Résumé :
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Skeletal muscles generate locomotor force and heat, and play an important metabolic role in mammals. They are composed of myofibers exhibiting distinct contractile and metabolic properties, and display a remarkable adaptation to functional and metabolic demands. Sedentariness induces a decrease of muscle oxidative capacities, and muscle fiber type switching towards lower oxidative capacity has been shown to promote obesity and type 2 diabetes. In contrast, endurance exercise induces a muscle fiber type switching from fast-glycolytic ti slow-oxidative, while caloric restriction retards age-related reduction of muscle oxidative capacity. The three members of the p160 transcriptional co-regulators [the steroid receptor co-activator 1 (SRC-1, also called NcoA-1), the transcriptional intermediary factor 2 (TIF2, also referred as SRC-2, GRIP1 or NcoA2), and SRC3 (also called p/CIP, AIB1, ACTR, RAC3 and TRAM-1)] are expressed in skeletal muscle. It has been proposed that TIF2 potentiates differentiation of cultured C2C12 myoblasts into myotubes through enhancement of myocyte enhancer factor (MEF)-2C mediated transactivation, even though it corepresses transcription mediated by the myogenic transactivator Myo-D. To investigate the in vivo function of TIF2 in skeletal muscles, we have generated TIF2(i)skm/- mice, in which TIF2 was selectively ablated in skeletal muscle myofibers at adulthood. Studies of these mice have revealed that increased energy expenditure was generated by SRC-1 dependent enhanced skeletal muscle mitochondrial uncoupling. As a consequence, sedentariness-induced adverse effects, such as reduced muscle oxidative capacities and type 2 diabetes, as well as high caloric diet-induced obesity, were attenuated in TIF2(i)skm-/- mice. Thus, TIF2 has highly beneficial effects in mammals living in the wilderness, where food supply is limiting and energy demands are high. In contrast, under sedentary conditions and food excess, two characteristics of industrialized societies, TIF2-induced optimized energy production in skeletal muscle myofibers promotes a slow/oxidative to fast/glycolytic fiber type switching, leading to type 2 diabetes and the development of obesity, and thus becomes detrimental for health. Lowering metabolic efficiency by decreasing TIF2 activity or increasing SRC-1 activity in skeletal muscles represents an attractive strategy to counteract Western lifestyle-induced metabolic disorders, such as obesity and diabetes, even though endurance exercise will be impaired.
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