Exercise-induced mitochondrial biogenesis in skeletal muscle

Abstract

Endurance exercise has a number of health benefits, including improvements in muscle metabolism, cardiovascular function, and increased exercise tolerance. The increase in endurance is a result of greater oxygen delivery and extraction by the exercising muscle. Oxygen extraction is a result of an improved capillary-to-fiber ratio, as well as a higher mitochondrial content within muscle. The increase in mitochondrial content is a well-established adaptation within the exercised muscle, but the molecular mechanisms underlying this change in muscle phenotype still remains to be clarified. An understanding of the cellular processes involved could help in the development of therapeutic applications other than exercise, and may help us better comprehend the pathology of mitochondrial diseases. This increase in mitochondrial content which occurs as a result of regular exercise is referred to as mitochondrial biogenesis. The process is complex because mitochondria are composed of proteins encoded by both nuclear and mitochondrial DNA (mtDNA). The major steps involved include: (1) signaling events leading to transcription, brought about by each exercise bout, (2) transcriptional regulation of nuclear genes encoding mitochondrial proteins, mainly mediated by the coactivator PGC-1α, (3) control of mitochondrial DNA gene expression by the transcription factor Tfam, (4) import of nuclear-derived gene products into the mitochondrion via the protein import machinery, and (5) assembly of nuclear- and mitochondrially-encoded subunits into functional holoenzyme complexes. A summary of these steps is provided in Fig. 1. Exercise can modify the rates of several of the steps leading to mitochondrial biogenesis, thus establishing exercise as an extremely useful model for understanding the underlying mechanisms involved in organelle synthesis. In this paper we summarize our current understanding of the fundamental mechanisms of mitochondrial biogenesis in muscle during exercise.