Beneficial effects of exercise on age-related mitochondrial dysfunction and oxidative stress in skeletal muscle

Abstract

Mitochondria are negatively affected by ageing leading to their inability to adapt to higher levels of oxidative stress and this ultimately contributes to the systemic loss of muscle mass and function termed sarcopenia. Since mitochondria are central mediators of muscle health, they have become highly sought-after targets of physiological and pharmacological interventions. Exercise is the only known strategy to combat sarcopenia and this is largely mediated through improvements in mitochondrial plasticity. More recently a critical role for mitochondrial turnover in preserving muscle has been postulated. Specifically, cellular pathways responsible for the regulation of mitochondrial turnover including biogenesis, dynamics and autophagy may become dysregulated during ageing resulting in the reduced clearance and accumulation of damaged organelles within the cell. When mitochondrial quality is compromised and homeostasis is not re-established, myonuclear cell death is activated and muscle atrophy ensues. In contrast, acute and chronic exercise attenuates these deficits, restoring mitochondrial turnover and promoting a healthier mitochondrial pool that leads to the preservation of muscle. Additionally, the magnitude of these exercise-induced mitochondrial adaptations is currently debated with several studies reporting a lower adaptability of old muscle relative to young, but the processes responsible for this diminished training response are unclear. Based on these observations, understanding the molecular details of how advancing age and exercise influence mitochondria in older muscle will provide invaluable insight into the development of exercise protocols that will maximize beneficial adaptations in the elderly. This information will also be imperative for future research exploring pharmacological targets of mitochondrial plasticity.

Figure 1. Factors contributing to age‐related muscle mass loss

Age‐related skeletal muscle loss is attributed to a wide range of factors including inadequate nutrient intake of proteins and vitamins, a sedentary lifestyle, declines in anabolic hormone levels, loss of motor neuron number and/or activation, and increased levels of inflammatory cytokines (e.g. interleukin 6 (IL‐6) and tumour necrosis factor α (TNF‐α)). Of the contributory factors involved in sarcopenia, decline in metabolic capacity and mitochondrial function are among the most important molecular changes proposed to have significant consequences for skeletal muscle tissue, due to higher levels of oxidative stress and damage and a reduced oxidative capacity (highlighted in red). The majority of the aetiological factors depicted can be improved and/or prevented with chronic endurance exercise and/or resistance training.

Figure 2. Proposed role of age‐induced oxidative stress and mtDNA mutations in sarcopenia

Increased levels of reactive oxygen species (ROS) generated by mitochondria lead to higher oxidative stress and progressive damage to mitochondrial DNA (mtDNA). Over time these changes create a vicious cycle whereby mitochondrial dysfunction drives the increased accumulation of ROS that exacerbates cell death and promotes the progressive decline in muscle fibre number and size.

Figure 3. Molecular adaptations in ageing skeletal muscle mitochondria with exercise

(1) Biogenesis. Following an acute exercise stimulus, signalling through AMP and MAPK leads to the upregulation of PPAR γ co‐activator 1α (PGC‐1α) and together with transcription factors (TFs) activate nuclear genes encoding mitochondrial proteins such as the mitochondrial transcription factor A (Tfam). Tfam is then targeted and imported via the protein import machinery (PIMs) to its final destination on mitochondrial DNA (mtDNA) where it upregulates genes encoding electron transport chain (ETC) subunits, which results in higher oxygen consumption, ATP synthesis and mitochondrial content. (2) Dynamics. Exercise also evokes changes in mitochondrial morphology by increasing the abundance of fusion (Mfns and Opa1) and fission (Drp1 and Fis1) proteins. These changes increase mitochondrial turnover to facilitate the dilution and clearance of damaged mitochondria, and also help dissipate energy to all parts of the muscle cell. (3) Autophagy. Acute and chronic endurance training alters the levels of key autophagy markers such as LC3‐II and the ubiquitin (Ub) binding protein p62, leading to greater autophagosome formation and degradation of damaged mitochondria via mitophagy. (4) Apoptosis. Exercise‐induced improvements in mitochondrial function lead to reduced levels of pro‐apoptotic release (cytochrome c, cyto c; apoptosis inducing factor, AIF; and endonuclease G, Endo G) and attenuated activation of caspase‐dependent and ‐independent signalling cascades ultimately decreasing DNA fragmentation to maintain myofibre number and size with age. For simplicity, the signalling pathways are depicted as distinct processes, but the dashed lines indicate the interconnectivity of these four processes as discussed in the text.