Compensatory increases in protein markers of mitochondrial dynamics during ageing are adaptable to physical activity

In most tissues of the human body, mitochondria play a key role in providing energy to support cellular and mechanical processes. In this regard, electrons are transferred through complexes I–IV of the electron transport chain (ETC), and the free energy released is used to generate an electrochemical gradient by pumping protons across the inner mitochondrial membrane. As protons flow down their concentration gradient through ATP synthase, stored energy is used to drive ATP synthesis from ADP and Pi (Mailloux et al. 2014). An intrinsic impairment of the ETC or ATP synthase, or compromised ADP transport can all increase electron leak and promote reactive oxygen species (ROS) production (Mailloux et al. 2014). In turn, excessive ROS accumulation can damage mitochondrial proteins and activate redox-sensitive pathways, which are implicated in many pathologies, including ageing-related ‘sarcopenia’, a condition characterized by lower muscle mass and greater muscle weakness. Therefore, interventions that target mitochondrial content and/or function can slow muscle loss during ageing. While changes in mitochondrial content that occur during ageing have been evaluated, much less is known about age-related changes in the fission and fusion dynamics that regulate mitochondrial turnover. In this regard, the mitochondrial fission proteins mitochondrial dynamics protein 49 (MiD49) and dynamin-related protein 1 (Drp1), and the fusion proteins mitofusin 1 and 2 (Mfn1; Mfn2) play a role in conserving functional protein, while segregating damaged subunits towards mitophagy (Mailloux et al. 2014). A recent article published in The Journal of Physiology by Wyckelsma and colleagues (2017) (1) provides insight regarding methodological advancement with implications for many populations; (2) highlights an increase in markers of fission and fusion proteins with ageing, potentially as a compensatory response to higher rates of protein damage; and (3) highlights the ability for Mfn2 and mitochondrial capacity to adapt to 12 weeks of high intensity interval training (HITT) in older adults (4 min at 90–95% , 4 min off; 4 repeats). Specifically, the study was conducted using non-fractionated whole muscle, as well as isolated type I and II muscle fibres from young and older subjects. From a methodological perspective, Wyckelsma and colleagues highlighted the importance of studying total mitochondria and fission and fusion proteins in non-fractionated whole homogenate, as there were varying degrees of protein loss following fractionation (i.e. centrifugation at 14,000 g) in young and old subjects. This is important, as a fractionation step can alter data interpretations. However, since centrifugation isolates two subcellular regions of mitochondria, the subsarcolemmal (SS) and intermyofibrillar (IMF), it is possible that the differences in the fractionated samples within the current study represent these subcellular types rather than protein loss per se. Specifically, isolation of the SS mitochondria usually occurs following low-grade centrifugation in a similar manner to that used in the current study. Therefore, it is possible that the differences observed between methodologies reflect biologically relevant differences between SS and IMF mitochondria with ageing. If this assumption is accurate, perhaps future studies should utilize both homogenization techniques, ensuring the total of all fractions are analysed in any fractionation examinations. Given that the SS and IMF mitochondria possess different functional properties, fibre type composition and response to exercise training (Menshikova et al. 2006), it may be important to consider the ratio between dynamics proteins and these mitochondrial pools during ageing, and how a physically active lifestyle and exercise training modulate adaptations across the lifespan. At least in aged rodents, SS and IMF mitochondria have varying degrees of abnormal morphology and a greater fusion index ratio (Mnf:Drp1), suggesting hyperfusion and accumulation of damaged proteins (Leduc-Gaudet et al. 2015). However, this occurred in a sedentary model of ageing, which often coincides with reductions in mitochondrial content, greater ROS production and compromised muscle mass (Mailloux et al. 2014). Since older subjects in the current study were physically active, and maintained similar lean mass and mitochondrial capacity to younger subjects, which coincided with greater markers of mitochondrial turnover (Wyckelsma et al. 2017), perhaps physical activity prevents fission protein loss with ageing – allowing for the maintenance of mitochondrial health, moderate ROS production and muscle mass. In support of this, the propensity for mitochondrial H2O2 production during limb immobilization (i.e. disuse) or exercise training was similar between physically active older and younger counterparts (Gram et al. 2015). Combined with the current data, there could be mechanisms in sedentary-aged people that have compromised mitochondrial content, higher ROS production and a redox-sensitive reduction in mitochondrial turnover that exacerbate ROS production and muscle loss. Therefore, it may be important to evaluate the role of fission and fusion mechanisms, mitochondrial capacity and intrinsic sensitivity for mitochondrial ROS production in age-matched sedentary participants. Together, this would help differentiate the influence of activity status on mitochondrial health and muscle quality during ageing, while elucidating the importance of mitochondrial turnover as an upstream regulator of sarcopenia. Moreover, it may also be interesting to assess mitochondria and fission/fusion parameters from all fibre types recovered, including hybrid fibres that are occasionally more prevalent in elderly individuals. These fibres may contribute more to the mitochondrial and fusion/fission adaptations during HIIT observed in the whole homogenate analyses from the current study. Therefore, the increase in mitochondrial content and decrease in fusion markers in type II fibres with training (Wyckelsma et al. 2017) may represent a lower total amount from older individuals if compared to younger subjects. Although these fibres may be difficult to analyse quantitatively at the single fibre level, the use of immunohistochemistry could qualitatively provide some insight into the proportion of mitochondrial improvement and fission and fusion proteins before and after HIIT. Overall, this study provides novel insight into the maintenance of mitochondrial capacity during ageing, as well as the benefit of HIIT on mitochondrial health. Future work can extend these findings by evaluating potential mitochondria-derived contributors to ageing in a sarcopenic population, as well as the protective response of physical activity on mitochondrial function and turnover, ROS production, and muscle quality in response to exercise intensity. None declared. P.M.M is supported by an NSERC graduate scholarship. The authors thank Dr Graham Holloway for his insight and helpful suggestions in preparing the manuscript.

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