Mechanisms of Exercise‐Induced Mitochondrial Biogenesis in Skeletal Muscle: Implications for Health and Disease

Abstract

Mitochondria have paradoxical functions within cells. Essential providers of energy for cellular survival, they are also harbingers of cell death (apoptosis). Mitochondria exhibit remarkable dynamics, undergoing fission, fusion, and reticular expansion. Both nuclear and mitochondrial DNA (mtDNA) encode vital sets of proteins which, when incorporated into the inner mitochondrial membrane, provide electron transport capacity for ATP production, and when mutated lead to a broad spectrum of diseases. Acute exercise can activate a set of signaling cascades in skeletal muscle, leading to the activation of the gene expression pathway, from transcription, to post-translational modifications. Research has begun to unravel the important signals and their protein targets that trigger the onset of mitochondrial adaptations to exercise. Exercise training leads to an accumulation of nuclear- and mtDNA-encoded proteins that assemble into functional complexes devoted to mitochondrial respiration, reactive oxygen species (ROS) production, the import of proteins and metabolites, or apoptosis. This process of biogenesis has important consequences for metabolic health, the oxidative capacity of muscle, and whole body fitness. In contrast, the chronic muscle disuse that accompanies aging or muscle wasting diseases provokes a decline in mitochondrial content and function, which elicits excessive ROS formation and apoptotic signaling. Research continues to seek the molecular underpinnings of how regular exercise can be used to attenuate these decrements in organelle function, maintain skeletal muscle health, and improve quality of life.

Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits

“…Mitochondrial Response to PA as an Example Dating back to the seminal work of Holloszy, who first observed that skeletal muscle from treadmill-trained rats express higher levels of mitochondrial proteins (Holloszy, 1967), molecular and functional remodeling of muscle mitochondria has remained a focal point of exercise research. Exercise training activates mitochondrial biogenesis in skeletal muscle, augmenting overall mitochondrial density and oxidative phosphorylation capacity by as much as 2-fold (Hood et al, 2011). Moreover, PA affects mitochondrial quality as well as quantity, and recent studies suggest that the functional properties of these organelles are much more heterogeneous and dynamic in nature than previously appreciated (Jacobs and Lundby, 2013).…”

“…Interestingly, PA-induced mitochondrial biogenesis also occurs in tissues other than skeletal muscle, including brain Steiner et al, 2011), liver (Boveris and Navarro, 2008;E et al, 2013;Navarro et al, 2004), adipose tissue (Laye et al, 2009;Sutherland et al, 2009), and kidney (Navarro et al, 2004), providing evidence that exercise also increases metabolic demand in these tissues and/or stimulates inter-organ crosstalk. At the cellular level, alterations in energy charge (ATP/ADP ratio), intracellular Ca 2+ , reactive oxygen species, and redox state have all been implicated as retrograde signals coordinating the induction of nuclear-and mitochondrialencoded genes needed for mitochondrial biogenesis (Hood et al, 2011). Over time, the increase in mitochondrial density, coupled with increased capacity of the heart and augmented blood flow, lessen the metabolic disturbance to homeostasis induced by each bout of PA, increasing the efficiency of energy utilization and enhancing the overall endurance capacity.…”

Molecular Basis of Exercise-Induced Skeletal Muscle Mitochondrial Biogenesis: Historical Advances, Current Knowledge, and Future Challenges

“…Although considerable work has shown that additional regulation of mitochondrial biogenesis exists at the level of protein import into mitochondria following muscle contraction in rodents (Joseph et al 2010;Hood et al 2011), less attention has focused on posttranscriptional control at the level of protein translation or mRNA stability. Recent results suggest mRNA stability decreases with muscle contraction or exercise in rodents (Lai et al 2010) along with increased mRNA-destabilizing proteins (Lai et al 2010;Matravadia et al 2013) and possibly with mRNA-stabilizing proteins (Lai et al 2010).…”

“…This review will present a brief historical overview of some of the seminal discoveries that have helped unravel the cellular events that underpin mitochondrial biogenesis as well as the more recent explosion of research into our current understanding of the signaling and genomic mechanisms regulating this process. We will focus on major breakthroughs in this area and for more detailed discussion of specific topics, the reader is referred to other reviews describing the various signaling networks involved in mitochondrial biogenesis following exercise (Wu et al 1999;Lin et al 2005;Hood et al 2011).…”

Effects of acute lipid overload on skeletal muscle insulin resistance, metabolic flexibility, and mitochondrial performance

“…However, there is evidence to suggest that mitochondrial content and performance are normal in insulinresistant obese subjects (14). Although there is controversy regarding the influence of mitochondrial performance on the development of insulin resistance (17,22), there is little debate that increased physical activity (i.e., aerobic exercise) provides a necessary stimulus for increased mitochondrial content (24), capacity for fat oxidation (6), and improved insulin sensitivity (13). Yet few studies have directly assessed the effects of lipid oversupply on skeletal muscle insulin resistance, metabolic flexibility, and mitochondrial performance in high-vs. lowoxidative muscle (9,40).…”