Mitochondria are the power plants of the cell, producing adenosine triphosphate (ATP) to power cellular processes. When mitochondrial function declines all cell functions are negatively affected as a consequence. Many age-related conditions clearly involve mitochondrial dysfunction, particularly in the most energy-hungry tissues, the muscles and the brain.
In addition to damage to the fragile mitochondrial DNA, some forms of which cause a small number of cells to become pathologically broken in ways that actively harms surrounding tissues, all mitochondria throughout the body become more worn and dysfunctional with age. Their dynamics change, the organelles becoming larger and more resistant to the quality control process of mitophagy. The deeper roots of this sweeping decline, and all of the gene expression changes that accompany it, are unclear, but many proximate contributing causes have been identified. Loss of NAD+, reduced expression of mitochondrial fission genes, dysfunction in specific portions of the mitophagy machinery, and so forth.
Efficient skeletal muscle bioenergetics hinge on mitochondria, and mitochondrial dysfunction is recognized as a major hallmark of aging. Indeed, protecting mitochondria is a determinant to preserve proteostasis in skeletal muscle. To date, a growing body of evidence on mitochondrial impairment in sarcopenia has been provided by both animal and human studies. Dysfunctional mitochondria are associated with both ATP depletion and ROS/RNS excess, with the consequent activation of harmful cellular pathways. A decrease in mitochondrial mass, activity of tricarboxylic acid cycle enzymes, as well as O2 consumption and ATP synthesis occurs in aged skeletal muscle tissue. Changes in function, dynamics, and biogenesis/mitophagy could explain in part alteration in oxidative capacity and content of skeletal muscle mitochondria. Furthermore, mitochondrial dysfunction induces the activation of apoptosis, potentially impairing skeletal muscle quality.
Several mitochondrial functions are impaired in old in comparison to young skeletal muscle, including the activity of metabolic enzymes and oxidative phosphorylation (OXPHOS) complexes (i.e., citrate synthase and cytochrome c oxidase), respiration, protein synthesis, and ATP production rate. The reduced mitochondrial content in aged skeletal muscle may be also related to lower PGC-1α gene and protein expression. However, the molecular mechanisms that underpin this reduction are worth further investigation. Apart from PGC-1α, different studies show divergent results in the levels of its downstream transcription factor Tfam in old skeletal muscle.
Changes related to mitochondrial content and function in old skeletal muscle may also be related to a reduced amount, increased mutations, deletions, and rearrangements of mitochondrial DNA (mtDNA). A greater prevalence of mtDNA deletion mutations is described in skeletal muscle fibers, which were more subjected to oxidative damage. An age-dependent increase in skeletal muscle fibers presenting with alterations of mitochondrial enzymes due to mtDNA deletion mutations is reported both in rhesus monkeys presenting with early-stage sarcopenia and in humans.
Morphological studies in aged skeletal muscle show giant mitochondria with disrupted cristae. Altered morphology in old skeletal muscle mitochondria may be the consequence of impaired mitochondrial dynamics, with a disbalance in favor of fission rather than fusion. Mutations in mtDNA may lead to dysregulation of mitochondrial dynamics in sarcopenia, as suggested by results from old mice expressing a defective mtDNA polymerase gamma, which showed higher mitochondrial fission in skeletal muscle. A shift toward mitochondrial fusion rather than fission was also reported in skeletal muscle of very old hip-fractured patients.
The reduced capacity of skeletal muscle cells to remove damaged organelles could be another cause of mitochondrial alteration in aging. Studies performed on rodent models describe controversial results on mitophagy modulators in aged skeletal muscle. A further investigation reported data indicative of increased mitophagy but lysosomal dysfunction in skeletal muscle from old mice, suggesting that lysosomal dysfunction may cause accumulation of disrupted mitochondria. Nevertheless, further investigation on the role of mitophagy in old skeletal muscle is needed in humans.