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.

Conflict of interest statement

Conflict of interest statement: the authors declare that they have no conflict of interest to disclose.

Copyright © 2013 Elsevier Ltd. All rights reserved.

Figures

Fig. 1

Hypothetical progression of mitochondrial dysfunction during the development sarcopenia and possible windows for interventions. Multiple, interrelated factors can impact muscle mitochondria function over the life course, including intrinsic muscular aging, lifestyle habits, chronic inflammation, vascular dysfunction, hormonal changes, etc. Young individuals should be advised to adopt a healthy lifestyle, avoiding all of the known risk factors for chronic degenerative diseases. At middle age, subjects at risk for sarcopenia should be promptly identified, for instance through the computation of a “sarcopenia risk chart” (Calvani et al. 2013b). Eventual chronic degenerative diseases associated with accelerated development and/or progression of sarcopenia need to be managed appropriately. Periodical assessments of muscle mitochondrial function may allow detecting early signs of dysfunction. Once the presence of sarcopenia has been established, interventions must be implemented. A hypothetical treatment targeting mitochondria requires a close monitoring of mitochondrial response to the intervention. Artwork by Francesco Antognarelli.

Fig. 2

Possible scenarios resulting from mitochondrial quality control failure during the progression of sarcopenia. An imbalance in mitochondrial dynamics towards fusion is associated with the appearance of giant mitochondria, characterized by highly interconnected networks, aberrant morphology, reduced bioenergetic efficiency, and increased ROS production. Enlarged mitochondria cannot be efficiently removed due to their larger size. The accumulation of lipofuscin within lysosomes further contributes to impairing the autophagosomal-lysosomal axis. Oxidants generated by dysfunctional mitochondria compromise the surrounding tissue and amplify mitochondrial damage, eventually triggering apoptosis and proteolysis via ROS-mediated activation of nuclear factor κB (NF-κB) and Forkhead box O (FoxO) (Dodd et al. 2010). These transcription factors stimulate the expression of the muscle-specific ubiquitin ligases atrogin-1 and muscle-specific RING finger 1 (MuRF-1). Protein fragments derived from the action of caspase-3 on actomyosin complexes are eventually degraded by the ubiquitin-proteasome system. A shift of dynamics towards fission leads to mitochondrial network disintegration and overactivation of mitophagy. ROS generation by fragmented mitochondria is increased, which together with the upregulation of fission, stimulates muscle protein breakdown and myonuclear apoptosis through mechanisms similar to those described above. Artwork by Francesco Antognarelli.