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BackgroundMitochondrial dysfunction has been implicated in sarcopenia. P-31 magnetic resonance spectroscopy (MRS) enables non-invasive measurement of adenosine triphosphate (ATP) synthesis rates to probe mitochondrial function. Here, we assessed muscle energetics in older sarcopenic and non-sarcopenic men and compared with muscle biopsy-derived markers of mitochondrial function. MethodsTwenty Chinese men with sarcopenia (SARC, age = 73.1 +/- 4.1 years) and 19 healthy aged and sex-matched controls (CON, age = 70.3 +/- 4.2 years) underwent assessment of strength, physical performance, and magnetic resonance imaging. Concentrations of phosphocreatine (PCr), ATP and inorganic phosphate (Pi) as well as muscle pH were measured at rest and during an interleaved rest-exercise protocol to probe muscle mitochondrial function. Results were compared to biopsy-derived mitochondrial complex activity and expression to understand underlying metabolic perturbations. ResultsDespite matched muscle contractile power (strength/cross-sectional area), the ATP contractile cost was higher in SARC compared with CON (low-intensity exercise: 1.06 +/- 0.59 vs. 0.57 +/- 0.22, moderate: 0.93 +/- 0.43 vs. 0.58 +/- 0.68, high: 0.70 +/- 0.57 vs. 0.43 +/- 0.51 mmol L-1 min(-1) bar(-1) cm(-2), P = 0.003

Summary Insulin resistance and muscle mass loss often coincide in individuals with type 2 diabetes. Most patients with type 2 diabetes are overweight, and it is well established that obesity and derangements in lipid metabolism play an important role in the development of insulin resistance in these individuals. Specifically, increased adipose tissue mass and dysfunctional adipose tissue lead to systemic lipid overflow and to low‐grade inflammation via altered secretion of adipokines and cytokines. Furthermore, an increased flux of fatty acids from the adipose tissue may contribute to increased fat storage in the liver and in skeletal muscle, resulting in an altered secretion of hepatokines, mitochondrial dysfunction, and impaired insulin signalling in skeletal muscle. Recent studies suggest that obesity and lipid derangements in adipose tissue can also lead to the development of muscle atrophy, which would make insulin resistance and muscle atrophy two sides of the same coin. Unfortunately, the exact relationship between lipid accumulation, type 2 diabetes, and muscle atrophy remains largely unexplored. The aim of this review is to discuss the relationship between type 2 diabetes and muscle loss and to discuss some of the joint pathways through which lipid accumulation in organs may affect peripheral insulin sensitivity and muscle mass.

Intramyocellular lipid (IMCL) hampers insulin sensitivity, albeit not in endurance-trained athletes (Trained). Compared to type 2 diabetes mellitus (T2DM) patients, Trained subjects have high levels of perilipin 5 (PLIN5). In the present study, we tested whether the fraction of PLIN5-coated lipid droplets (LDs) is a determinant of skeletal muscle insulin sensitivity and contributes to the athlete's paradox. Muscle biopsies were taken from eight Trained, Lean sedentary, Obese and T2DM subjects. Trained, Obese and T2DM subjects were matched for total IMCL content. Confocal images were analysed for lipid area fraction, LD size and number and PLIN5+ and PLIN5- LDs were measured. A stepwise linear regression was performed to identify factors explaining observed variance in glucose infusion rate (GIR). Trained and T2DM subjects stored IMCL differently; Trained subjects had a higher number of LDs compared to T2DM subjects (0.0370.004m(-2)vs. 0.0230.003m(-2), P=0.024) that were non-significantly smaller (0.270.01m(2)vs. 0.320.02m(2), P=0.197, Trained vs. T2DM). Even though total PLIN5 protein content was almost double in Trained vs. T2DM subjects (1.650.21AU vs. 0.89 +/- 0.09AU, P=0.004), PLIN5 coating did not affect LD number or size significantly. Of the observed variance in GIR, the largest fraction by far (70.2%) was explained by maximal oxygen uptake. Adding PLIN5 protein content or PLIN5+ LDs increased the explained variance in GIR (74.7% and 80.7% for PLIN5 protein content and PLIN5+ LDs, respectively). Thus, the putative relationship between PLIN5 and insulin sensitivity is at best indirect and is apparent only in conjunction with maximal oxygen uptake. Hence, PLIN5 abundance cannot be causally linked to the athlete's paradox.

Background Cachectic patients with chronic obstructive pulmonary disease (COPD) may benefit from nutritional support. This double-blind, randomized, controlled trial evaluated the safety and efficacy of targeted medical nutrition (TMN) vs. an isocaloric comparator in pre-cachectic and cachectic patients with COPD.Methods Patients aged >= 50 years with moderate-to-severe COPD and involuntary weight loss or low body mass index (1618 kg/m(2)) were randomized 1: 1 to receive TMN (similar to 230 kcal; 2 g omega-3 fatty acids; 10 mu g 25-hydroxy-vitamin D3) or isocaloric comparator twice daily for 12 weeks (ClinicalTrials.gov Identifier: NCT02442908). Primary safety endpoints comprised adverse events and changes in vital signs, laboratory parameters, and concomitant medications. Secondary efficacy endpoints included changes in weight, body composition, exercise tolerance, metabolic biomarkers, and systemic inflammation.Results Forty-five patients were randomized to receive TMN (n = 22; mean 69.2 years) or isocaloric comparator (n = 23; mean 69.7 years). TMN was well tolerated. Adverse events were similar in number and type in both groups. Compliance to both products was good (TMN, 79%; comparator, 77%). Both groups gained weight, but the TMN group gained comparatively more fat mass (P = 0.0013). Reductions in systolic blood pressure (P = 0.0418) and secondary endpoints of triglycerides (P = 0.0217) and exercise-induced fatigue (P = 0.0223) and dyspnoea (P = 0.0382), and increases in high-density lipoprotein cholesterol (P = 0.0254), were observed in the TMN vs. the comparator group by week 12.Conclusions Targeted medical nutrition containing high-dose omega-3 fatty acids, vitamin D, and high-quality protein is well tolerated with a good safety profile and has positive effects on blood pressure and blood lipids and on exercise-induced fatigue and dyspnoea. Therefore, this TMN could be clinically beneficial in the nutritional and metabolic support of precachectic and cachectic patients with COPD.

Introduction: Quadriceps dysfunction is important in chronic obstructive pulmonary disease (COPD), with an associated increased proportion of type II fibers. Investigation of protein synthesis and degradation has yielded conflicting results, possibly due to study of whole biopsy samples, whereas signalling may be fiber-specific. Our objective was to develop a method for fiber-specific gene expression analysis. Methods: 12 COPD and 6 healthy subjects underwent quadriceps biopsy. Cryosections were immunostained for type II fibers, which were separated using laser capture microdissection (LCM). Whole muscle and different fiber populations were subject to quantitative polymerase chain reaction (qPCR). Results: Muscle-RING-finger-protein-1(MURF-1) and Atrogin-1 were lower in type II fibers of COPD versus healthy subjects (P=0.02 and P=0.03, respectively), but differences were not apparent in whole muscle or type I fibers. Discussion: We describe a novel method for studying fiber-specific gene expression in optimum-cutting-temperature (OCT) compound-embedded muscle specimens. LCM offers a more sensitive way to identify molecular changes in COPD muscle. This article is protected by copyright. All rights reserved.

Key points Skeletal muscle hypertrophy is one of the main outcomes from resistance training (RT), but how it is modulated throughout training is still unknown. We show that changes in myofibrillar protein synthesis (MyoPS) after an initial resistance exercise (RE) bout in the first week of RT (T1) were greater than those seen post-RE at the third (T2) and tenth week (T3) of RT, with values being similar at T2 and T3. Muscle damage (Z-band streaming) was the highest during post-RE recovery at T1, lower at T2 and minimal at T3. When muscle damage was the highest, so was the integrated MyoPS (at T1), but neither were related to hypertrophy; however, integrated MyoPS at T2 and T3 were correlated with hypertrophy. We conclude that muscle hypertrophy is the result of accumulated intermittent increases in MyoPS mainly after a progressive attenuation of muscle damage.AbstractSkeletal muscle hypertrophy is one of the main outcomes of resistance training (RT), but how hypertrophy is modulated and the mechanisms regulating it are still unknown. To investigate how muscle hypertrophy is modulated through RT, we measured day-to-day integrated myofibrillar protein synthesis (MyoPS) using deuterium oxide and assessed muscle damage at the beginning (T1), at 3weeks (T2) and at 10weeks of RT (T3). Ten young men (27(1)years, mean (SEM)) had muscle biopsies (vastus lateralis) taken to measure integrated MyoPS and muscle damage (Z-band streaming and indirect parameters) before, and 24h and 48h post resistance exercise (post-RE) at T1, T2 and T3. Fibre cross-sectional area (fCSA) was evaluated using biopsies at T1, T2 and T3. Increases in fCSA were observed only at T3 (P=0.017). Changes in MyoPS post-RE at T1, T2 and T3 were greater at T1 (P

Background Adequate muscle fibre perfusion is critical for the maintenance of muscle mass, it is essential in the rapid delivery of oxygen, nutrients and growth factors to the muscle, stimulating muscle fibre growth. Muscle fibre capillarization is known to decrease substantially with advancing age. However, whether (relative) low muscle fibre capillarization negatively impacts the muscle hypertrophic response following resistance exercise training in older adults is unknown. Methods Twenty-two healthy older men (71 ± 1 years) performed 24 weeks of progressive resistance type exercise training. To assess the change in muscle fibre characteristics, percutaneous biopsies from the vastus lateralis muscle were taken before and following 12 and 24 weeks of the intervention programme. A comparison was made between participants who had a relatively low type II muscle fibre capillary-to-fibre perimeter exchange index (CFPE, LOW group) and high type II muscle fibre CFPE (HIGH group) at baseline. Type I and type II muscle fibre size, satellite cell, capillary content and distance between satellite cells to the nearest capillary were determined by immunohistochemistry. Results Overall, type II muscle fibre size (from 5150 ± 234 to 6719 ± 446 µm2, P < 0.05) and satellite cell content (from 0.058 ± 0.006 to 0.090 ± 0.010 satellite cells per muscle fibre, P < 0.05) had increased significantly in response to 24 weeks of resistance exercise training. However, these improvements where mainly driven by differences in baseline type II muscle fibre capillarization, whereas muscle fibre size (from 5170 ± 390 to 7133 ± 314 µm2, P < 0.05) and satellite cell content (from 0.059 ± 0.009 to 0.102 ± 0.017 satellite cells per muscle fibre, P < 0.05) increased significantly in the HIGH group, no significant changes were observed in LOW group following exercise training. No significant changes in type I and type II muscle fibre capillarization were observed in response to 12 and 24 weeks of resistance exercise training in both the LOW and HIGH group. Conclusions Type II muscle fibre capillarization at baseline may be a critical factor for allowing muscle fibre hypertrophy to occur during prolonged resistance exercise training in older men.

Creatine (Cr) plays an important role in muscle energy homeostasis by its participation in the ATP-phosphocreatine phosphoryl exchange reaction mediated by creatine kinase. Given that the consequences of Cr depletion are incompletely understood, we assessed the morphological, metabolic and functional consequences of systemic depletion on skeletal muscle in a mouse model with deficiency of L-arginine: glycine amidinotransferase (AGAT(-/-)), which catalyses the first step of Cr biosynthesis. In vivo magnetic resonance spectroscopy showed a near-complete absence of Cr and phosphocreatine in resting hindlimb muscle of AGAT(-/-) mice. Compared with wild-type, the inorganic phosphate/beta-ATP ratio was increased fourfold, while ATP levels were reduced by nearly half. Activities of proton-pumping respiratory chain enzymes were reduced, whereas F1F0-ATPase activity and overall mitochondrial content were increased. The Cr-deficient AGAT(-/-) mice had a reduced grip strength and suffered from severe muscle atrophy. Electron microscopy revealed increased amounts of intramyocellular lipid droplets and crystal formation within mitochondria of AGAT(-/-) muscle fibres. Ischaemia resulted in exacerbation of the decrease of pH and increased glycolytic ATP synthesis. Oral Cr administration led to rapid accumulation in skeletal muscle (faster than in brain) and reversed all the muscle abnormalities, revealing that the condition of the AGAT(-/-) mice can be switched between Cr deficient and normal simply by dietary manipulation. Systemic creatine depletion results in mitochondrial dysfunction and intracellular energy deficiency, as well as structural and physiological abnormalities. The consequences of AGAT deficiency are more pronounced than those of muscle-specific creatine kinase deficiency, which suggests a multifaceted involvement of creatine in muscle energy homeostasis in addition to its role in the phosphocreatine-creatine kinase system.

Alternate methods to quantify mitochondrial activity or function have been extensively used for studying insulin resistance and type 2 diabetes mellitus, namely saturation transfer and phosphocreatine (PCr) recovery. As these methods are in fact determining different parameters, this study aimed to compare saturation transfer results to PCr recovery measurements within the same group. Fifteen subjects underwent saturation transfer and ischemic exercise-recovery experiments. PCr decrease during ischemia (Q), induced by cuff inflation, served as an additional measure of resting ATP (adenosine triphosphate) production. ATP synthetic rate (fATP) measured by saturation transfer (0.234 +/- 0.043 mM/s) was greater than (Q = 0.0077 +/- 0.0011 mM/s), but correlated well with Q (r = 0.63 P = 0.013). Parameters of PCr recovery correlated well with fATP (Q(max,lin) : r = 0.71, P = 0.003, Q(max,ADP) : r = 0.66, P = 0.007) and Q (Q(max,lin) : r = 0.92, P = 0.000002, Q(max,ADP) : r = 0.76, P = 0.001). In conclusion, although saturation transfer yields higher ATP synthetic rates than PCr decrease during ischemia, their significant correlation indicates that fATP can be used as a marker of mitochondrial activity. The finding that both Q and fATP correlate with PCr recovery kinetics suggests that skeletal muscle with greater maximal aerobic ATP synthetic rates is also metabolically more active at rest. Magn Reson Med, 2011. (c) 2011 Wiley-Liss, Inc.

Endurance-type exercise training represents a cornerstone in type 2 diabetes treatment. However, the effects of prolonged continuous, endurance-type exercise on muscle fiber characteristics remain equivocal. Fifteen obese male type 2 diabetes patients (61 +/- 6 years) participated in a 6-month continuous, endurance-type exercise program. Muscle biopsies were collected before, and after 2 and 6 months of intervention. Muscle fiber type-specific composition, size, and satellite cell (SC) and myonuclear content were determined by immunohistochemistry. Although continuous endurance-type exercise training lowered total body weight and reduced fat mass, no changes were observed in leg lean mass. At baseline, SC content was significantly lower in type II compared with type I muscle fibers. No change in SC content was observed after exercise training. Continuous endurance-type exercise training lowers fat mass, but it does not increase leg lean mass and/or modulate muscle fiber characteristics in type 2 diabetes patients. Muscle Nerve, 2010.

Lipotoxicity in skeletal muscle plays a critical role in the aetiology of insulin resistance and type 2 diabetes mellitus by interference of lipid metabolites with insulin signalling and action. The dynamics of lipid oxidation and fine tuning with fatty acid uptake and intramyocellular triacylglycerol turnover may be very important to limit the accumulation of lipid intermediates. The use of metabolic inflexibility, defined as the impaired capacity to increase fat oxidation upon increased fatty acid availability and to switch between fat and glucose as the primary fuel source after a meal, does more justice to the complexity of changes in fuel oxidation during the day. Fatty acid availability, uptake and oxidation all play a role in metabolic flexibility and insulin resistance. During high fatty acid availability, fatty acid transporters may limit cellular and mitochondrial fatty acid uptake and thus limit fat oxidation. After a meal, when the demand for fatty acids as fuel is low, an increased fractional extraction of lipids from plasma may promote intramyocellular lipid accumulation and insulin resistance. Furthermore, defects in fuel switching cluster together with impaired mitochondrial content and/or function. Lifestyle changes in dietary fat intake, physical activity and weight loss may improve metabolic flexibility in skeletal muscle, and thereby contribute to the prevention of type 2 diabetes.

Muscles are usually stimulated by shocks delivered at some constant rate. However, human thenar motor units generate optimum force per pulse when excited by impulse trains that begin with one or two short interpulse intervals ("doublets"), followed by longer intervals. Our aim was to determine whether the rate of force and force-time integral reduction during fatigue of thenar muscles is influenced by an initial doublet, and/or the number of pulses per train. We first matched thenar force-time integral using two different pulse patterns, one of which began with a doublet. Fatigue induced by trains that contained a doublet resulted in slower rates of force and force-time integral reduction and smaller increases in half-relaxation time than that evoked by bursts of 40-Hz stimulation. When the force was measured in each protocol after equal numbers of pulses had been delivered, the force loss was still significantly less for pulse trains containing a doublet, These results have useful implications when designing stimulation to strengthen weak muscles or to drive paralyzed muscles. (C) 2000 John Wiley & Sons, Inc.

Muscles are usually stimulated by shocks delivered at some constant rate. However, human thenar motor units generate optimum force per pulse when excited by impulse trains that begin with one or two short interpulse intervals ("doublets"), followed by longer intervals. Our aim was to determine whether the rate of force and force-time integral reduction during fatigue of thenar muscles is influenced by an initial doublet, and/or the number of pulses per train. We first matched thenar force-time integral using two different pulse patterns, one of which began with a doublet. Fatigue induced by trains that contained a doublet resulted in slower rates of force and force-time integral reduction and smaller increases in half-relaxation time than that evoked by bursts of 40-Hz stimulation. When the force was measured in each protocol after equal numbers of pulses had been delivered, the force loss was still significantly less for pulse trains containing a doublet, These results have useful implications when designing stimulation to strengthen weak muscles or to drive paralyzed muscles. (C) 2000 John Wiley & Sons, Inc.

The pattern of cytosolic ADP recovery after exercise has not been fully characterized in human skeletal muscle. ADP recovery after brief, ischemic exercise was studied by 31phosphorus magnetic resonance spectroscopy in calf muscles of 33 normal control subjects, four patients with McArdle's disease and 13 patients with mitochondrial myopathy. In normal muscle, the half-time for the initial ADP decline was 0.18 +/- 0.07 min and was unaffected by the pH or the metabolic state at the end of exercise. ADP decreased to below rest values during the second min of recovery in 27 out of 33 control subjects. There was a significant (p < 0.001) linear correlation for both the size (r = 0.65) and duration (r = 0.64) of this ADP undershoot with intracellular pH. Phosphocreatine resynthesis continued during the ADP undershoot. ADP undershoot was also found in patients with mitochondrial diseases (in 11 out of 13), but not McArdle's disease (six patients). Thus ADP recovery follows a complex time course that is partly dependent on pH. Only the initial ADP recovery is independent of pH, which makes it suitable for comparative assessment of muscle mitochondrial function in vivo. As phosphocreatine recovery continues during the ADP undershoot, mitochondrial regulation must be different from that at the onset of recovery. These observations are consistent with variable, changing regulators of mitochondrial metabolism in human skeletal muscle.

Measurements were done on the biceps muscles of 6 healthy volunteers to record simultaneously the surface electromyogram (EMG) and vibromyogram (VMG) by means of a piezoelectric device (accelerometer). The VMG is generated by mechanical waves due to the contraction mechanism and often measured as sound. The frequency spectrum and integrated value (IEMG and IVMG) of both signals were calculated. Both IEMG and IVMG showed a clear linear correlation with force, although at high forces, the variability of the VMG became rather high. Two series of experiments were performed to study the EMG and VMG changes in relation to changes induced by fatigue: (1) during constant force at 50% of the maximal voluntary contraction (MVC) and recovery; (2) for one 1 minute during declining force at MVC. The main finding was that the IVMG was related to the absolute force, irrespective of the fatigue state of the muscle. In contrast, the IEMG showed the well-known changes during fatigue, such as an increase during endurance. The spectral changes of the two measurements also showed a divergence. The spectra of the EMG shifted to lower frequencies in both fatigue protocols. In contrast, the spectra of the vibratory signal did not shift, except for several measurements at MVC. However, the shape did change to a somewhat flatter spectrum with less pronounced peaks. Possible explanations for this different behavior are discussed. It is concluded that the vibratory energy generated by the contraction mechanism is linearly related to force. Changes induced by fatigue do not alter this relationship: this contrasts with the behavior of the EMG. The combination of these two measurements give supplemental information regarding the state of the working muscle.