Parkin sarcopenia in its tracks by improving mitochondrial health

Abstract

Our global population is increasingly represented by the elderly. Consequently, developing clinical strategies to combat age-related diseases have become increasingly important. At the cellular level, there is a vital yet incompletely understood relationship between mitochondria, organelles responsible for energy production and cell signalling, and sarcopenia, the age-related loss of muscle mass and function. In this issue of The Journal of Physiology, Leduc-Gaudet et al. (2019) report on their study examining whether genetically increasing the expression of Parkin, a protein involved in maintaining ‘mitochondrial quality control’, slows the development of sarcopenia. Mitochondria have been implicated in the ageing process through a variety of inter-related mechanisms (see recent review by Sun et al. 2016). Ageing is associated with declines in mitochondrial content and oxidative efficiency that limit the ability of mitochondria to produce ATP. Ageing is also associated with an increase in mitochondrial oxidant production and cellular oxidative damage. Increasing the ability of mitochondria to scavenge reactive oxygen species (via transgenic expression of the antioxidant enzyme catalase) preserves muscle mass in aged mice (Umanskaya et al. 2014), suggesting a causal role for mitochondrial metabolism in sarcopenia. Dysfunctional regions of mitochondria can be sequestered via fission, which in turn initiates machinery to remove the organelle. Mitophagy recognizes damaged mitochondria and removes them via ubiquitin-proteasome or receptor-mediated pathways. Accelerating mitophagy extends lifespan (Rana et al. 2013), suggesting that mitochondrial quality control is impaired with ageing. The best understood components regulating mitophagy are Parkin and PINK1. These two proteins promote the accumulation of ubiquitin on damaged proteins and organelles that ‘tag’ them for subsequent degradation. Despite being a known regulator of mitochondrial turnover, until recently, a role for Parkin in the regulation of skeletal muscle mass had not been described. Leduc-Gaudet et al. (2019) built upon their recently published work showing that mice lacking Park2, the gene that encodes Parkin, have reduced skeletal muscle force and mitochondrial energetic capacity (Gouspillou et al. 2018). Since deleting Parkin appeared to mimic the effect of ageing on skeletal muscle, the authors hypothesized that overexpressing Parkin would have a beneficial effect on muscle mass and mitochondrial function in ageing. This hypothesis was tested by overexpressing Parkin using intramuscular injections of adeno-associated virus (AAV) in young (3 months of age) and aged (18 months of age) mice. A notable feature of this study was that, by using AAVs, Parkin was overexpressed in mice for four consecutive months during the time period that sarcopenia typically emerges. Thus, the authors were able to examine not only the mechanistic role of Parkin in regulating muscle mass, but also whether Parkin might be efficacious when administered during an important therapeutic window in the etiology of sarcopenia. Consistent with their hypothesis, the authors found multiple lines of evidence indicating that Parkin overexpression can mitigate sarcopenia in mice. First, they found that aged mice had increased muscle mass and contractile force in situ in the limb injected with the AAV designed to overexpress Parkin. This finding is consistent with recent work by the same group demonstrating that whole body deletion of Parkin reduces muscle specific force (Gouspillou et al. 2018). Furthermore, the limbs overexpressing Parkin displayed increased mitochondrial content. The skeletal muscle of these mice also displayed a reduction in 4-hydroxynonenal, a marker of oxidative damage. It is unclear whether reduced oxidative damage contributed to the improved muscle function when Parkin was overexpressed; however, it is worth reiterating that genetically improving the intrinsic ability of mitochondria to scavenge oxidants has been shown to improve muscle mass and function in aged mice (Umanskaya et al. 2014). Collectively, the data presented in this new report broadly align with a model in which unhealthy mitochondria precipitate key aspects of sarcopenia. Furthermore, this paper adds to a rapidly growing body of evidence supporting mitophagy as a putative therapeutic strategy for treating sarcopenia. It is important to note that autophagy was not directly measured in this study and Parkin may play roles outside of the regulation of mitophagy, so future studies are needed to fully elucidate how Parkin preserves muscle mass and mitochondrial health across the lifespan.