A PGC-1α Isoform Induced by Resistance Training Regulates Skeletal Muscle Hypertrophy

PGC-1 alpha is a transcriptional coactivator induced by exercise that gives muscle many of the best known adaptations to endurance-type exercise but has no effects on muscle strength or hypertrophy. We have identified a form of PGC-1 alpha (PGC-1 alpha 4) that results from alternative promoter usage and splicing of the primary transcript. PGC-1 alpha 4 is highly expressed in exercised muscle but does not regulate most known PGC-1 alpha targets such as the mitochondrial OXPHOS genes. Rather, it specifically induces IGF1 and represses myostatin, and expression of PGC-1 alpha 4 in vitro and in vivo induces robust skeletal muscle hypertrophy. Importantly, mice with skeletal muscle-specific transgenic expression of PGC-1 alpha 4 show increased muscle mass and strength and dramatic resistance to the muscle wasting of cancer cachexia. Expression of PGC-1 alpha 4 is preferentially induced in mouse and human muscle during resistance exercise. These studies identify a PGC-1 alpha protein that regulates and coordinates factors involved in skeletal muscle hypertrophy.