Skeletal muscle aging and the mitochondrion

Abstract

Decline in human muscle mass and strength (sarcopenia) is a hallmark of the aging process. A growing body of research in the areas of bioenergetics and protein turnover has placed the mitochondria at the center of this process. It is now clear that, unless an active lifestyle is rigorously followed, skeletal muscle mitochondrial decline occurs as humans age. Increasing research on mitochondrial biology has elucidated the regulatory pathways involved in mitochondrial biogenesis, many of which are potential therapeutic targets, and highlight the beneficial effects of vigorous physical activity on skeletal muscle health for an aging population.

Figure 1. Mitochondrial protein turnover

The turnover of mitochondrial DNA (mtDNA) encoded proteins may occur independently of nuclear DNA (nDNA) encoded proteins and can be regulated in part by damage to mitochondrial proteins. Moderately damaged mitochondrial proteins can be degraded by intrinsic proteases (Lon) while severely damaged proteins can dissipate the membrane potential (ψ) and lead to fission of the membrane for degradation by the lysosome (mitophagy). The free pool of amino acids in the mitochondria reflects the amino acid content of mitochondrial proteins encoded by mtDNA [101] and suggests the mitochondrial free amino acid pool is sustained by degradation of mitochondrial proteins. AMPK and downstream targets help coordinate the expression of nDNA and mtDNA encoded proteins. Abbreviations: AA [Amino acids], AMPK [AMP activated protein kinase], LON [Lon protease], mTOR [Mammalian target of rapamycin complex 1], PGC-1α [Peroxisome proliferator-activated receptor γ coactivator 1α], ROS [Reactive oxygen species], SIRT1 [sirtuin 1].

Figure 2. Age associated changes in muscle mitochondrial function

Damaged skeletal muscle proteins with less function are normally degraded and replaced with newly synthesized proteins. Aging is associated with the accumulation of damaged proteins through both increased rates of damage and decreased degradation.

Figure 3. The role of declining mtDNA copy number on skeletal muscle aging

A hypothetical model that shows how declining mtDNA copy number in aging skeletal muscle may relate to sarcopenia, and the role of exercise training on reversing sarcopenia.