Muscle PGC-1α is required for long-term systemic and local adaptations to a ketogenic diet in mice.

Low-carbohydrate/high-fat (LCHF) diets are increasingly popular dietary interventions for body weight control and as treatment for different pathological conditions. However, the mechanisms of action are still poorly understood, in particular, in long-term administration. Besides liver, brain, and heart, skeletal muscle is one of the major organs involved in the regulation of physiological and pathophysiological ketosis. We assessed the role of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in skeletal muscle of male wild-type control and PGC-1α muscle-specific knockout mice upon 12 wk of LCHF diet feeding. Interestingly, LCHF diet administration increased oxygen consumption in a muscle PGC-1α-dependent manner, concomitant with a blunted transcriptional induction of genes involved in fatty acid oxidation and impairment in exercise performance. These data reveal a new role for muscle PGC-1α in regulating the physiological adaptation to long-term LCHF diet administration.