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New findings What is the central question of this study? What are the initial metabolic and molecular events that underpin bed rest-induced skeletal muscle deconditioning, and what is the contribution of energy balance? What is the main finding and its importance? A single day of bed rest, irrespective of energy balance, did not lead to overt changes in skeletal muscle gene expression or insulin sensitivity. More than 1 day of physical inactivity is required to observe the insulin resistance and robust skeletal muscle transcriptional responses associated with bed rest and consequent alterations in energy balance. Abstract The initial metabolic and molecular events that underpin disuse-induced skeletal muscle deconditioning, and the contribution of energy balance, remain to be investigated. Ten young, healthy men (age 25 ± 1 years; body mass index 25.3 ± 0.8 kg·m-2 ) underwent three 24 h laboratory-based experimental periods in a randomized, crossover manner: (i) controlled habitual physical activity with an energy-balanced diet (CON); (ii) strict bed rest with a diet to maintain energy balance (BR-B); and (iii) strict bed rest with a diet identical to CON, consequently resulting in positive energy balance. Continuous glucose monitoring was performed throughout each visit, with vastus lateralis muscle biopsies and an oral glucose tolerance test performed before and after. In parallel with muscle samples collected from a previous 7 day bed rest study, biopsies were used to examine the expression of genes associated with the regulation of muscle mass and insulin sensitivity. A single day of bed rest, irrespective of energy balance, did not lead to overt changes in whole-body substrate oxidation, indices of insulin sensitivity [i.e. homeostatic model assessment of insulin resistance, BR-B from 2.7 ± 1.7 to 3.1 ± 1.5 (P > 0.05) and Matsuda index, BR-B from 5.9 ± 3.3 to 5.2 ± 2.9 (P > 0.05)] or 24 h glycaemic control/variability compared with CON. Seven days of bed rest led to ∼30-55% lower expression of genes involved in insulin signalling, lipid storage/oxidation and muscle protein breakdown, whereas no such changes were observed after 1 day of bed rest. In conclusion, more than a single day of physical inactivity is required to observe the insulin resistance and robust skeletal muscle transcriptional responses associated with bed rest and consequent alterations in energy balance.

IntroductionPhysical inactivity significantly contributes to loss of muscle mass and performance in bed-bound patients. Loss of skeletal muscle mitochondrial content has been well-established in muscle unloading models, but the underlying molecular mechanism remains unclear. We hypothesized that apparent unloading-induced loss of muscle mitochondrial content is preceded by increased mitophagy- and decreased mitochondrial biogenesis-signaling during the early stages of unloading.MethodsWe analyzed a comprehensive set of molecular markers involved in mitochondrial-autophagy, -biogenesis, -dynamics, and -content, in the gastrocnemius muscle of C57BL/6J mice subjected to 0- and 3-days hind limb suspension, and in biopsies from human vastus lateralis muscle obtained before and after 7days of one-leg immobilization.ResultsIn both mice and men, short-term skeletal muscle unloading results in molecular marker patterns indicative of increased receptor-mediated mitophagy and decreased mitochondrial biogenesis regulation, before apparent loss of mitochondrial content.DiscussionThese results emphasize the early-onset of skeletal muscle disuse-induced mitochondrial remodeling.

Skeletal muscle regeneration after disuse is essential for muscle maintenance and involves the regulation of both mass- and metabolic plasticity-related processes. However, the relation between these processes during recovery from disuse remains unclear. In this study, we explored the potential interrelationship between the molecular regulation of muscle mass and oxidative metabolism during recovery from disuse. Molecular profiles were measured in biopsies from the vastus lateralis of healthy men after 1-leg cast immobilization and after 1 wk reloading, and in mouse gastrocnemius obtained before and after hindlimb suspension and during reloading (RL-1, -2, -3, -5, and -8 d). Cluster analysis of the human recovery response revealed correlations between myogenesis and autophagy markers in 2 clusters, which were distinguished by the presence of markers of early myogenesis, autophagosome formation, and mitochondrial turnover vs. markers of late myogenesis, autophagy initiation, and mitochondrial mass. In line with these findings, an early transient increase in B-cell lymphoma-2 interacting protein-3 and sequestosome-1 protein, and GABA type A receptor-associated protein like-1 protein and mRNA and a late increase in myomaker and myosin heavy chain-8 mRNA, microtubule-associated protein 1 light chain 3-II:I ratio, and FUN14 domain-containing-1 mRNA and protein were observed in mice. In summary, the regulatory profiles of protein, mitochondrial, and myonuclear turnover are correlated and temporally associated, suggesting a coordinated regulation of muscle mass- and oxidative metabolism-related processes during recovery from disuse.Kneppers, A., Leermakers, P., Pansters, N., Backx, E., Gosker, H., van Loon, L., Schols, A., Langen, R., Verdijk, L. Coordinated regulation of skeletal muscle mass and metabolic plasticity during recovery from disuse.

BackgroundA few days of bed rest or immobilization following injury, disease, or surgery can lead to considerable loss of skeletal muscle mass and strength. It has been speculated that such short, successive periods of muscle disuse may be largely responsible for the age-related loss of muscle mass throughout the lifespan.ObjectiveTo assess whether a single intramuscular injection of nandrolone decanoate prior to immobilization can attenuate the loss of muscle mass and strength in vivo in humans.Design, setting and participantsThirty healthy (22 +/- 1 years) men were subjected to 7 days of one-legged knee immobilization by means of a full leg cast with (NAD, n = 15) or without (CON, n = 15) prior intramuscular nandrolone decanoate injection (200 mg).MeasuresBefore and immediately after immobilization, quadriceps muscle cross-sectional area (CSA) (by means of single-slice computed tomography (CT) scans of the upper leg) and one-legged knee extension strength (one-repetition maximum [1-RM]) were assessed for both legs. Furthermore, muscle biopsies from the immobilized leg were taken before and after immobilization to assess type I and type II muscle fiber cross-sectional area.ResultsQuadriceps muscle CSA decreased during immobilization in both CON and NAD (-6 +/- 1% and -6 +/- 1%, respectively; main effect of time PConclusionsThis is the first study to report that nandrolone decanoate administration does not preserve skeletal muscle mass and strength during a short period of leg immobilization in vivo in humans.