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Endurance exercise, when performed regularly as part of a training program, leads to increases in whole-body and skeletal muscle-specific oxidative capacity. At the cellular level, this adaptive response is manifested by an increased number of oxidative fibers (Type I and IIA myosin heavy chain), an increase in capillarity and an increase in mitochondrial biogenesis. The increase in mitochondrial biogenesis (increased volume and functional capacity) is fundamentally important as it leads to greater rates of oxidative phosphorylation and an improved capacity to utilize fatty acids during sub-maximal exercise. Given the importance of mitochondrial biogenesis for skeletal muscle performance, considerable attention has been given to understanding the molecular cues stimulated by endurance exercise that culminate in this adaptive response. In turn, this research has led to the identification of pharmaceutical compounds and small nutritional bioactive ingredients that appear able to amplify exercise-responsive signaling pathways in skeletal muscle. The aim of this review is to discuss these purported exercise mimetics and bioactive ingredients in the context of mitochondrial biogenesis in skeletal muscle. We will examine proposed modes of action, discuss evidence of application in skeletal muscle in vivo and finally comment on the feasibility of such approaches to support endurance-training applications in humans.

Performing exercise in a glycogen depleted state increases skeletal muscle lipid utilization and the transcription of genes regulating mitochondrial β-oxidation. Potential candidates for glycogen-mediated metabolic adaptation are the peroxisome proliferator activated receptor (PPAR) coactivator-1α (PGC-1α) and the transcription factor/nuclear receptor PPAR-∂. It was therefore the aim of the present study to examine whether acute exercise with or without glycogen manipulation affects PGC-1α and PPAR-∂ function in rodent skeletal muscle. Twenty female Wistar rats were randomly assigned to 5 experimental groups (n = 4): control [CON]; normal glycogen control [NG-C]; normal glycogen exercise [NG-E]; low glycogen control [LG-C]; and low glycogen exercise [LG-E]). Gastrocnemius (GTN) muscles were collected immediately following exercise and analyzed for glycogen content, PPAR-∂ activity via chromatin immunoprecipitation (ChIP) assays, AMPK α1/α2 kinase activity, and the localization of AMPK and PGC-1α. Exercise reduced muscle glycogen by 47 and 75% relative to CON in the NG-E and LG-E groups, respectively. Exercise that started with low glycogen (LG-E) finished with higher AMPK-α2 activity (147%, p

The transcriptional coactivator PGC-1α is a potent regulator of skeletal muscle metabolism. Less is known about the structurally similar PGC-1α-related coactivator (PRC) that is enriched in myoblasts and adult skeletal muscle. The present study was designed to determine the effect of PRC on the metabolic profile of C2C12 myotubes. Overexpression of full-length PRC increased PRC gene expression by 2.7 ± 0.3-fold and protein content by 108 ± 5.3%. This modest elevation in PRC resulted in an increased rate of myoblast proliferation (61.5 ± 2.7%) and resulted in myotubes characterized by increased MyoD (18.2 ± 0.52%) and myosin heavy chain (15.4 ± 3.13%) protein. PRC overexpressing myotubes showed increases in mRNA for some-COX4 (2.6 ± 0.18-fold), ATP5B (2.7 ± 0.34-fold) cytochrome c (5.1 ± 0.68-fold)-but not all, MTCO1 (0.61 ± 0.18-fold) and HAD (0.98 ± 0.36-fold) mitochondrial genes, as well as a significant increase in cytochrome-c (28.7 ± 7.02%) protein content. The enzyme activity of the electron transport chain (ETC) complex IV (3.7 ± 0.01-fold) and citrate synthase (2.1 ± 0.14-fold) was increased by PRC, as was the mtDNA:nucDNA ratio (11 ± 0.3%). PRC increased cellular respiration (142%), basal (197%) and insulin-stimulated (253%) glucose uptake, as well as palmitate uptake (28.6 ± 3.31%) and oxidation (31.1 ± 2.17%). Associated with these changes in function, PRC overexpression increased GLUT4 mRNA (4.5 ± 0.22-fold) and protein (13.8 ± 2.08%) and CPT1 protein (28.9 ± 4.23%). Electrical stimulation of C2C12 myotubes resulted in a transient increase in PRC mRNA that was smaller (2.1 ± 0.3-fold vs. 4.4 ± 0.23-fold) and occurred earlier (3 h vs. 6 h) than PGC-1α. Collectively, our data show that PRC promotes skeletal muscle myogenesis and metabolism in vitro, thus identifying PRC as a functional skeletal muscle coactivator capable of regulating mitochondrial substrate utilization and respiration.