significant correlation between IMCL content and insulin or glucose concentration. There was no significant difference in IMCL content in subjects with or without the metabolic syndrome or in subjects with LDL particle pattern A or B., Conclusions: Our results suggest that IMCL content is not modulated by dietary fat type but by total fat intake and that reducing fat intake effectively lowers IMCL. However, the metabolic implications of having lower IMCL concentrations are not clear.

Increases in plasma lipids, tissue triglycerides and decreases in mitochondrial function have been linked to insulin resistance and aging. In animals, peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonists decrease plasma lipids, intramyocellular fat (IMCL) and liver fat (LFAT) and improve mitochondrial beta-oxidative function and insulin sensitivity, but the effects in elderly were not known. Insulin sensitivity was assessed with a 2-h oral glucose tolerance test, magnetic resonance spectroscopy was used to asses IMCL, LFAT and plasma lipids were measured before and after 6, 11 and 61 days of PPAR-alpha agonist (fenofibrate) administration in 19 elderly (age 70+/-1 years) volunteers. Volunteers were stratified into healthy (N=7) and insulin resistant (N=12) groups. The baseline insulin sensitivity index (8.1+/-1.2 vs. 3.8+/-0.5, healthy vs. insulin resistant; P<0.001) was significantly higher in the healthy group. Fenofibrate treatment induced significant reductions in plasma triglycerides (P<0.001) and total cholesterol (P<0.001) in both groups. Nonetheless, neither fasted free fatty acids, glucose, insulin, nor insulin sensitivity improved in either group (day 1 vs. day 61, 8.1+/-1.2 vs. 8.1+/-0.9, healthy; and 3.8+/-0.5 vs. 4.2+/-0.05, insulin resistant). Furthermore, there was no change in IMCL or LFAT. These results indicate that whereas fenofibrate significantly lowers plasma lipids it neither affects insulin sensitivity nor intracellular lipids in elderly.

A new high-resolution MRSI technique was used to measure extracellular lipids (EMCL), intracellular lipids (IMCL), and total muscle lipids (TML). The purpose of this study was to assess the feasibility and reproducibility of this new technique. This study also compared results obtained from small regions of interest (ROIs) vs. a summation of a large ROI of voxels representing the total soleus or anterior tibialis (TA) muscles. Eight volunteers were studied with the use of a conventional single-slice MR spectroscopic imaging (MRSI) sequence run with the following parameters: TR = 145.9 ms, FOV = 16 cm, slice thickness = 1 cm, and 64 x 64 phase encodes. EMCL, IMCL, and TML values from the small ROIs proved to be reproducible (coefficient of variation (CV) = 7.8-13.8% for soleus, and 8.2-18% for TA). EMCL, IMCL, and TML values from the larger soleus ROI proved to be reproducible (CV = 7.3-16.1%), whereas the larger TA ROIs were less reproducible. The small and larger soleus ROIs produced statistically equivalent measures of EMCL and TML per unit area. However, the small soleus and TA ROIs showed a trend toward yielding different IMCL contents as compared to the larger ROIs. This study demonstrates that high-resolution 1H MRSI of the calf muscle is feasible and can reproducibly measure EMCL, IMCL, and TML., ((c) 2007 Wiley-Liss, Inc.)

Background: Insulin resistance is often associated with increased levels of intracellular triglycerides, diacylglycerol and decreased fat beta-oxidation. It was unknown if this relationship was present in patients with acute insulin resistance induced by trauma., Methods: A double blind placebo controlled trial was conducted in 18 children with severe burn injury. Metabolic studies to assess whole body palmitate oxidation and insulin sensitivity, muscle biopsies for mitochondrial palmitate oxidation, diacylglycerol, fatty acyl Co-A and fatty acyl carnitine concentrations, and magnetic resonance spectroscopy for muscle and liver triglycerides were compared before and after two weeks of placebo or PPAR-alpha agonist treatment., Results: Insulin sensitivity and basal whole body palmitate oxidation as measured with an isotope tracer increased significantly (P = 0.003 and P = 0.004, respectively) after PPAR-alpha agonist treatment compared to placebo. Mitochondrial palmitate oxidation rates in muscle samples increased significantly after PPAR-alpha treatment (P = 0.002). However, the concentrations of muscle triglyceride, diacylglycerol, fatty acyl CoA, fatty acyl carnitine, and liver triglycerides did not change with either treatment. PKC-theta activation during hyper-insulinemia decreased significantly following PPAR-alpha treatment., Conclusion: PPAR-alpha agonist treatment increases palmitate oxidation and decreases PKC activity along with reduced insulin sensitivity in acute trauma, However, a direct link between these responses cannot be attributed to alterations in intracellular lipid concentrations.

We have previously shown that muscle metabolic function measured during exercise is related to exercise performance and subsequent 1-yr weight gain. Because it is well established that physical activity is important in weight maintenance, we examined muscle function relationships with free-living energy expenditure and physical activity. Subjects were 71 premenopausal black and white women. Muscle metabolism was evaluated by (31)P magnetic resonance spectroscopy during 90-s isometric plantar flexion contractions (45% maximum). Free-living energy expenditure (TEE) was measured using doubly labeled water, activity-related energy expenditure (AEE) was calculated as 0.9 x TEE - sleeping energy expenditure from room calorimetry, and free-living physical activity (ARTE) was calculated by dividing AEE by energy cost of standard physical activities. At the end of exercise, anaerobic glycolytic rate (ANGLY) and muscle concentration of phosphomonoesters (PME) were negatively related to TEE, AEE, and ARTE (P < 0.05). Multiple regression analysis showed that both PME (partial r = -0.29, <0.02) and ANGLY (partial r = -0.24, P < 0.04) were independently related to ARTE. PME, primarily glucose-6-phosphate and fructose-6-phosphate, was significantly related to ratings of perceived exertion (r = 0.21, P < or = 0.05) during a maximal treadmill test. PME was not related to ARTE after inclusion of RPE in the multiple regression model, suggesting that PME may be obtaining its relationship with ARTE through an increased perception of effort during physical activity. In conclusion, physically inactive individuals tend to be more dependent on anaerobic glycolysis during exercise while relying on a glycolytic pathway that may not be functioning optimally.

Recent data have shown that individuals with low insulin sensitivity (S(I)) also have reduced whole body maximal oxygen uptake. The objectives of this study were to determine 1) whether muscle mitochondrial function was independently related to S(I) after being adjusted for known determinants of S(I) and 2) whether lower S(I) among African-American (AA) vs. Caucasian-American (CA) women was due to lower muscle mitochondrial function among AA women. Subjects were 37 CA and 22 AA premenopausal women (age: 33.6 +/- 6.3 yr). Mitochondrial function [time constant of ADP (ADP(tc))] was assessed during a 90-s unilateral isometric contraction using (31)P magnetic resonance spectroscopy, S(I) with an intravenous glucose tolerance test, body composition by dual-energy X-ray absorptiometry, and visceral adipose tissue (VAT) with computed tomography. ANOVA was used to compare AA and CA groups, and multiple linear regression modeling was used to identify independent predictors of S(I). Between-race comparisons indicated that muscle oxidative capacity was lower among AAs vs. CAs (ADP(tc): 25.6 +/- 9.8 vs. 21.4 +/- 9.9 s). Multiple linear regression models for the dependent variable S(I) contained 1) VAT and race and 2) VAT, race, and ADP(tc). Significant independent effects for all predictor variables were observed in both the first (r(2) = 0.345) and second (r(2) = 0.410) models. The partial correlation for race was lower in the second model (-0.404 vs. -0.300), suggesting that muscle mitochondrial function contributed to the racial difference in S(I). Lower muscle mitochondrial function among AAs may in part explain lower S(I) among them.

The purposes of this study were to (a) determine whether structural differences in triceps surae muscle-tendon complex and walking economy exist between 14 African American and 19 Caucasian sedentary women and (b) determine whether muscle-tendon parameters are associated with walking economy. African American and Caucasian subjects were matched on body weight, height, and body composition. Muscle-tendon parameters were determined by magnetic resonance imaging and walking economy was evaluated at 4.8 km.h(-1). Medial gastrocnemius and total triceps surae muscle shape were different across ethnicity despite no ethnic differences in plantar flexion strength or in maximal cross-sectional area for any triceps surae muscles. African American women had shorter gastrocnemius muscles and longer tendons and performed walking more economically. Tendon length was the only variable related to walking economy. No ethnic differences were observed in walking economy after adjusting for tendon length. Data show gastrocnemius tendon length is related to level walking and longer gastrocnemius tendons may partly explain more economical walking in African American women. These preliminary findings indicate the structure of the muscle-tendon complex could be a factor partially accounting for reported ethnic differences in certain types of athletic-related performance.

The purpose of this study was to further explore factors that may be related to ethnic differences in the maximum rate at which an individual can consume oxygen (VO2max) between 20 African American (AA) and 30 European American (EA) sedentary women who were matched for body weight (kg) and fat-free mass (FFM). VO2max (l/min) was determined during a graded treadmill exercise test. Submaximal steady-state heart rate and submaximal VO2 were determined at a treadmill speed of 1.3 m/sec and a 2.5% grade. Hemoglobin (Hb) was determined by the cyanide method, muscle oxidative capacity by 31P magnetic resonance spectroscopy (ADP time constant), and FFM (kg) by dual-energy x-ray absorptiometry. Genetic classification was self-reported, and in a subset of the sample (N = 32), the determinants of ethnicity were measured by African genetic admixture. AA women had significantly reduced VO2max, Hb levels, and muscle oxidative capacity (longer ADP time constants, P < or = 0.05) than EA women. Submaximal oxygen pulse (O2Psubmax), ADP time constant, Hb, and ethnic background were all significantly related to VO2max (ml/kg/min and ml/kg FFM/min, all P < or = 0.01). By multiple regression modeling, Hb, O2Psubmax, muscle oxidative capacity, and ethnicity were found to explain 61% and 57% of the variance of VO2max in ml/kg/min and ml/kg FFM/min, respectively. Muscle oxidative capacity and O2Psubmax were both significantly and independently related to VO2max in all three models (P < or = 0.05), whereas Hb and ethnicity were not. These results suggest that mitochondrial muscle oxidative capacity and oxygen delivery capabilities, as determined by O2Psubmax, account for most if not all of the ethnic differences in VO2max.

Objective: Muscle triglyceride can be assessed in vivo using computed tomography (CT) and 1H magnetic resonance spectroscopy (MRS), two techniques that are based on entirely different biophysical principles. Little is known, however, about the cross-correlation between these techniques and their test-retest reliability., Research Methods and Procedures: We compared mean muscle attenuation (MA) in soleus and tibialis anterior (TA) muscles measured by CT with intra- and extramyocellular lipids (IMCL and EMCL, respectively) measured by MRS in 51 volunteers (26 to 72 years of age, BMI = 25.5 to 39.3 kg/m2). MA of midthighs was also measured in a subset (n = 19). Test-retest measurements were performed by CT (n = 6) and MRS (n = 10) in separate sets of volunteers., Results: MA of soleus was significantly associated with IMCL (r = -0.64) and EMCL, which by multiple regression analysis was explained mostly by IMCL (p < 0.001) rather than EMCL (beta = -0.010, p = 0.94). Muscle triglyceride was lower in TA than in soleus, and MA of TA was significantly correlated with EMCL (r = -0.40) but not IMCL (r = -0.16). By CT, MA of midthighs was correlated with MA in soleus (r = 0.40, p = 0.07) and whole calf (r = 0.62, p < 0.05). Finally, both MA and IMCL were highly reliable in soleus (coefficient of variation = < 2% and 6.7%, respectively) and less reliable in TA (4% and 10%, respectively)., Discussion: These results support the use of both CT and MRS as reliable methods for assessing skeletal muscle lipid.

An inverse relationship has been shown between running and cycling exercise economy and maximum oxygen uptake (VO2max). The purposes were: 1) determine the relationship between walking economy and VO2max; and 2) determine the relationship between muscle metabolic economy and muscle oxidative capacity and fiber type. Subjects were 77 premenopausal normal weight women. Walking economy (1/VO2max) was measured at 3 mph and VO2max during graded treadmill test. Muscle oxidative phosphorylation rate (OxPhos), and muscle metabolic economy (force/ATP) were measured in calf muscle using 31P MRS during isometric plantar flexion at 70 and 100% of maximum force, (HI) and (MI) respectively. Muscle fiber type and citrate synthase activity were determined in the lateral gastrocnemius. Significant inverse relationships (r from -0.28 to -0.74) were observed between oxidative metabolism measures and exercise economy (walking and muscle). Type IIa fiber distribution was inversely related to all measures of exercise economy (r from -0.51 to -0.64) and citrate synthase activity was inversely related to muscle metabolic economy at MI (r = -0.56). In addition, Type IIa fiber distribution and citrate synthase activity were positively related to VO2max and muscle OxPhos at HI and MI (r from 0.49 to 0.70). Type I fiber distribution was not related to any measure of exercise economy or oxidative capacity. Our results support the concept that exercise economy and oxidative capacity are inversely related. We have demonstrated this inverse relationship in women both by indirect calorimetry during walking and in muscle tissue by 31P MRS.

Magnetic resonance spectroscopy studies have shown that intramyocellular lipids (IMCL) and liver fat (LFAT) levels vary with insulin sensitivity and obesity, which are common in the elderly. Thus, magnetic resonance spectroscopy was used to investigate the hypothesis that IMCL and LFAT are increased in the elderly. IMCL and LFAT in young (aged 20-32 yr) and elderly (aged 65-74 yr) were measured fasted, and glucose, insulin, total free fatty acids levels, and free fatty acids profiles were measured during a 2-h oral glucose tolerance test. Body fat percentage was determined with dual x-ray absorptiometry. The elderly had significantly greater IMCL (0.12 +/- 0.01 vs. 0.08 +/- 0.01, mean +/- sem; P = 0.01) and LFAT (0.28 +/- 0.06 vs. 0.08 +/- 0.01; P = 0.004; expressed as ratios to Intralipid standard) than the young. The elderly had increased insulin resistance as calculated by the Matsuda model compared with the young (5.1 +/- 0.9 vs. 9.9 +/- 1.4; P = 0.02). Regression analysis of all subjects indicated that the increases in IMCL and LFAT were correlated with insulin sensitivity, glycosylated hemoglobin, plasma lipids, and body fat. Furthermore, the correlation between insulin sensitivity and IMCL and LFAT remained significant, after accounting for the effect of body fat. Increases of IMCL and LFAT occur in elderly individuals and may be related to insulin resistance.

The purpose of this study was to determine whether muscle metabolic capacity was inversely related to age after adjusting for physical activity in sedentary premenopausal women. Eighty-three women (ages 23-47 yr) had their free-living, activity-related energy expenditure evaluated with doubly labeled water procedures, and room calorimeter determined sleeping energy expenditure. Maximum O(2) uptake and strength were evaluated in all subjects, whereas 31P-magnetic resonance spectroscopy determined metabolic economy during maximal exercise, and muscle biopsy maximal enzyme activity was evaluated in subsets of the sample (48 and 18 subjects, respectively). Age was significantly related to whole body treadmill endurance time (r = -0.32), plantar flexion strength (r = -0.29), maximum O(2) uptake (r = -0.27), (31)P-magnetic resonance spectroscopy ADP recovery rate (r = -0.44), and anaerobic glycolytic capacity (r = -0.37), and muscle biopsy citrate synthase activity (r = -0.48), glyceraldehyde-3-phosphate dehydrogenase (r = -0.54), phosphofructokinase (r = -0.62), and phosphorylase (r = -0.58) activity even after adjusting for activity-related energy expenditure. These data suggest that, in sedentary premenopausal women, both oxidative and glycolytic muscle capacity decrease with age even when physical activity is taken into account.

Using a randomly assigned crossover design, we evaluated the change in intramyocellular lipid stores (IMCL) from baseline after a 2-h treadmill run [67% of maximal oxygen uptake (VO2 max)] and the recovery of IMCL in response to a postexercise very low-fat (10% of energy, LFAT) or moderate-fat (35% of energy, MFAT) recovery diet in seven female runners. IMCL was measured in soleus muscle by use of water-suppressed 1H-NMR spectroscopic imaging before (baseline), after, and approximately 22 h and 70 h after the run. IMCL fell by approximately 25% (P < 0.05) during the endurance run and was dependent on dietary fat content for postexercise recovery (P = 0.038, diet x time interaction). Consumption of the MFAT recovery diet allowed IMCL stores to return to baseline by 22 h and to overshoot (vs. baseline) by 70 h postexercise. In contrast, consumption of the LFAT recovery diet did not allow IMCL stores to return to baseline even by 70 h after the endurance run (P < 0.01 at 70 h). These results suggest that a certain quantity of dietary fat is required to replenish IMCL after endurance running.