Looking beyond PGC-1α: emerging regulators of exercise-induced skeletal muscle mitochondrial biogenesis and their activation by dietary compounds.

Despite its widespread acceptance as the "master regulator" of mitochondrial biogenesis (i.e., the expansion of the mitochondrial reticulum), peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1 alpha (PGC-1α) appears to be dispensable for the training-induced augmentation of skeletal muscle mitochondrial content and respiratory function. In fact, a number of regulatory proteins have emerged as important players in skeletal muscle mitochondrial biogenesis and many of these proteins share key attributes with PGC-1α. In an effort to move past the simplistic notion of a "master regulator" of mitochondrial biogenesis, we highlight the regulatory mechanisms by which nuclear factor erythroid 2-related factor 2 (Nrf2), estrogen-related receptor gamma (ERRγ), PPARβ, and leucine-rich pentatricopeptide repeat-containing protein (LRP130) may contribute to the control of skeletal muscle mitochondrial biogenesis. We also present evidence supporting/refuting the ability of sulforaphane, quercetin, and epicatechin to promote skeletal muscle mitochondrial biogenesis and their potential to augment mitochondrial training adaptations. Targeted activation of specific pathways by these compounds may allow for greater mechanistic insight into the molecular pathways controlling mitochondrial biogenesis in human skeletal muscle. Dietary activation of mitochondrial biogenesis may also be useful in clinical populations with basal reductions in mitochondrial protein content, enzyme activities, and/or respiratory function as well as individuals who exhibit a blunted skeletal muscle responsiveness to contractile activity. Novelty The existence of redundant pathways leading to mitochondrial biogenesis refutes the simplistic notion of a "master regulator" of mitochondrial biogenesis. Dietary activation of specific pathways may provide greater mechanistic insight into the exercise-induced mitochondrial biogenesis in human skeletal muscle.