Mitochondrial death effectors: relevance to sarcopenia and disuse muscle atrophy

Abstract

Accelerated apoptosis in skeletal muscle is increasingly recognized as a potential mechanism contributing to the development of sarcopenia of aging and disuse muscle atrophy. Given their central role in the regulation of apoptosis, mitochondria are regarded as key players in the pathogenesis of myocyte loss during aging and other atrophying conditions. Oxidative damage to mitochondrial constituents, impaired respiration and altered mitochondrial turnover have been proposed as potential triggering events for mitochondrial apoptotic signaling. In addition, iron accumulation within mitochondria may enhance the susceptibility to apoptosis during the development of sarcopenia and possibly acute muscle atrophy, likely through exacerbation of oxidative stress. Mitochondria can induce myocyte apoptosis via both caspase-dependent and independent pathways, although the apoptogenic mediators involved may be different depending on age, muscle type and specific atrophying conditions. Despite the considerable advances made, additional research is necessary to establish a definite causal link between apoptotic signaling and the development of sarcopenia and acute atrophy. Furthermore, a translational effort is required to determine the role played by apoptosis in the pathogenesis of sarcopenia and disuse-induced muscle loss in human subjects.

Fig. 1

Schematic overview of mitochondrial apoptotic signaling in skeletal muscle. The left panel shows an apoptotic myonucleus (circled bright spot) identified by TUNEL staining. The right panel depicts the various molecules that may be involved in mitochondria-mediated apoptosis. Release of apoptogenic factors from the mitochondrial intermembrane space occurs as a result of an imbalance between pro- and anti-apoptotic members of the Bcl-2 family proteins and/or following mitochondrial permeability transition pore (mPTP) opening. This latter causes a sudden increase in membrane permeability, collapse of membrane potential, mitochondrial swelling and rupture of the outer membrane, with subsequent release of mitochondrial death effectors. Mitochondria-mediated apoptosis can be executed via caspase-dependent and independent pathways. The former is initiated by the release of cytochrome c (Cyto c) which associates with apoptotic protease-activating factor-1 (Apaf-1), dATP and procaspase-9. The resulting macromolecular complex (apoptosome) promotes the activation of caspase-9, followed by the engagement of caspase-3, which in turn carries out DNA fragmentation (via caspase-activated DNase, CAD) and protein breakdown. The release of the second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with low pI (Smac/Diablo) and heat requirement A2 protein (Omi/HtrA2), which block the activity of the inhibitor of apoptosis proteins (IAPs), ensures complete activation of caspases for the execution of apoptosis. Additionally, mitochondria can induce apoptosis via a caspase-independent mechanism, executed by the apoptosis-inducing factor (AIF) and endonuclease G (EndoG), both of which can cleave DNA without the participation of caspases. Finally, crosstalk between death receptor-mediated and mitochondria-driven apoptosis can occur via cleavage and activation of Bid by caspase-8.