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Objective: To determine whether the obesity-related decrement in fatty acid oxidation (FAO) in primary human skeletal muscle cells (HSkMC) is linked with lower mitochondrial content and whether this deficit could be corrected via overexpression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha). Research Design and Methods: FAO was studied in HSkMC from lean (BMI 22.4 +/- 0.9 kg/m(2); N = 12) and extremely obese (45.3 +/- 1.4 kg/m(2); N = 9) subjects. Recombinant adenovirus was used to increase HSkMC PGC-1alpha expression (3.5- and 8.0-fold), followed by assessment of mitochondrial content (mtDNA and cytochrome C oxidase IV [COXIV]), complete ((14)CO(2) production from labeled oleate), and incomplete (acid soluble metabolites [ASM]) FAO, and glycerolipid synthesis. Results: Obesity was associated with a 30% decrease (P < 0.05) in complete FAO, which was accompanied by higher relative rates of incomplete FAO ([(14)C]ASM production/(14)CO(2)), increased partitioning of fatty acid toward storage, and lower (P < 0.05) mtDNA (-27%), COXIV (-35%), and mitochondrial transcription factor (mtTFA) (-43%) protein levels. PGC-1alpha overexpression increased (P < 0.05) FAO, mtDNA, COXIV, mtTFA, and fatty acid incorporation into triacylglycerol in both lean and obese groups. Perturbations in FAO, triacylglycerol synthesis, mtDNA, COXIV, and mtTFA in obese compared with lean HSkMC persisted despite PGC-1alpha overexpression. When adjusted for mtDNA and COXIV content, FAO was equivalent between lean and obese groups. Conclusion: Reduced mitochondrial content is related to impaired FAO in HSkMC derived from obese individuals. Increasing PGC-1alpha protein levels did not correct the obesity-related absolute reduction in FAO or mtDNA content, implicating mechanisms other than PGC-1alpha abundance. [ABSTRACT FROM AUTHOR]

Growth hormone (GH) is a powerful stimulator of the Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) pathway. Acute exercise is a known stimulus for GH secretion. Purpose: The purpose of this study was to determine the phosphorylation of the JAK2-STAT5 pathway in human skeletal muscle in response to acute aerobic exercise. Methods: Eleven young (22.5 +/- 0.6, mean +/- SE), healthy, aerobically trained males performed 30 min of cycling at 70% V[spacing dot above]O2max. Blood samples were collected at 10- to 15-min intervals and analyzed for human GH, immunofunctional (IF) GH, GH binding protein, and insulin-like growth factor I (IGF-I). Muscle biopsies were taken from the vastus lateralis before exercise, immediately after exercise, as well as, 30 and 60 min postexercise. Muscle samples were analyzed for changes in JAK2 and STAT5 tyrosine phosphorylation, as well as changes in JAK2 and STAT5 protein content. Results: Multivariate ANOVA with post hoc comparisons demonstrated that GH and IF GH were significantly elevated immediately after exercise compared with preexercise (P < 0.001). Exercise significantly increased the phosphorylation of JAK2 immediately after exercise (P = 0.004). A trend toward increasing levels of STAT5 phosphorylation was observed immediately after exercise (P = 0.08) and was significantly elevated 30 min after exercise (P = 0.002), compared with preexercise levels. Muscle JAK2 and STAT5 protein content did not change. Conclusion: The results demonstrate that the JAK2-STAT5 pathway is activated in response to acute aerobic exercise in human skeletal muscle and suggests that the exercise-induced release of GH may play a role in the activation of this pathway. [ABSTRACT FROM AUTHOR]

Objective: Apolipoprotein A4 (APOA4) is synthesized by the small intestine in response to dietary lipids. Chronic exposure to a high-fat diet (HFD) desensitizes lipid-induced APOA4 production and attenuates brown adipose tissue (BAT) thermogenesis. We hypothesized that exogenous APOA4 could increase BAT thermogenesis and energy expenditure in HFD-fed mice, resulting in decreased obesity and improved glucose tolerance., Methods: BAT and inguinal white adipose tissue (IWAT) thermogenesis, body composition, energy intake and expenditure, and locomotor activity were measured using an infrared camera, immunoblots, quantitative magnetic resonance imaging, and a comprehensive lab animal monitoring system. An intraperitoneal glucose tolerance test and hepatic lipid accumulation and steatosis were assayed., Results: Mice receiving continuous infusion of APOA4 for the last 4 weeks of 10 weeks of HFD feeding gained no additional body weight and had reduced fat mass but enhanced BAT and IWAT thermogenesis and energy expenditure, despite unaltered food intake and locomotor activity. Additionally, APOA4 infusion elevated fatty acid β oxidation; decreased lipogenesis, lipid accumulation, and steatosis in liver; and improved glucose tolerance., Conclusions: Maintenance of plasma APOA4 via exogenous APOA4 protein parallels elevation of BAT and IWAT thermogenesis, hepatic fatty acid β oxidation, and overall energy expenditure, with subsequent prevention of additional weight gain in HFD-fed obese mice., (© 2024 The Author(s). Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

The purpose of the present study was to determine the effects of obesity and biological sex on myostatin expression in humans and to examine the direct effects of myostatin, SMAD2, and SMAD3 on insulin signaling in primary human skeletal muscle cells (HSkMCs). For cohort 1 , 15 lean [body mass index (BMI): 22.1 ± 0.5 kg/m 2 ; n = 8 males; n = 7 females] and 14 obese (BMI: 40.6 ± 1.4 kg/m 2 ; n = 7 males; n = 7 females) individuals underwent skeletal muscle biopsies and an oral glucose tolerance test. For cohort 2 , 14 young lean (BMI: 22.4 ± 1.9 kg/m 2 ; n = 6 males; n = 8 females) and 14 obese (BMI: 39.3 ± 7.9 kg/m 2 ; n = 6 males; n = 8 females) individuals underwent muscle biopsies for primary HSkMC experiments. Plasma mature myostatin ( P = 0.041), skeletal muscle precursor myostatin ( P = 0.048), and skeletal muscle SMAD3 ( P = 0.029) were elevated in obese females compared to lean females, and plasma mature myostatin ( r = 0.58, P = 0.029) and skeletal muscle SMAD3 ( r = 0.56, P = 0.037) were associated with insulin resistance in females but not males. Twenty-four hours of myostatin treatment impaired insulin signaling in primary HSkMCs derived from females ( P < 0.024) but not males. Overexpression of SMAD3, but not SMAD2, impaired insulin-stimulated AS160 phosphorylation in HSkMCs derived from lean females (-27%, P = 0.040), whereas silencing SMAD3 improved insulin-stimulated AS160 phosphorylation and insulin-stimulated glucose uptake (25%, P < 0.014) in HSkMCs derived from obese females. These results suggest for the first time that myostatin-induced impairments in skeletal muscle insulin signaling are sex specific and that increased body fat in females is associated with detrimental elevations in myostatin and SMAD3, which contribute to obesity-related insulin resistance. NEW & NOTEWORTHY Obesity is considered a main risk factor for the development of insulin resistance and type 2 diabetes. The present study utilizes in vivo and in vitro experiments in human skeletal muscle to demonstrate for the first time that females are inherently more susceptible to myostatin-induced insulin resistance, which is further enhanced with obesity due to increased myostatin and SMAD3 expression.

Elevated circulating lactate has been associated with obesity and insulin resistance. The aim of the current study was to determine if lactate-induced lysine lactylation (kla), a post-translational modification, was present in human skeletal muscle and related to insulin resistance. Fifteen lean (Body Mass Index: 22.1 ± 0.5 kg/m 2 ) and fourteen obese (40.6 ± 1.4 kg/m 2 ) adults underwent a muscle biopsy and 2-h oral glucose tolerance test. Skeletal muscle lactylation was increased in obese compared to lean females (19%, p < 0.05) and associated with insulin resistance (r = 0.37, p < 0.05) in the whole group. Skeletal muscle lactylation levels were significantly associated with markers of anaerobic metabolism (plasma lactate and skeletal muscle lactate dehydrogenase [LDH], p < 0.05) and negatively associated with markers of oxidative metabolism (skeletal muscle cytochrome c oxidase subunit 4 and Complex I [pyruvate] OXPHOS capacity, p < 0.05). Treatment of primary human skeletal muscle cells (HSkMC) with sodium lactate for 24 h increased protein lactylation and IRS-1 serine 636 phosphorylation in a similar dose-dependent manner ( p < 0.05). Inhibition of glycolysis (with 2-deoxy-d-glucose) or LDH-A (with sodium oxamate or LDH-A siRNA) for 24 h reduced HSkMC lactylation which paralleled reductions in culture media lactate accumulation. This study identified the existence of a lactate-derived post-translational modification in human skeletal muscle and suggests skeletal muscle lactylation could provide additional insight into the regulation of skeletal muscle metabolism, including insulin resistance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Maschari, Saxena, Law, Walsh, Campbell and Consitt.)

Optimal health benefits from exercise are achieved by meeting both aerobic and muscle strengthening guidelines, however, most older adults (OAs) do not exercise and the majority of those who do only perform one type of exercise. A pragmatic solution to this problem may be emphasizing a single exercise strategy that maximizes health benefits. The loss of muscle mass and strength at an accelerated rate are hallmarks of aging that, without intervention, eventually lead to physical disability and loss of independence. Additionally, OAs are at risk of developing several chronic diseases. As such, participating in activities that can maintain or increase muscle mass and strength, as well as decrease chronic disease risk, is essential for healthy aging. Unfortunately, there is a widely held belief that adaptations to aerobic and resistance exercise are independent of each other, requiring the participation of both types of exercise to achieve optimal health. However, we argue that this assertion is incorrect, and we discuss crossover adaptations of both aerobic and resistance exercise. Aerobic exercise can increase muscle mass and strength, though not consistently and may be limited to exercise that overloads a particular muscle group, such as stationary bicycling. In contrast, resistance exercise is effective at maintaining muscle health with increasing age, and also has significant effects on cardiovascular disease (CVD) risk factors, type 2 diabetes (T2D), cancer, and mortality. We posit that resistance exercise is the most effective standalone exercise strategy for improving overall health in OAs and should be emphasized in future guidelines., (Copyright © 2020 Tavoian, Russ, Consitt and Clark.)

Aging is associated with insulin resistance and the development of type 2 diabetes. While this process is multifaceted, age-related changes to skeletal muscle are expected to contribute to impaired glucose metabolism. Some of these changes include sarcopenia, impaired insulin signaling, and imbalances in glucose utilization. Endurance and resistance exercise training have been endorsed as interventions to improve glucose tolerance and whole-body insulin sensitivity in the elderly. While both types of exercise generally increase insulin sensitivity in older adults, the metabolic pathways through which this occurs can differ and can be dependent on preexisting conditions including obesity and type 2 diabetes. In this review, we will first highlight age-related changes to skeletal muscle which can contribute to insulin resistance, followed by a comparison of endurance and resistance training adaptations to insulin-stimulated glucose metabolism in older adults.

Aging decreases skeletal muscle mass and strength, but aerobic and resistance exercise training maintains skeletal muscle function. NAD + is a coenzyme for ATP production and a required substrate for enzymes regulating cellular homeostasis. In skeletal muscle, NAD + is mainly generated by the NAD + salvage pathway in which nicotinamide phosphoribosyltransferase (NAMPT) is rate-limiting. NAMPT decreases with age in human skeletal muscle, and aerobic exercise training increases NAMPT levels in young men. However, whether distinct modes of exercise training increase NAMPT levels in both young and old people is unknown. We assessed the effects of 12 weeks of aerobic and resistance exercise training on skeletal muscle abundance of NAMPT, nicotinamide riboside kinase 2 (NRK2), and nicotinamide mononucleotide adenylyltransferase (NMNAT) 1 and 3 in young (≤35 years) and older (≥55 years) individuals. NAMPT in skeletal muscle correlated negatively with age (r 2  = 0.297, P < 0.001, n = 57), and VO 2 peak was the best predictor of NAMPT levels. Moreover, aerobic exercise training increased NAMPT abundance 12% and 28% in young and older individuals, respectively, whereas resistance exercise training increased NAMPT abundance 25% and 30% in young and in older individuals, respectively. None of the other proteins changed with exercise training. In a separate cohort of young and old people, levels of NAMPT, NRK1, and NMNAT1/2 in abdominal subcutaneous adipose tissue were not affected by either age or 6 weeks of high-intensity interval training. Collectively, exercise training reverses the age-dependent decline in skeletal muscle NAMPT abundance, and our findings highlight the value of exercise training in ameliorating age-associated deterioration of skeletal muscle function., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Background and Aims: Wnt5a is a highly studied member of the Wnt family and recently has been implicated in the pathogenesis of atherosclerosis, but its precise role is unknown. Foam cell development is a critical process to atherosclerotic plaque formation. In the present study, we investigated the role of noncanonical Wnt5a signaling in the development of foam cells., Methods: Human carotid atherosclerotic tissue and THP-1-derived macrophages were used to investigate the contribution of Wnt5a signaling in the formation of foam cells. Immunohistochemistry was used to evaluate protein expression of scavenger receptors and noncanonical Wnt5a receptors [frizzled 5 (Fz5) and receptor tyrosine kinase-like orphan receptor 2 (Ror2)] in human atherosclerotic macrophages/foam cells. Changes in protein expression in response to Wnt5a stimulation/inhibition were determined by Western blot, and lipid accumulation was evaluated by fluorescent lipid droplet staining., Results: Wnt5a (P<.05), Fz5 (P<.01), and Ror2 (P<.01) were significantly expressed in advanced atherosclerotic lesions compared to less advanced lesions (N=10). Wnt5a, Fz5, and Ror2 were expressed in macrophages/foam cells within the plaque. In vitro studies revealed that Wnt5a significantly increased the expression of the lipid uptake receptor CD36 (P<.05) but not the lipid efflux receptor ATP-binding cassette transporter (P>.05). rWnt5a also significantly increased lipid accumulation in THP-1 macrophages (P<.05). Furthermore, inhibition of Wnt5a signaling with Box5 prevented lipid accumulation (P<.01) and prevented CD36 up-regulation (P<.01)., Conclusions: These results suggest a direct role for Wnt5a signaling in the pathogenesis of atherosclerosis, specifically the accumulation of lipid in macrophages and the formation of foam cells., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: The high molecular weight (HMW) adiponectin isoform is considered the active form of adiponectin and is linked to insulin sensitivity and the reduced risk of developing cardiovascular disease. The purpose of the first study was to determine the effects of age and sex on the plasma HMW adiponectin response to acute hyperinsulinemia, and secondly determine whether either endurance or resistance exercise training could affect this response., Design and Participants: Twenty-six healthy males (19-84 years) and twenty-six healthy females (18-76 years) were recruited and matched for BMI to examine the effects of sex and age on the plasma adiponectin response to a 2-hour hyperinsulinemic-euglycemic clamp. To examine the effects of exercise training, a subgroup of young (<35 years) and aged (>55 years) individuals were randomized into a 12-week endurance or resistance training programme and had their adiponectin response to hyperinsulinemia measured before and after training. High molecular weight (HMW) and total adiponectin were measured by ELISA., Results: In response to hyperinsulinemia, plasma HMW adiponectin decreased in females (-9%, P < .005), but not males. After 12 weeks of endurance training, the response of plasma HMW adiponectin to hyperinsulinemia increased in older females (36%, P < .05) only. Resistance training had no effect on the plasma adiponectin response to hyperinsulinemia. Despite no age or sex differences at baseline, skeletal muscle AdipoR1 increased in response to endurance training (~120%, P < .001) and resistance training (~38%, P < .05), regardless of age or sex., Conclusion: The inhibitory action of hyperinsulinemia on plasma HMW adiponectin occurs in females but not males, irrespective of age. Twelve weeks of endurance training protects older females against the hyperinsulinemic inhibition of plasma HMW adiponectin, which could promote healthy ageing., (© 2018 John Wiley & Sons Ltd.)

Evidence suggests that paternal diet can predispose offspring to metabolic dysfunction. Despite this knowledge, little is known regarding the effects of paternal high-fat feeding on offspring insulin sensitivity. The purpose of this study was to investigate for the first time the effects of paternal high-fat feeding on whole-body and skeletal muscle insulin action in young and adult offspring. At 4 weeks of age, founder C57BL6/N males (F0) were fed a high-fat diet or control diet for 12 weeks and then bred with females on a control diet. Offspring (F1) were euthanized at 6 weeks, 6 months, or 12 months and insulin-stimulated insulin signaling was measured ex vivo in isolated soleus muscle. At 6 weeks of age, paternal high fat offspring (HFO) had enhanced whole-body insulin sensitivity (35%, P < 0.05), as well as, increased insulin-stimulated skeletal muscle phosphorylation of Akt threonine 308 (70%, P < 0.05) and AS160 threonine 642 (80%, P < 0.05) compared to paternal control fed offspring (CFO), despite both offspring groups consuming standard chow. At 6 months of age, HFO had increased percent body fat compared to CFO (74%, P < 0.005) and whole-body and skeletal muscle insulin signaling normalized to CFO. Body fat was inversely related with insulin signaling in HFO, but not CFO. These findings suggest that paternal high-fat feeding contributes to enhanced whole-body and skeletal muscle insulin sensitivity in HFO early in life; however, these benefits are lost by early adulthood, potentially due to premature increases in body fat., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

The age-related loss of skeletal muscle (sarcopenia) is a major health concern as it is associated with physical disability, metabolic impairments, and increased mortality. The coexistence of sarcopenia with obesity, termed 'sarcopenic obesity', contributes to skeletal muscle insulin resistance and the development of type 2 diabetes, a disease prevalent with advancing age. Despite this knowledge, the mechanisms contributing to sarcopenic obesity remain poorly understood, preventing the development of targeted therapeutics. This article will discuss the clinical and physiological consequences of sarcopenic obesity and propose myostatin as a potential candidate contributing to this condition. A special emphasis will be placed on examining the role of myostatin signaling in impairing both skeletal muscle growth and insulin signaling. In addition, the role of myostatin in regulating muscle-to fat cross talk, further exacerbating metabolic dysfunction in the elderly, will be highlighted. Lastly, we discuss how this knowledge has implications for the design of myostatin-inhibitor clinical trials., Competing Interests: None declared by authors

Background: In contrast to the acute effects of growth hormone (GH) on skeletal muscle protein synthesis, long-term GH treatment appears to have negligible effects on muscle mass. Despite this knowledge, little is known regarding the chronic effects of GH on skeletal muscle protein synthesis and atrophy signaling pathways. The purpose of this study was to determine if protein synthesis pathways are attenuated and/or muscle atrophy intracellular signaling pathways are altered in the skeletal muscle of transgenic bovine GH (bGH) mice., Methods: The gastrocnemius and soleus from 5-month-old male bGH mice (n = 9) and wild type (WT) controls (n = 9) were harvested and analyzed for proteins involved in the protein synthesis (Akt/mTOR), growth and proliferation (MAPK), and muscle atrophy (MuRF1 and myostatin) pathways., Results: Total body mass was significantly increased in bGH mice compared to WT controls (49%, P < 0.0001). When expressed relative to total body mass, the gastrocnemius (- 28%, P < 0.0001), but not the soleus, was significantly lower in mice overexpressing GH, compared to controls. Transgenic bGH mice had elevated phosphorylation levels of protein kinase b (Akt1), 4E-binding protein 1 (4E-BP1), p70 S6 kinase, p42/44, and p38 (P < 0.05) compared to WT littermates. Mature myostatin (26 kDa), premature myostatin (52 kDa), and activin receptor type IIB (AcvR2B) protein levels were increased in bGH mice (P < 0.05), along with elevated phosphorylation levels of mothers against decapentaplegic homolog (Smad2) (59%, P < 0.0001). Mice overexpressing GH had increased MuRF1 expression (30%, P < 0.05) and insulin receptor substrate 1 (IRS1) serine phosphorylation (44%, P < 0.05) in the gastrocnemius, but not the soleus, when compared to controls., Conclusions: These findings demonstrate that chronic elevations in circulating GH have a critical impact on signaling pathways involved in skeletal muscle protein synthesis and atrophy, and suggest that MuRF1, myostatin, and IRS1 serine phosphorylation may act to inhibit exaggerated glycolytic muscle growth, in environments of chronic GH/IGF-1 excess.

The purpose of this study was to determine if plasma acylcarnitine (AC) profiling is altered under hyperinsulinemic conditions as part of the aging process. Fifteen young, lean (19-29 years) and fifteen middle-to older-aged (57-82 years) individuals underwent a 2-hr euglycemic-hyperinsulinemic clamp. Plasma samples were obtained at baseline, 20 min, 50 min, and 120 min for analysis of AC species and amino acids. Skeletal muscle biopsies were performed after 60 min of insulin-stimulation for analysis of acetyl-CoA carboxylase (ACC) phosphorylation. Insulin infusion decreased the majority of plasma short-, medium-, and long-chain (SC, MC, and LC, respectively) AC. However, during the initial 50 min, a number of MC and LC AC species (C10, C10:1, C12:1, C14, C16, C16:1, C18) remained elevated in aged individuals compared to their younger counterparts indicating a lag in responsiveness. Additionally, the insulin-induced decline in skeletal muscle ACC phosphorylation was blunted in the aged compared to young individuals (-24% vs. -56%, P < 0.05). These data suggest that a desensitization to insulin during aging, possibly at the level of skeletal muscle ACC phosphorylation, results in a diminished ability to transition to glucose oxidation indicative of metabolic inflexibility., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The purpose of this study was to determine whether plasma lactate and skeletal muscle glucose regulatory pathways, specifically PDH dephosphorylation, are impaired during hyperinsulinemic conditions in middle- to older-aged individuals and determine whether exercise training could improve key variables responsible for skeletal muscle PDH regulation. Eighteen young (19-29 yr; n = 9 males and 9 females) and 20 middle- to older-aged (57-82 yr; n = 10 males and 10 females) individuals underwent a 2-h euglycemic hyperinsulinemic clamp. Plasma samples were obtained at baseline and at 30, 50, 90, and 120 min for analysis of lactate, and skeletal muscle biopsies were performed at 60 min for analysis of protein associated with glucose metabolism. In response to insulin, plasma lactate was elevated in aged individuals when normalized to insulin action. Insulin-stimulated phosphorylation of skeletal muscle PDH on serine sites 232, 293, and 300 decreased in young individuals only. Changes in insulin-stimulated PDH phosphorylation were positively related to changes in plasma lactate. No age-related differences were observed in skeletal muscle phosphorylation of LDH, GSK-3α, or GSK-3β in response to insulin or PDP1, PDP2, PDK2, PDK4, or MPC1 total protein. Twelve weeks of endurance- or strength-oriented exercise training improved insulin-stimulated PDH dephosphorylation, which was related to a reduced lactate response. These findings suggest that impairments in insulin-induced PDH regulation in a sedentary aging population contribute to impaired glucose metabolism and that exercise training is an effective intervention for treating metabolic inflexibility., (Copyright © 2016 the American Physiological Society.)

The purpose of this study was to determine if site-specific phosphorylation at the level of Akt substrate of 160 kDa (AS160) is altered in skeletal muscle from sedentary humans across a wide range of the adult life span (18-84 years of age) and if endurance- and/or strength-oriented exercise training could rescue decrements in insulin action and skeletal muscle AS160 phosphorylation. A euglycemic-hyperinsulinemic clamp and skeletal muscle biopsies were performed in 73 individuals encompassing a wide age range (18-84 years of age), and insulin-stimulated AS160 phosphorylation was determined. Decrements in whole-body insulin action were associated with impairments in insulin-induced phosphorylation of skeletal muscle AS160 on sites Ser-588, Thr-642, Ser-666, and phospho-Akt substrate, but not Ser-318 or Ser-751. Twelve weeks of endurance- or strength-oriented exercise training increased whole-body insulin action and reversed impairments in AS160 phosphorylation evident in insulin-resistant aged individuals. These findings suggest that a dampening of insulin-induced phosphorylation of AS160 on specific sites in skeletal muscle contributes to the insulin resistance evident in a sedentary aging population and that exercise training is an effective intervention for treating these impairments.

Context: In lean individuals, increasing dietary lipid can elicit an increase in whole body lipid oxidation; however, with obesity the capacity to respond to changes in substrate availability appears to be compromised., Objective: To determine whether the responses of genes regulating lipid oxidation in skeletal muscle differed between lean and insulin resistant obese humans upon exposure to a high-fat diet (HFD)., Design and Setting: A 5-d prospective study conducted in the research unit of an academic center., Participants: Healthy, lean (n = 12; body mass index = 22.1 ± 0.6 kg/m(2)), and obese (n=10; body mass index = 39.6 ± 1.7 kg/m(2)) males and females, between ages 18 and 30., Intervention: Participants were studied before and after a 5-d HFD (65% fat)., Main Outcome Measures: Skeletal muscle biopsies (vastus lateralis) were obtained in the fasted and fed states before and after the HFD and mRNA content for genes involved with lipid oxidation determined. Skeletal muscle acylcarnitine content was determined in the fed states before and after the HFD., Results: Peroxisome proliferator activated receptor (PPAR) α mRNA content increased in lean, but not obese, subjects after a single high-fat meal. From Pre- to Post-HFD, mRNA content exhibited a body size × HFD interaction, where the lean individuals increased while the obese individuals decreased mRNA content for pyruvate dehydrogenase kinase 4, uncoupling protein 3, PPARα, and PPARγ coactivator-1α (P ≤ 0.05). In the obese subjects medium-chain acylcarnitine species tended to accumulate, whereas no change or a reduction was evident in the lean individuals., Conclusions: These findings indicate a differential response to a lipid stimulus in the skeletal muscle of lean and insulin resistant obese humans.

Context: Intracellular lipid partitioning toward storage and the incomplete oxidation of fatty acids (FA) have been linked to insulin resistance., Objective: To gain insight into how intracellular lipid metabolism is related to insulin signal transduction, we examined the effects of severe obesity, excess FA, and overexpression of the FA transporter, FA translocase (FAT)/CD36, in primary human skeletal myocytes., Design, Setting, and Patients: Insulin signal transduction, FA oxidation, and metabolism were measured in skeletal muscle cells harvested from lean and severely obese women. To emulate the obesity phenotype in our cell culture system, we incubated cells from lean individuals with excess FA or overexpressed FAT/CD36 using recombinant adenoviral technology., Results: Complete oxidation of FA was significantly reduced, whereas total lipid accumulation, FA esterification into lipid intermediates, and incomplete oxidation were up-regulated in the muscle cells of severely obese subjects. Insulin signal transduction was reduced in the muscle cells from severely obese subjects compared to lean controls. Incubation of muscle cells from lean subjects with lipids reduced insulin signal transduction and increased lipid storage and incomplete FA oxidation. CD36 overexpression increased FA transport capacity, but did not impair complete FA oxidation and insulin signal transduction in muscle cells from lean subjects., Conclusions: Cultured myocytes from severely obese women express perturbations in FA metabolism and insulin signaling reminiscent of those observed in vivo. The obesity phenotype can be recapitulated in muscle cells from lean subjects via exposure to excess lipid, but not by overexpressing the FAT/CD36 FA transporter.

Purpose: To determine substrate utilization and energy expenditure during maximal and submaximal exercise and recovery in adolescents with cystic fibrosis (CF) and healthy age-matched controls (C)., Methods: Ten clinically stable CF patients (four girls, six boys; age = 10-22 yr) were matched by body mass index, age, gender, and Tanner stage to healthy controls. Subjects completed VO(2peak) testing and submaximal exercise (20 min) on a cycle ergometer at a relative intensity of 50% VO2(peak) and at an absolute power output (PO). Metabolic parameters were assessed during exercise and recovery (20 min)., Results: Similar respiratory quotient (RQ) values occurred in both groups during maximal exercise and recovery, despite differences in the maximal PO [CF = 114 (60-180) W and C = 171 (105-280) W, P = 0.006], the total work completed [CF = 27 (9.0-54.3) kJ and C = 55 (25.3-126.5) kJ, P = 0.008], or the VO(2peak) value attained [CF = 30.6 (8.5-45.2) mL kg(-1) min(-1) and C = 40.6 (29-64.5) mL kg(-1) min(-1), P = 0.027]. Submaximal exercise at the same absolute PO resulted in similar RQ values during exercise and recovery despite higher heart rates and average VO2 [CF = 18.8 (9.3-28.7) mL kg(-1) min(-1) and C = 15.2 (6.5-20.1) mL kg(-1)min(-1), P = 0.031] values in CF adolescents, and submaximal exercise at the same relative intensity also resulted in similar RQ values despite significantly greater average PO in the C group [CF = 38.7 (12.3-80) W and C = 67.8 (25.5-140) W, P = 0.039]. Excess postexercise oxygen consumption (EPOC) was greater in CF [2.79 (1.14-5.24) L O2] than C [1.46 (0.56-2.80) L O2] after submaximal exercise at a fixed PO (P = 0.036) but not after the relative exercise bout., Conclusions: Habitual physical activity participation does not warrant adjustment of macronutrient intake ratios in adolescents with mild to moderate CF, but total caloric intake may need to be increased based on the level of EPOC and upon the intensity and the duration of the habitual activity.

With the increasing prevalence of obesity, research has focused on the molecular mechanism(s) linking obesity and skeletal muscle insulin resistance. Metabolic alterations within muscle, such as changes in the cellular location of fatty acid transporter proteins, decreased mitochondrial enzyme activity, and defects in mitochondrial morphology, likely contribute to obesity and insulin resistance. These defects are thought to play a role in the reduced skeletal muscle fatty acid oxidation and increased intramuscular lipid (IMCL) accumulation that is apparent with obesity and other insulin-resistant states such as type 2 diabetes. Intramuscular triacylglycerol does not appear to be a ubiquitous marker of insulin resistance, although specific IMCL intermediates such as long-chain fatty acyl-CoAs, ceramide, and diacylglycerol may inhibit insulin signal transduction. In this review, we will briefly summarize the defects in skeletal muscle lipid metabolism associated with obesity, and discuss the proposed mechanisms by which these defects may contribute to insulin resistance.

The purpose of this study was to compare the growth hormone (GH) response, including the immunfunctional (IF) GH response, between an acute bout of aerobic and resistance exercise in the same subjects. Ten cross-trained males (24.3 +/- 1.2 years) performed both 30 min of continuous cycling at 70% of VO(2max), and intermittent free weight squatting at 70% of 1-RM, in a randomly assigned crossover design, separated by at least 1 week. Blood samples were collected at 10-min intervals for 2 h (30 min rest, 30 min exercise, 60 min recovery) and analyzed for total human and IF GH. After adjusting for the amount of work performed per minute of exercise, integrated GH AUC was significantly greater during the resistance session than the aerobic session as measured by both the total and IF GH assays (P = 0.008 and P = 0.014, respectively). Peak GH concentrations were significantly greater during the resistance session than the aerobic session (P = 0.05). A similar overall GH pattern was observed in response to both types of exercise, with peak values occurring at the end of exercise, regardless of the GH assay used. These data demonstrate that in young, cross-trained males, intermittent resistance exercise elicits a greater response of GH, including IF GH, compared to a continuous aerobic session, when controlling for the work performed per minute, intersubject variability, relative exercise intensity and session duration.

The purpose of this study was to determine the effect of aerobic exercise duration on plasma protein carbonyl concentrations, a marker of protein oxidation, in aerobically trained men and women. Eight men (age: 27 +/- 4 years, VO (2peak): 4.09 +/- 0.26 L x min (-1); mean +/- SD) and 7 women (age: 27 +/- 6 years, VO (2peak): 2.33 +/- 0.24 L x min (-1)) exercised on an electrically-braked cycle ergometer at 70 % VO (2peak) for 30, 60 or 120 minutes on three separate days. Plasma samples collected before and immediately, 30- and 60-minutes post-exercise were analyzed for protein carbonyls. Mean oxygen uptake was greater for men in all conditions (2.75 +/- 0.03 L x min (-1); 38 +/- 0.43 ml x kg (-1) x min (-1)) compared to women (1.57 +/- 0.03 L x min (-1); 24.1 +/- 0.47 ml x kg (-1) x min (-1)). Total work performed during the exercise sessions was also greater for men than for women during the 30 (368 +/- 11 versus 223 +/- 7 kJ), 60 (697 +/- 17 versus 423 +/- 18 kJ), and 120-minute conditions (1173 +/- 44 versus 726 +/- 28 kJ) (Mean +/- SEM). Although these comparisons were significant (p < 0.0001), sex differences in total work performed and mean VO (2) did not result in sex differences in protein carbonyls. However, a condition by time interaction was observed with greater post-exercise values following the 120-minute condition compared to both the 30- and 60-minute conditions. Protein carbonyl concentration was greatest immediately post-exercise for both men and women and generally declined in a linear trend through one hour of recovery. These data suggest that protein carbonyl concentration is elevated by cycling exercise performed at 70 % VO (2peak), is greater following longer duration rides, begins to recover within one hour following exercise, and is not different between men and women.

The purpose of this study was to compare oxidative modification of blood proteins, lipids, DNA, and glutathione in the 24 hours following aerobic and anaerobic exercise using similar muscle groups. Ten cross-trained men (24.3 +/- 3.8 years, [mean +/- SEM]) performed in random order 30 minutes of continuous cycling at 70% of Vo(2)max and intermittent dumbbell squatting at 70% of 1 repetition maximum (1RM), separated by 1-2 weeks, in a crossover design. Blood samples taken before, and immediately, 1, 6, and 24 hours postexercise were analyzed for plasma protein carbonyls (PC), plasma malondialdehyde (MDA), and whole-blood total (TGSH), oxidized (GSSG), and reduced (GSH) glutathione. Blood samples taken before and 24 hours postexercise were analyzed for serum 8-hydroxy-2'-deoxyguanosine (8-OHdG). PC values were greater at 6 and 24 hours postexercise compared with pre-exercise for squatting, with greater PC values at 24 hours postexercise for squatting compared with cycling (0.634 +/- 0.053 vs. 0.359 +/- 0.018 nM.mg protein(-1)). There was no significant interaction or main effects for MDA or 8-OHdG. GSSG experienced a short-lived increase and GSH a transient decrease immediately following both exercise modes. These data suggest that 30 minutes of aerobic and anaerobic exercise performed by young, cross-trained men (a) can increase certain biomarkers of oxidative stress in blood, (b) differentially affect oxidative stress biomarkers, and (c) result in a different magnitude of oxidation based on the macromolecule studied. Practical applications: While protein and glutathione oxidation was increased following acute exercise as performed in this study, future research may investigate methods of reducing macromolecule oxidation, possibly through the use of antioxidant therapy.

Thirty cross-trained, female subjects (19-69 years) completed an endurance exercise session (ES), a resistance exercise session (RS), and a control session (CS) in a randomized, balanced design. The ES consisted of 40 minutes of cycling at 75% maximum heart rate, and the RS consisted of 3 sets of 10 repetitions of eight exercises. During the CS, subjects performed no exercise. Before and after exercise, and after 30 minutes of recovery, blood samples were analyzed for plasma lactate and serum growth hormone, insulin-like growth factor 1, testosterone, estradiol, dehydroepiandrosterone, and cortisol. Samples were taken during the CS at the same intervals as during the exercise sessions. There were no age-related differences in intensity measures during exercise. Absolute change from baseline in testosterone (p <.001), estradiol (p <.05), and growth hormone (p <.01) was significantly greater in the ES and RS compared with that in the CS. Absolute change in dehydroepiandrosterone was significantly greater in the RS only (p <.05). Results indicate that an acute bout of exercise can increase concentrations of anabolic hormones in females across a wide age range.

Research in exercise endocrinology has flourished over the past few decades. In general, research examining short- and long-term hormone responses to endurance exercise preceded studies on resistance exercise, and research on women lagged behind research on men. Sufficient data are now available to allow a comparison of endogenous anabolic hormone responses to endurance versus resistance exercise and training in women. Circulating levels of testosterone, dehydroepiandrosterone, dehydroepiandrosterone sulphate, estradiol, growth hormone and cortisol have been shown to increase in response to an acute bout of endurance exercise in women. However, only growth hormone, estradiol and cortisol have been reported to increase following resistance exercise. Hormone changes following training, either endurance or resistance, have been variable, probably because of differences in experimental design and major differences in the length, intensity and volume of training programmes. With the notable exception of growth hormone, the anabolic hormones reviewed here appear to decline with endurance training. Resistance training has little effect on resting hormone levels, except insulin-like growth factor-I, which has been shown to increase following a training programme. These hormone changes potentially have both metabolic and hypertrophic implications, and future research needs to focus on the biological significance of these adaptations.

Sixteen, cross-trained, premenopausal women participated in an endurance, resistance, and control session to compare hormone responses. The resistance session included 3 sets of eight exercises at 10 RM intensity. The endurance session consisted of a 40-min cycling protocol at 75% of maximal heart rate. During the control session, subjects rested for 35 min. Serum DHEA, estradiol, testosterone, growth hormone, IGF-I, cortisol, and plasma lactate concentrations were measured pre-exercise, post-exercise, and 30 min into recovery. Differences in intensity variables existed between the three sessions. Endurance exercise elicited increases in growth hormone, estradiol, and testosterone compared to the control session, and growth hormone increased after the resistance compared to the control session. The exercise protocols used in this study indicate that an acute bout of exercise can stimulate the endocrine system in premenopausal females. In addition, these results indicate that differences exist between these two exercise protocols when compared to a control session.