Increasing mitochondrial muscle fatty acid oxidation induces skeletal muscle remodeling toward an oxidative phenotype

ABSTRACT Adult skeletal muscle is a dynamic, remarkably plastic tissue, which allows myofibers to switch from fast/glycolytic to slow/oxidative types and to increase mitochondrial fatty acid oxidation (mFAO) capacity and vascularization in response to exercise training. mFAO is the main muscle energy source during endurance exercise, with carnitine palmitoyltransferase 1 (CPT1) being the key regulatory enzyme. Whether increasing muscle mFAO affects skeletal muscle physiology in adulthood actually remains unknown. To investigate this, we used in vivo electrotransfer technology to express in mouse tibialis anterior (TA), a fast/glycolytic muscle, a mutated CPT1 form (CPT1mt) that is active but insensitive to malonyl‐CoA, its physiologic inhibitor. In young (2‐mo‐old) adult mice, muscle CPT1mt expression enhanced mFAO (+40%), but also increased the percentage of oxidative fibers (+28%), glycogen content, and capillary‐to‐fiber density (+45%). This CPT1mt‐induced muscle remodeling, which mimicked exercise‐induced oxidative phenotype, led to a greater resistance to muscle fatigue. In the context of aging, characterized by sarcopenia and reduced oxidative capacity, CPT1mt expression in TAs from aged (20‐mo‐old) mice partially reversed aging‐associated sarcopenia and fiber‐type transition, and increased muscle capillarity. These findings provide evidence that mFAO regulates muscle phenotype and may be a potential target to combat age‐related decline in muscle function.—Hénique, C., Mansouri, A., Vavrova, E., Lenoir, V., Ferry, A., Esnous, C., Ramond, E., Girard, J., Bouillaud, F., Prip‐Buus, C., Cohen, I. Increasing mitochondrial muscle fatty acid oxidation induces skeletal muscle remodeling toward an oxidative phenotype. FASEB J. 29, 2473‐2483 (2015). www.fasebj.org