Metabolic stresses such as dietary energy restriction or physical activity exert beneficial metabolic effects. In the liver, endospanin-1 and endospanin-2 cooperatively modulate calorie restriction–mediated (CR-mediated) liver adaptations by controlling growth hormone sensitivity. Since we found CR to induce endospanin protein expression in skeletal muscle, we investigated their role in this tissue. In vivo and in vitro endospanin-2 triggers ERK phosphorylation in skeletal muscle through an autophagy-dependent pathway. Furthermore, endospanin-2, but not endospanin-1, overexpression decreases muscle mitochondrial ROS production, induces fast-to-slow fiber-type switch, increases skeletal muscle glycogen content, and improves glucose homeostasis, ultimately promoting running endurance capacity. In line, endospanin-2–/– mice display higher lipid peroxidation levels, increased mitochondrial ROS production under mitochondrial stress, decreased ERK phosphorylation, and reduced endurance capacity. In conclusion, our results identify endospanin-2 as a potentially novel player in skeletal muscle metabolism, plasticity, and function.
Steve Lancel, Matthijs K.C. Hesselink, Estelle Woldt, Yves Rouillé, Emilie Dorchies, Stephane Delhaye, Christian Duhem, Quentin Thorel, Alicia Mayeuf-Louchart, Benoit Pourcet, Valérie Montel, Gert Schaart, Nicolas Beton, Florence Picquet, Olivier Briand, Jean Pierre Salles, Hélène Duez, Patrick Schrauwen, Bruno Bastide, Bernard Bailleul, Bart Staels, Yasmine Sebti