Mitochondrial dysfunction and sarcopenia of aging: From signaling pathways to clinical trials

Abstract

Sarcopenia, the age-related loss of muscle mass and function, imposes a dramatic burden on individuals and society. The development of preventive and therapeutic strategies against sarcopenia is therefore perceived as an urgent need by health professionals and has instigated intensive research on the pathophysiology of this syndrome. The pathogenesis of sarcopenia is multifaceted and encompasses lifestyle habits, systemic factors (e.g., chronic inflammation and hormonal alterations), local environment perturbations (e.g., vascular dysfunction), and intramuscular specific processes. In this scenario, derangements in skeletal myocyte mitochondrial function are recognized as major factors contributing to the age-dependent muscle degeneration. In this review, we summarize prominent findings and controversial issues on the contribution of specific mitochondrial processes – including oxidative stress, quality control mechanisms and apoptotic signaling – on the development of sarcopenia. Extramuscular alterations accompanying the aging process with a potential impact on myocyte mitochondrial function are also discussed. We conclude with presenting methodological and safety considerations for the design of clinical trials targeting mitochondrial dysfunction to treat sarcopenia. Special emphasis is placed on the importance of monitoring the effects of an intervention on muscle mitochondrial function and identifying the optimal target population for the trial.

Defects in calcium homeostasis and mitochondria can be reversed in Pompe disease

“…56 Among these, collagen VI myopathies and Duchene muscular dystrophy (DMD) are the most studied. 57,58 Mitochondrial dysfunction in collagen VI dystrophies-Ulrich congenital muscular dystrophy and the less severe Bethlem myopathy-is characterized as a "latent" defect, which manifests as mitochondrial depolarization following oligomycin treatment. 57 The process of accumulation of abnormal mitochondria leading to apoptotic cell death is exacerbated by defective autophagy, and the reactivation of the autophagic flux rescues muscle degeneration.…”

“…It has been suggested that the caspase-independent apoptosis is specific to skeletal muscle myonuclei, whereas other cells may undergo apoptosis through the more-classical caspase-dependent pathway. 76 While the contribution of caspase-dependent and independent pathways in aging human muscle has not been definitively established, 58 the expression levels of AIFM1 were elevated (by 10% to 25%) in muscle samples from older individuals, whereas the levels of CASP3 remained unchanged. 77 Activation of mitochondrial caspase-independent apoptotic signaling was also shown in aged rat gastrocnemius muscle.…”

“…Dysfunctional mitochondria are recognized as a major factor contributing to the age-related loss of muscle mass, sarcopenia. 58,79,80 Both Pompe and aging muscle exhibit inadequate Ca 2C control and apoptosis of some of the nuclei in multinucleated muscle cells (syncytial apoptosis); the latter can cause myofiber atrophy without myofiber death. 81 Our current findings of decreased oxygen consumption, increased oxidative stress, and activation of apoptosis in Pompe muscle cells, as well as our previous data on autophagic block (a failure of autophagosomal-lysosomal fusion) and the buildup of lipofuscin in muscle tissue of both KO mice and Pompe patients, 29,30 all support the similarity between Pompe and aged muscle.…”

Cell death, clearance and immunity in the skeletal muscle

“…Programmed death causes the selective removal of individual targeted myonuclei and of 'myonuclear domains', the limited areas of cytoplasm that individual myonuclei support. 13,14 Muscle fiber segment with TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling)-positive nuclei alongside intact nuclei has been described. 15 Myonuclear apoptosis might contribute to skeletal muscle atrophy (however, see Bruusgaard et al 16 ).…”

“…Both apoptosis and autophagy possibly contribute to age-related sarcopenia that is associated with loss in the overall mass and with a reduced number of myofibers. 14,[21][22][23][24][25] Disorganization of myofibrils with Z line loss, mitochondrial swelling and sarcolemmal disruption are hallmarks of the skeletal muscle necrosis. Intracellular moieties including myoglobin, creatine phosphokinase (CK) and other sarcoplasm proteins are released into the bloodstream.…”