Intercellular: local and systemic actions of skeletal muscle PGC-1s

• PGC-1 coactivators mediate many of the known effects of exercise in skeletal muscle.
• PGC-1s improve skeletal muscle mass, energy metabolism, and neuromuscular function.
• Skeletal muscle PGC-1s elicit integrated systemic adaptations to physiological cues.
• PGC-1s are promising therapeutic targets for muscular, metabolic, and psychiatric diseases.

Physical exercise promotes complex adaptations in skeletal muscle that benefit various aspects of human health. Many of these adaptations are coordinated at the gene expression level by the concerted action of transcriptional regulators. Peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1 (PGC-1) proteins play a prominent role in skeletal muscle transcriptional reprogramming induced by numerous stimuli. PGC-1s are master coactivators that orchestrate broad gene programs to modulate fuel supply and mitochondrial function, thus improving cellular energy metabolism. Recent studies unveiled novel biological functions for PGC-1s that extend well beyond skeletal muscle bioenergetics. Here we review recent advances in our understanding of PGC-1 actions in skeletal muscle, with special focus on their systemic effects.