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. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.

Keywords: (31)P nuclear magnetic resonance; (31)P-NMR; AIF; AngII; Apoptosis; Atg protein; B-cell leukemia-2; Bcl-2; Biomarkers; COPD; COX; CSA; Drp1; ETC; EndoG; Fis1; Forkhead box O3; FoxO3; Fusion and fission; GH; IFM; IGF-1; LAMP-2; LC3; MFRTA; MQC; Mfn; Mitophagy; NF-κB; NOS; OMM; OXPHOS; PGC-1α; RCT; ROS; SDH; SSM; TA; TFAM; TNF-α; UPS; VDR; VL; Vascular dysfunction; angiotensin II; apoptosis-inducing factor; autophagy-related protein; chronic obstructive pulmonary disease; cross-sectional area; cytochrome c oxidase; dynamin-related protein 1; eNOS; electron transport chain; endonuclease G; endothelial nitric oxide synthase; fission protein 1; growth hormone; iNOS; inducible nitric oxide synthase; insulin-like growth factor-1; interfibrillar mitochondria; lysosomal-associated membrane protein 2; microtubule-associated protein 1 light chain 3; mitochondrial DNA; mitochondrial free radical theory of aging; mitochondrial quality control; mitochondrial transcription factor A; mitofusin; mtDNA; nNOS; neuronal nitric oxide synthase; nitric oxide synthase; nuclear factor κB; outer mitochondrial membrane; oxidative phosphorylation; peroxisome proliferator-activated receptor-γ coactivator-1α; randomized controlled trial; reactive oxygen species; subsarcolemmal mitochondria; succinate dehydrogenase; tibialis anterior; tumor-necrosis factor α; ubiquitin–proteasome system; vastus lateralis; vitamin D receptor.