Mitochondrial Dysfunction as a Contribution to Muscle Aging
How much of the characteristic loss of muscle mass and strength that takes place with aging is the result of mitochondrial dysfunction? Mitochondria produce the chemical energy store molecules needed to power cellular processes, but in addition to the loss of this capacity, dysfunction in mitochondria can also generate oxidative stress that further impairs cell function. Some degree of mitochondrial dysfunction emerges from damage to mitochondrial DNA, but it is also the case that age-related changes in gene expression reduce the efficiency of mitochondrial quality control, the process of mitophagy responsible for removing damaged mitochondria. These processes are well investigated, and researchers are presently establishing ways to transplant mitochondria in large enough numbers to restore function throughout the body, but how great a benefit this systemic rejuvenation will produce has yet to be assessed in animal studies.
A hallmark of muscle aging is the buildup of dysfunctional and damaged mitochondria. However, the mechanisms leading to the accumulation of unhealthy mitochondria and whether this drives some of the aging-induced alterations are not fully understood yet. The process responsible for the selective degradation of damaged mitochondria, also known as mitophagy, is key in the maintenance of mitochondrial quality. Besides, mitophagy is tightly tuned with mitochondrial dynamics, and this coordination is essential during mitochondrial quality control. Indeed, alterations in these processes have been found to contribute to the accumulation of dysfunctional mitochondria in aged muscles.
In particular, we have shown that a reduction in the mitochondrial fusion protein Mitofusin 2 (Mfn2) during aging drives metabolic deterioration, muscle atrophy, and sarcopenia by a deregulation of mitochondrial dynamics and mitophagy. Interestingly, as a consequence of the accumulation of damaged and ROS-generating mitochondria, an adaptive mitophagy pathway involving ROS-induced expression of the mitophagy protein BNIP3 is activated in order to minimize mitochondrial damage. Pharmacological inhibition of this adaptive mitophagy pathway or genetic downregulation of muscle BNIP3 worsens mitochondrial quality and potentiates muscle atrophy. In contrast, re-expression of Mfn2 to levels comparable to those of young mice prevents muscle atrophy in old mice. Altogether, these data demonstrate a tight connection between mitochondrial health and the development of muscle atrophy and sarcopenia.