Sarcopenia, the degenerative loss of skeletal muscle mass, quality and strength, lacks early diagnostic tools and new therapeutic strategies to prevent the frailty-to-disability transition often responsible for the medical institutionalization of elderly individuals. Herein we report that production of the endogenous peptide apelin, induced by muscle contraction, is reduced in an age-dependent manner in humans and rodents and is positively associated with the beneficial effects of exercise in older persons. Mice deficient in either apelin or its receptor (APLNR) presented dramatic alterations in muscle function with increasing age. Various strategies that restored apelin signaling during aging further demonstrated that this peptide considerably enhanced muscle function by triggering mitochondriogenesis, autophagy and anti-inflammatory pathways in myofibers as well as enhancing the regenerative capacity by targeting muscle stem cells. Taken together, these findings revealed positive regulatory feedback between physical activity, apelin and muscle function and identified apelin both as a tool for diagnosis of early sarcopenia and as the target of an innovative pharmacological strategy to prevent age-associated muscle weakness and restore physical autonomy.

Microgravity and hypoactivity are associated with skeletal muscle deconditioning. The decrease of muscle mass follows an exponential decay, with major changes in the first days. The purpose of the study was to dissect out the effects of a short-term 3-day dry immersion (DI) on human quadriceps muscle function and structure. The DI model, by suppressing all support zones, accurately reproduces the effects of microgravity. Twelve healthy volunteers (32 ± 5 years) completed 3 days of DI. Muscle function was investigated through maximal voluntary contraction (MVC) tests and muscle viscoelasticity. Structural experiments were performed using MRI analysis and invasive experiments on muscle fibres. Our results indicated a significant 9.1% decrease of the normalized MVC constant (P = 0.048). Contraction and relaxation modelization kinetics reported modifications related to torque generation (k = -29%; P = 0.014) and to the relaxation phase (k = +34%; P = 0.040) after 3 days of DI. Muscle viscoelasticity was also altered. From day one, rectus femoris stiffness and tone decreased by, respectively, 7.3% (P = 0.002) and 10.2% (P = 0.002), and rectus femoris elasticity decreased by 31.5% (P = 0.004) after 3 days of DI. At the cellular level, 3 days of DI translated into a significant atrophy of type I muscle fibres (-10.6 ± 12.1%, P = 0.027) and an increased proportion of hybrid, type I/IIX fibre co-expression. Finally, we report an increase (6-fold; P = 0.002) in NCAM+ muscle fibres, showing an early denervation process. This study is the first to report experiments performed in Europe investigating human short-term DI-induced muscle adaptations, and contributes to deciphering the early changes and biomarkers of skeletal muscle deconditioning.

A population of fibro/adipogenic but non-myogenic progenitors located between skeletal muscle fibers was recently discovered. The aim of this study was to determine the extent to which these progenitors differentiate into fully functional adipocytes. The characterization of muscle progenitor-derived adipocytes is a central issue in understanding muscle homeostasis. They are considered as being the cellular origin of intermuscular adipose tissue that develops in several pathophysiological situations. Here fibro/adipogenic progenitors were isolated from a panel of 15 human muscle biopsies on the basis of the specific cell-surface immunophenotype CD15+/PDGFRα+CD56−. This allowed investigations of their differentiation into adipocytes and the cellular functions of terminally differentiated adipocytes. Adipogenic differentiation was found to be regulated by the same effectors as those regulating differentiation of progenitors derived from white subcutaneous adipose tissue. Similarly, basic adipocyte functions, such as triglyceride synthesis and lipolysis occurred at levels similar to those observed with subcutaneous adipose tissue progenitor-derived adipocytes. However, muscle progenitor-derived adipocytes were found to be insensitive to insulin-induced glucose uptake, in association with the impairment of phosphorylation of key insulin-signaling effectors. Our findings indicate that muscle adipogenic progenitors give rise to bona fide white adipocytes that have the unexpected feature of being insulin-resistant.

1OBJECTIVE-Obesity and diabetes are characterized by the incapacity to use fat as fuel. We hypothesized that this reduced fat oxidation is secondary to a sedentary lifestyle. RESEARCH DESIGN AND METHODS-We investigated the effect of a 2-month bed rest on the dietary oleate and palmitate trafficking in lean women (control group, n ϭ 8) and the effect of concomitant resistance/aerobic exercise training as a countermeasure (exercise group, n ϭ 8). Trafficking of stable isotope-labeled dietary fats was combined with muscle gene expression and magnetic resonance imaging-derived muscle fat content analyses. 31 ]palmitate oxidation by Ϫ8.2 Ϯ 4.9% (P Ͻ 0.0001). Despite a decreased spontaneous energy intake and a reduction of 1.9 Ϯ 0.3 kg (P ϭ 0.001) in fat mass, exercise training did not mitigate these alterations but partially maintained fat-free mass, insulin sensitivity, and total lipid oxidation in fasting and fed states. In both groups, muscle fat content increased by 2.7% after bed rest and negatively correlated with the reduction in [d 31 ]palmitate oxidation (r 2 ϭ 0.48, P ϭ 0.003). I n our search of the environmental factors that fuelled the pandemic of obesity, we face a paradox. Although sedentary lifestyle has been highlighted for decades as one of the main factors triggering weight gain, the physiology of physical inactivity has received little attention (1). Clearly, the causal relationships between sedentary behaviors and obesity are essentially based on epidemiological studies or on the indirect beneficial effects of exercise training (2). None of these studies provide evidence to support a cause-and-effect relationship. RESULTS-In CONCLUSIONS-WhileObesity is a fat storage disease characterized by insulin resistance and a decreased capacity to oxidize lipids (3) in fasting (4) and postprandial (5) conditions. Because weight reduction was not associated with improvement in fat utilization (6), it was suggested as a primary impairment in the etiology of obesity, rather than an adaptive response. Consequently, the delineation of the causes responsible for this reduced capacity to oxidize fat appears to be a fundamental prerequisite to develop efficient strategies against obesity.We previously extended the early Mayer hypothesis (7) and hypothesized that the decreased fat oxidation observed in obese and postobese subjects is due to the generalized adoption of sedentary behaviors (8). Using strict bed rest as a model, we showed that physical inactivity, per se (i.e., independent of the known physical inactivity-induced energy balance changes), lowers fasting and postprandial fat oxidation (9). Unexpectedly, whereas monounsaturated dietary fat (oleate) oxidation remained unaffected by bed rest, saturated fat (palmitate) oxidation decreased by 11% (9). These results are interesting when considering the north/south gradient in obesity prevalence in France that was not associated with the overall energy intake but in the greater amount of saturated fat in the diet (10).The main objective of our present study wa...