Targeting mitochondrial function and proteostasis to mitigate dynapenia

Abstract

Traditionally, interventions to treat skeletal muscle aging have largely targeted sarcopenia-the age-related loss of skeletal muscle mass. Dynapenia refers to the age-related loss in skeletal muscle function due to factors outside of muscle mass, which helps to inform treatment strategies for aging skeletal muscle. There is evidence that mechanisms to maintain protein homeostasis and proteostasis, deteriorate with age. One key mechanism to maintain proteostasis is protein turnover, which is an energetically costly process. When there is a mismatch between cellular energy demands and energy provision, inelastic processes related to metabolism are maintained, but there is competition for the remaining energy between the elastic processes of somatic maintenance and growth. With aging, mitochondrial dysfunction reduces ATP generation capacity, constraining the instantaneous supply of energy, thus compromising growth and somatic maintenance processes. Further, with age the need for somatic maintenance increases because of the accumulation of protein damage. In this review, we highlight the significant role mitochondria have in maintaining skeletal muscle proteostasis through increased energy provision, protein turnover, and substrate flux. In addition, we provide evidence that improving mitochondrial function could promote a cellular environment that is conducive to somatic maintenance, and consequently for mitigating dynapenia. Finally, we highlight interventions, such as aerobic exercise, that could be used to improve mitochondrial function and improve outcomes related to dynapenia.

Circadian gene variants and the skeletal muscle circadian clock contribute to the evolutionary divergence in longevity across Drosophila populations

“…maintained in the O lines ( Fig. 4E), suggesting that improved mitochondrial function could contribute to longevity and proteostasis (Musci et al 2018). Altogether, the regulated expression of many gene categories relevant for aging likely contributes to the longevity of O lines.…”

Impaired Mitochondrial Energetics Characterize Poor Early Recovery of Muscle Mass Following Hind Limb Unloading in Old Mice

“…This could reduce the capacity to generate the reducing equivalents needed to produce ATP and in turn contribute to poor anabolic response as the energetic cost of protein synthesis is quite substantial. It is estimated that the energetic cost of protein synthesis accounts for approximately 20% of basal metabolism ( 51 , 52 ). Protein breakdown is estimated to account for another 5% to 15% of basal metabolism ( 53 ).…”

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

“…Apart from the aforementioned pathways, there are still other proteostatic systems that participate in the development of cancer and Alzheimer's disease, such as molecular chaperones and mitochondrial homeostasis (Kim, Hipp, Bracher, Hayer‐Hartl, & Hartl, 2013; Musci, Hamilton & Miller, 2017). Molecular chaperones are proteins that function to assist refolding of misfolded proteins or degradation of damaged proteins, which are mainly constituted by heat‐shock proteins (HSPs) (Kim et al., 2013).…”