Apoptosis in skeletal myocytes: a potential target for interventions against sarcopenia and physical frailty - a mini-review

Abstract

Background: Sarcopenia, the age-related loss of muscle mass and function, represents a relevant public health issue due to its high prevalence and detrimental consequences. While the exact mechanisms underlying the pathogenesis of sarcopenia are not clear, growing experimental evidence indicates that progressive myonuclear elimination over the course of aging via an apoptosis-like process may represent a converging mechanism through which muscle atrophy and loss of physical function develop. Notably, the proapoptotic environment taking place in aged muscle appears amenable to interventions.

Objective: We aimed at providing (1) an overview of signaling pathways of apoptosis relevant to sarcopenia, and (2) a review of the literature supporting myocyte apoptosis as a target for interventions against muscle aging.

Methods: We summarized findings from studies focused on skeletal myocyte apoptosis as a mechanism in the development of sarcopenia and reports supporting myonuclear apoptosis as a target for interventions against age-related muscle loss.

Results: Advanced age is associated with increased signaling through extrinsic and intrinsic apoptotic pathways in skeletal myocytes. In contrast, downregulation of myocyte apoptosis through calorie restriction, exercise training, hormonal supplementation, drugs (e.g. angiotensin-converting enzyme inhibitors, acetaminophen, antimyostatin antibodies), nutraceuticals or genetic interventions (e.g. PGC-1α overexpression) is linked with preservation of muscle integrity and improved physical performance in late life. Preliminary data also indicate that skeletal myocyte apoptotic signaling may be downregulated by compounds, such as resveratrol, with calorie restriction-mimicking properties. Whether exercise mimetics exert a similar effect has not yet been investigated.

Conclusions: Available evidence suggests that targeting myonuclear apoptosis might provide novel and effective therapeutic tools to combat sarcopenia. Further research is required to definitely establish if downregulating myonuclear apoptosis is effective in maintaining muscle mass and function in late life, identify the most relevant apoptotic pathway(s) to target, and determine the optimal timing for intervening.

Fig. 1

Schematic overview of major extrinsic and intrinsic apoptotic signaling pathways. Binding of TNF-α to its cell membrane receptor (TNF-R) initiates the extrinsic apoptotic pathway through the recruitment of adaptor proteins (e.g. FADD, TRADD, TRAF). The resulting death-inducing signaling complex engages caspase-8, which subsequently activates caspase-3. The mitochondrial intrinsic apoptotic pathway involves the release of apoptogenic factors from the intermembrane compartment. This process is regulated by the balance between pro- and antiapoptotic Bcl-2 family proteins, such as Bax and Bcl-2, respectively. In addition, opening of the mitochondrial permeability transition pore (mPTP) can induce a sudden increase in membrane permeability, collapse of membrane potential, mitochondrial swelling and rupture of the outer membrane, with subsequent release of death effectors. For instance, following outer membrane permeabilization, cytochrome c can complex with Apaf-1, dATP and caspase-9, forming an apoptosome, which engages caspase-3. Alternatively, mitochondria can release AIF and EndoG, which perform DNA fragmentation independent of caspase activation. Finally, the endoplasmic reticulum-mediated intrinsic apoptotic pathway is initiated by the engagement of caspase-12, followed by caspase-3 activation. AIF = Apoptosis-inducing factor; Apaf-1 = apoptotic protease-activating factor-1; Bcl-2 = B-cell lymphoma-2; Bax = Bcl-2-associated X protein; CAD = caspase-activated DNase; Cyto c = cytochrome c; EndoG = endonuclease G; FADD = Fas-associated death domain; TRADD = TNF-receptor-associated death domain; TRAF = TNF-receptor-associated factor.