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Purpose To develop a protocol for diffusion-tensor imaging (DTI) of the complete upper legs and to demonstrate feasibility of detection of subclinical sports-related muscle changes in athletes after strenuous exercise, which remain undetected by using conventional T2-weighted magnetic resonance (MR) imaging with fat suppression. Materials and Methods The research was approved by the institutional ethics committee review board, and the volunteers provided written consent before the study. Five male amateur long-distance runners underwent an MR examination (DTI, T1-weighted MR imaging, and T2-weighted MR imaging with fat suppression) of both upper legs 1 week before, 2 days after, and 3 weeks after they participated in a marathon. The tensor eigenvalues (λ1, λ2, and λ3), the mean diffusivity, and the fractional anisotropy (FA) were derived from the DTI data. Data per muscle from the three time-points were compared by using a two-way mixed-design analysis of variance with a Bonferroni posthoc test. Results The DTI protocol allowed imaging of both complete upper legs with adequate signal-to-noise ratio and within a 20-minute imaging time. After the marathon, T2-weighted MR imaging revealed grade 1 muscle strains in nine of the 180 investigated muscles. The three eigenvalues, mean diffusivity, and FA were significantly increased (P < .05) in the biceps femoris muscle 2 days after running. Mean diffusivity and eigenvalues λ1 and λ2 were significantly (P < .05) increased in the semitendinosus and gracilis muscles 2 days after the marathon. Conclusion A feasible method for DTI measurements of the upper legs was developed that fully included frequently injured muscles, such as hamstrings, in one single imaging session. This study also revealed changes in DTI parameters that over time were not revealed by qualitative T2-weighted MR imaging with fat suppression. © RSNA, 2014 Online supplemental material is available for this article.

The hemodynamic concept of insulin resistance assumes that vasodilatory effects of insulin determine glucose uptake. Sickle cell disease (SCD) is characterized by microangiopathy and microvascular occlusion. Therefore, we hypothesized that patients with SCD have a reduced insulin-mediated glucose uptake. In 8 patients with SCD and 8 matched normal controls, we studied the effects of a 4-hour insulin infusion (50 mU/kg/h) on glucose uptake and leg blood flow (LBF) using the euglycemic clamp technique and venous occlusion plethysmography. Time-control experiments were performed in the same subjects. Insulin-mediated glucose uptake (M value, mg/kg/min) did not differ between patients with SCD and control subjects during the second (6.3 +/- 4.6 and 7.6 +/- 2.6, P = .5), third (7.5 +/- 4.6 and 9.3 +/- 3.4, P = .4) and fourth hour (8.6 +/- 4.7 and 11.0 +/- 2.9, P = .2) of the clamp. At baseline, LBF was higher in the patients with SCD than in the controls (3.28 +/- 1.68 and 1.37 +/- 0.47 mL/min/dL, respectively; P = .005). Insulin-induced increases in LBF in patients with SCD and in normal subjects were not different (P = .9). Respectively, 56% and 24% of the changes in glucose uptake could be explained from changes in LBF in the course of the insulin infusion in the patients with SCD and controls. We suppose that the comparable insulin sensitivity between both groups is due to a compensatory hemodynamic state in SCD characterized by vasodilation and increased flow. Copyright (C) 2001 by W.B. Saunders Company.

Objective: To examine the response of short hamstring muscles to repeated passive stretching. Design: A repeated measures design. Setting: A university laboratory for human movement analysis in a department of rehabilitation. Subjects: Students (7 men, 10 women) from the Department of Human Movement Sciences. Main Outcome Measures: The lift force, range of motion, pelvic-femoral angle, first sensation of pain, and electromyogram of the hamstrings were measured. Results: Comparison of the data of the test group (n = 17) after five successive passive stretch tests by means of an instrumental straight-leg raising test showed no significant change of the variables passive muscle stiffness and extensibility (P >.05). Conclusion: The acute effect of repeated passive stretching of short hamstring muscles is negligible. With an instrumental straight-leg raising test, the relevant muscle variables can be examined noninvasively. (C) 1999 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation.

International audience; Abstract: Objective: To evaluate muscle bioenergetics, muscle cross-sectional area (CSA), and soreness when the gastrocnemius was subjected to concentric and concentric/eccentric resistance training modes. Design: Prospective study, before and after training. The subjects served as their own controls. Setting: Rehabilitation center and nuclear magnetic resonance spectroscopy unit of a university hospital. Participants: Sixteen healthy young volunteers from the local physiotherapist school. Intervention: Two distinct resistive training programs were evaluated on the gastrocnemius: a protocol consisting of concentric contractions only and a mixed concentric/eccentric program. Main Outcome Measures: Maximal isometric resistance was measured after each training session. Before and after training, muscle CSA was appreciated using magnetic resonance imaging, whereas changes in muscle pH, phosphorus metabolite ratios, maximal oxidative power (P-max), and oxidative phosphorylation were studied using P-31 nuclear magnetic resonance spectroscopy at rest and during an incremental exercise protocol. Results: Magnetic resonance imaging revealed a significant increase (7.1%) in the gastrocnemius CSA in the concentric-eccentric group only. The PCr/Pi (8.3 +/- 0.9 vs 10.4 +/- 1.7) and PCr/ATP (3.68 +/- .36 vs 4.07 +/- .27) resting ratios increased significantly (p =.008) after concentric-eccentric resistance training. P-max was significantly improved in the concentric-eccentric group (7.0 +/- 2.1W vs 8.4 +/- 1.8W: p

International audience; Abstract: Objective: To evaluate muscle bioenergetics, muscle cross-sectional area (CSA), and soreness when the gastrocnemius was subjected to concentric and concentric/eccentric resistance training modes. Design: Prospective study, before and after training. The subjects served as their own controls. Setting: Rehabilitation center and nuclear magnetic resonance spectroscopy unit of a university hospital. Participants: Sixteen healthy young volunteers from the local physiotherapist school. Intervention: Two distinct resistive training programs were evaluated on the gastrocnemius: a protocol consisting of concentric contractions only and a mixed concentric/eccentric program. Main Outcome Measures: Maximal isometric resistance was measured after each training session. Before and after training, muscle CSA was appreciated using magnetic resonance imaging, whereas changes in muscle pH, phosphorus metabolite ratios, maximal oxidative power (P-max), and oxidative phosphorylation were studied using P-31 nuclear magnetic resonance spectroscopy at rest and during an incremental exercise protocol. Results: Magnetic resonance imaging revealed a significant increase (7.1%) in the gastrocnemius CSA in the concentric-eccentric group only. The PCr/Pi (8.3 +/- 0.9 vs 10.4 +/- 1.7) and PCr/ATP (3.68 +/- .36 vs 4.07 +/- .27) resting ratios increased significantly (p =.008) after concentric-eccentric resistance training. P-max was significantly improved in the concentric-eccentric group (7.0 +/- 2.1W vs 8.4 +/- 1.8W: p

There is no generally effective therapy for mitochondrial myopathies.In this study, we measured responses to combined aerobic training and oral dichloroacetate (DCA) therapy in a 25-year-old woman with a mitochondrial myopathy caused by cytochrome oxidase deficiency. The patient trained for 14 weeks, and DCA therapy was begun after 8 weeks. Independent indices of aerobic capacity and oxidative metabolism showed substantial improvement. Venous lactate concentrations at rest, and after a constant amount of work, decreased by approximately 50% after 8 weeks of aerobic training, and by more than 70% with the combination of training and DCA treatment. Heart rate at rest and after a constant amount of submaximal work decreased progressively. Aerobic capacity on a graded submaximal exercise test improved by 71% from baseline by the end of the treatment period.31 P magnetic resonance spectroscopy measurements of rate constants for recovery of muscle phosphocreatine increased 1.7-fold and metabolically active adenine diphosphate increased 2.8-fold after 8 weeks of training alone, and 4.5-fold and 23.0-fold after 14 weeks of training plus DCA treatment. Responses to the SF-36 Health Survey suggested a marked reduction in handicap. Thus, in this open study of a patient with cytochrome oxidase deficiency, a combination of aerobic training and DCA treatment resulted in substantial improvements in biochemical indices, exercise performance, and handicap. We conclude that exercise limitation in patients with mitochondrial myopathy may arise from effects of chronic deconditioning in addition to the effects of primary mitochondrial dysfunction and may be partially reversed by training and administration of DCA.NEUROLOGY 1996;47: 529-534

In daily life, muscle fatigue often becomes noticeable as an apparent decline in the efficiency of force production by central commands, making it necessary to increase drive (or ''effort'') to produce a constant motor output. Such aspects of fatigue may be caused by changes in the way in which synaptic messages arriving at the motoneurons are translated into forces by the muscle fibers. Therefore, an understanding of these neuromuscular gradation mechanisms is essential for any analysis of motor fatigue. A brief general review is given of 1) how muscle fibers transduce motoneuronal discharge rates into force; 2) how synaptic currents are transduced into motoneuronal discharge rates; 3) how activity-dependent changes in the neuromuscular transduction mechanisms contribute to neuromuscular fatigue; and 4) how the matching between the transduction mechanisms of motoneurons and those of their muscle fibers may help to optimize neuromuscular gradation efficiency and decrease the severity of fatigue.

In daily life, muscle fatigue often becomes noticeable as an apparent decline in the efficiency of force production by central commands, making it necessary to increase drive (or ''effort'') to produce a constant motor output. Such aspects of fatigue may be caused by changes in the way in which synaptic messages arriving at the motoneurons are translated into forces by the muscle fibers. Therefore, an understanding of these neuromuscular gradation mechanisms is essential for any analysis of motor fatigue. A brief general review is given of 1) how muscle fibers transduce motoneuronal discharge rates into force; 2) how synaptic currents are transduced into motoneuronal discharge rates; 3) how activity-dependent changes in the neuromuscular transduction mechanisms contribute to neuromuscular fatigue; and 4) how the matching between the transduction mechanisms of motoneurons and those of their muscle fibers may help to optimize neuromuscular gradation efficiency and decrease the severity of fatigue.

How type I skeletal muscle inherently maintains high oxidative and vascular capacity in the absence of exercise is unclear. We show that nuclear receptor ERR gamma is highly expressed in type I muscle and, when transgenically expressed in anaerobic type II muscles (ERRGO mice), dually induces metabolic and vascular transformation in the absence of exercise. ERRGO mice show increased expression of genes promoting fat metabolism, mitochondrial respiration, and type I fiber specification. Muscles in ERRGO mice also display an activated angiogenic program marked by myofibrillar induction and secretion of proangiogenic factors, neovascularization, and a 100% increase in running endurance. Surprisingly, the induction of type I muscle properties by ERR gamma does not involve PGC-1 alpha. Instead, ERR gamma genetically activates the energy sensor AMPK in mediating the metabovascular changes in ERRGO mice. Therefore, ERR gamma represents a previously unrecognized determinant that specifies intrinsic vascular and oxidative metabolic features that distinguish type I from type II muscle.

We examined the effect of an acute bout of resistance exercise on fractional muscle protein synthesis rates in human type I and type II muscle fibres. After a standardised breakfast (31 ± 1 kJ kg(-1) body weight, consisting of 52 Energy% (En%) carbohydrate, 34 En% protein and 14 En% fat), 9 untrained men completed a lower-limb resistance exercise bout (8 sets of 10 repetitions leg press and leg extension at 70% 1RM). A primed, continuous infusion of L: -[ring-(13)C(6)]phenylalanine was combined with muscle biopsies collected from both legs immediately after exercise and after 6 h of post-exercise recovery. Single muscle fibres were dissected from freeze-dried biopsies and stained for ATPase activity with pre-incubation at a pH of 4.3. Type I and II fibres were separated under a light microscope and analysed for protein-bound L: -[ring-(13)C(6)]phenylalanine labelling. Baseline (post-exercise) L: -[ring-(13)C(6)]phenylalanine muscle tissue labelling, expressed as (∂(13)C/(12)C), averaged -32.09 ± 0.28, -32.53 ± 0.10 and -32.02 ± 0.16 in the type I and II muscle fibres and mixed muscle, respectively (P = 0.14). During post-exercise recovery, muscle protein synthesis rates were marginally (8 ± 2%) higher in the type I than type II muscle fibres, at 0.100 ± 0.005 versus 0.094 ± 0.005%/h, respectively (P 0.05), whereby rates of mixed muscle protein were 0.091 ± 0.005%/h. Muscle protein synthesis rates following resistance-type exercise are only marginally higher in type I compared with type II muscle fibres.

Diabetologia : organ of the European Association for the Study of Diabetes 59(5), 1040-1048 (2016). doi:10.1007/s00125-016-3865-z, Published by Springer, Berlin

Objective: Exercise is a cornerstone in the management of skeletal muscle insulin-resistance. A well-established benefit of a single bout of exercise is increased insulin sensitivity for hours post-exercise in the previously exercised musculature. Although rodent studies suggest that the insulin-sensitization phenomenon involves enhanced insulin-stimulated GLUT4 cell surface translocation and might involve intramuscular redistribution of GLUT4, the conservation to humans is unknown. Methods: Healthy young males underwent an insulin-sensitizing one-legged kicking exercise bout for 1 h followed by fatigue bouts to exhaustion. Muscle biopsies were obtained 4 h post-exercise before and after a 2-hour hyperinsulinemic-euglycemic clamp. Results: A detailed microscopy-based analysis of GLUT4 distribution within seven different myocellular compartments revealed that prior exercise increased GLUT4 localization in insulin-responsive storage vesicles and T-tubuli. Furthermore, insulin-stimulated GLUT4 localization was augmented at the sarcolemma and in the endosomal compartments. Conclusions: An intracellular redistribution of GLUT4 post-exercise is proposed as a molecular mechanism contributing to the insulin-sensitizing effect of prior exercise in human skeletal muscle. (C) 2020 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Physical activity increases muscle protein synthesis rates. However, the impact of exercise on the coordinated up- and/or downregulation of individual protein synthesis rates in skeletal muscle tissue remains unclear. The authors assessed the impact of exercise on mixed muscle, myofibrillar, and mitochondrial protein synthesis rates as well as individual protein synthesis rates in vivo in rats. Adult Lewis rats either remained sedentary (n = 3) or had access to a running wheel (n = 3) for the last 2 weeks of a 3-week experimental period. Deuterated water was injected and subsequently administered in drinking water over the experimental period. Blood and soleus muscle were collected and used to assess bulk mixed muscle, myofibrillar, and mitochondrial protein synthesis rates using gas chromatography–mass spectrometry and individual muscle protein synthesis rates using liquid chromatography–mass spectrometry (i.e., dynamic proteomic profiling). Wheel running resulted in greater myofibrillar (3.94 ± 0.26 vs. 3.03 ± 0.15%/day; p p p = .71) protein synthesis rates, when compared with the sedentary condition. Exercise impacted the synthesis rates of 80 proteins, with the difference from the sedentary condition ranging between −64% and +420%. Significantly greater synthesis rates were detected for F1-ATP synthase, ATP synthase subunit alpha, hemoglobin, myosin light chain-6, and synaptopodin-2 (p

Functional electrical stimulation (FES) is limited by the rapid onset of muscle fatigue caused by localized nerve excitation repeatedly activating only a subset of motor units. The purpose of this study was to investigate reducing fatigue by sequentially changing, pulse by pulse, the area of stimulation using multiple surface electrodes that cover the same area as one electrode during conventional stimulation. Paralyzed triceps surae muscles of an individual with complete spinal cord injury were stimulated, via the tibial nerve, through four active electrodes using spatially distributed sequential stimulation (SDSS) that was delivered by sending a stimulation pulse to each electrode one after another with 90 degrees phase shift between successive electrodes. For comparison, single electrode stimulation was delivered through one active electrode. For both modes of stimulation, the resultant frequency to the muscle as a whole was 40 Hz. Isometric ankle torque was measured during fatiguing stimulations lasting 2 min. Each mode of stimulation was delivered a total of six times over 12 separate days. Three fatigue measures were used for comparison: fatigue index (final torque normalized to maximum torque), fatigue time (time for torque to drop by 3 dB), and torque-time integral (over the entire trial). The measures were all higher during SDSS (P < 0.001), by 234, 280, and 171%, respectively. The results are an encouraging first step toward addressing muscle fatigue, which is one of the greatest problems for FES.

Mice deficient in α-sarcoglycan (Sgca-null mice) develop progressive muscular dystrophy and serve as a model for human limb girdle muscular dystrophy type 2D. Sgca-null mice suffer a more severe myopathy than that of mdx mice, the model for Duchenne muscular dystrophy. This is the opposite of what is observed in humans and the reason for this is unknown. In an attempt to understand the cellular basis of this severe muscular dystrophy, we isolated clonal populations of myogenic progenitor cells (MPCs), the resident postnatal muscle progenitors of dystrophic and wild-type mice. MPCs from Sgca-null mice generated much smaller clones than MPCs from wild-type or mdx dystrophic mice. Impaired proliferation of Sgca-null myogenic precursors was confirmed by single fiber analysis and this difference correlated with Sgca expression during MPC proliferation. In the absence of dystrophin and associated proteins, which are only expressed after differentiation, SGCA complexes with and stabilizes FGFR1. Deficiency of Sgca leads to an absence of FGFR1 expression at the membrane and impaired MPC proliferation in response to bFGF. The low proliferation rate of Sgca-null MPCs was rescued by transduction with Sgca-expressing lentiviral vectors. When transplanted into dystrophic muscle, Sgca-null MPCs exhibited reduced engraftment. The reduced proliferative ability of Sgca-null MPCs explains, at least in part, the severity of this muscular dystrophy and also why wild-type donor progenitor cells engraft efficiently and consequently ameliorate disease. Mice deficient in alpha-sarcoglycan (Sgca-null mice) develop progressive muscular dystrophy and serve as a model for human limb girdle muscular dystrophy type 2D. Sgca-null mice suffer a more severe myopathy than that of mdx mice, the model for Duchenne muscular dystrophy. This is the opposite of what is observed in humans and the reason for this is unknown. In an attempt to understand the cellular basis of this severe muscular dystrophy, we isolated clonal populations of myogenic progenitor cells (MPCs), the resident postnatal muscle progenitors of dystrophic and wild-type mice. MPCs from Sgca-null mice generated much smaller clones than MPCs from wild-type or mdx dystrophic mice. Impaired proliferation of Sgca-null myogenic precursors was confirmed by single fiber analysis and this difference correlated with Sgca expression during MPC proliferation. In the absence of dystrophin and associated proteins, which are only expressed after differentiation, SGCA complexes with and stabilizes FGFR1. Deficiency of Sgca leads to an absence of FGFR1 expression at the membrane and impaired MPC proliferation in response to bFGF. The low proliferation rate of Sgca-null MPCs was rescued by transduction with Sgca-expressing lentiviral vectors. When transplanted into dystrophic muscle, Sgca-null MPCs exhibited reduced engraftment. The reduced proliferative ability of Sgca-null MPCs explains, at least in part, the severity of this muscular dystrophy and also why wild-type donor progenitor cells engraft efficiently and consequently ameliorate disease. Funding This work was supported in part by FWO-Odysseus Program Grant No. G.0907.08; Research Council of the University of Leuven, Grant No. OT/09/053 and EME-C2161-GOA/11/012; Wicka Charity Funds, USA, Grant No. zkb8720; the Italian Ministry of University and Scientific Research Grant No. 2005067555_003, PRIN 2006-08, CARIPLO 2007.5639 and 2005.2008; EC FP7 CARE-MI No. 242038; and Optistem No. 223098. Acknowledgements We thank Gianpaolo Papaccio for critical discussion of the manuscript; K. P. Campbell for providing Sgca-null mice; Laura Perani, Rossana Tonlorenzi and Rudi Micheletti for technical assistance; Christina Vochten for professional secretarial service; Paolo Luban for a kind donation; Dr Shea Carter for manuscript editing; and Dr Maurizio Moggio (Bank of DNA, Cell Lines and Nerve-Muscle-Cardiac Tissues/Telethon Genetic BioBank Network, Ospedale Maggiore Policlinico Mangiagalli e Regina Elena, Milan, Italy) for providing the LGMD2D sample

OBJECTIVE Sirtuin 1 (SIRT1) is implicated in the regulation of mitochondrial function, energy metabolism, and insulin sensitivity in rodents. No studies are available in humans to demonstrate that SIRT1 expression in insulin-sensitive tissues is associated with energy expenditure and insulin sensitivity. RESEARCH DESIGN AND METHODS Energy expenditure (EE), insulin sensitivity, and SIRT1 mRNA adipose tissue expression (n = 81) were measured by indirect calorimetry, hyperinsulinemic-euglycemic clamp, and quantitative RT-PCR in 247 nondiabetic offspring of type 2 diabetic patients. RESULTS High EE during the clamp (r = 0.375, P = 2.8 × 10−9) and high ΔEE (EE during the clamp − EE in the fasting state) (r = 0.602, P = 2.5 × 10−24) were associated with high insulin sensitivity. Adipose tissue SIRT1 mRNA expression was significantly associated with EE (r = 0.289, P = 0.010) and with insulin sensitivity (r = 0.334, P = 0.002) during hyperinsulinemic-euglycemic clamp. Furthermore, SIRT1 mRNA expression correlated significantly with the expression of several genes regulating mitochondrial function and energy metabolism (e.g., peroxisome proliferator–activated receptor γ coactivator-1β, estrogen-related receptor α, nuclear respiratory factor-1, and mitochondrial transcription factor A), and with several genes of the respiratory chain (e.g., including NADH dehydrogenase [ubiquinone] 1α subcomplex 2, cytochrome c, cytochrome c oxidase subunit IV, and ATP synthase). CONCLUSIONS Impaired stimulation of EE by insulin and low SIRT1 expression in insulin-sensitive tissues is likely to reflect impaired regulation of mitochondrial function associated with insulin resistance in humans.

Background A blunted muscle protein synthetic response to protein ingestion may contribute to the age related loss of muscle tissue. We hypothesized that the greater endogenous insulin release following co-ingestion of carbohydrate facilitates post-prandial muscle protein accretion after ingesting a meal-like bolus of protein in older males. Methods Twenty-four healthy older men (75±1 y) were randomly assigned to ingest 20 g intrinsically L-[1-13C] phenylalanine-labeled casein protein with (PRO-CHO) or without (PRO) 40 g carbohydrate. Ingestion of specifically produced intrinsically L-[1-13C] phenylalanine labeled protein allowed us to assess post-prandial incorporation of dietary protein derived amino acids into muscle protein. Blood samples were collected at regular intervals, with muscle biopsies being obtained prior to and 2 and 6 h after protein ingestion. Results Plasma glucose and insulin concentrations showed a greater increase in PRO-CHO compared with PRO (P13C] phenylalanine enrichments tended to increase to a greater extent in PRO-CHO compared with PRO during the first 2 h after protein ingestion (0.0072±0.0013 vs 0.0046±0.010 MPE, respectively; P=0.13). However, 6 h after protein ingestion, differences in muscle protein-bound L-[1-13C] phenylalanine enrichments were no longer observed between experiments (0.0213±0.0024 vs 0.0185±0.0010 MPE, respectively; P=0.30). Conclusions This study shows that carbohydrate ingestion may accelerate, but does not further augment post-prandial incorporation of dietary protein derived amino acids into muscle protein in healthy elderly men.