Mitochondrial pathways in sarcopenia of aging and disuse muscle atrophy

Abstract

Muscle loss during aging and disuse is a highly prevalent and disabling condition, but knowledge about cellular pathways mediating muscle atrophy is still limited. Given the postmitotic nature of skeletal myocytes, the maintenance of cellular homeostasis relies on the efficiency of cellular quality control mechanisms. In this scenario, alterations in mitochondrial function are considered a major factor underlying sarcopenia and muscle atrophy. Damaged mitochondria are not only less bioenergetically efficient, but also generate increased amounts of reactive oxygen species, interfere with cellular quality control mechanisms, and display a greater propensity to trigger apoptosis. Thus, mitochondria stand at the crossroad of signaling pathways that regulate skeletal myocyte function and viability. Studies on these pathways have sometimes provided unexpected and counterintuitive results, which suggests that they are organized into a complex, heterarchical network that is currently insufficiently understood. Untangling the complexity of such a network will likely provide clinicians with novel and highly effective therapeutics to counter the muscle loss associated with aging and disuse. In this review, we summarize the current knowledge on the mechanisms whereby mitochondrial dysfunction intervenes in the pathogenesis of sarcopenia and disuse atrophy, and highlight the prospect of targeting specific processes to treat these conditions.

Figure 1

The dynamic nature of the mitochondrial network in skeletal muscle. Mitochondria are organized in a complex and dynamic network regulated by highly coordinated fusion and fission processes. Outer mitochondrial membrane (OMM) fusion is performed by Mfn1 and Mfn2, while optic atrophy protein 1 (OPA1) connects the inner mitochondrial membranes (IMM) of joining mitochondria. Fission is mediated by Drp1, which interacts with other proteins such as Fis1, to form a collar-like structure on the mitochondrial surface. The constriction of this structure eventually splits mitochondrial membranes.

Figure 2

Synoptic representation of the putative mitochondrial pathways contributing to sarcopenia of aging and disuse muscle atrophy. The aging muscle is characterized by an imbalance in mitochondrial fusion – fission events, associated with lower mitochondrial degradation. This leads to the formation of giant mitochondria, characterized by highly interconnected networks, aberrant morphology, reduced bioenergetic efficiency, and increased ROS production. The accumulation of lipofuscin within lysosomes contributes to the age-associated dysfunction of the autophagy – lysosomal pathway, resulting in reduced mitophagic efficiency. Oxidative stress eventually triggers apoptosis. During muscle disuse, mitochondrial dynamics shift toward fission and autophagy is over-activated. ROS generation by mitochondria is increased, which together with the up-regulation of fission stimulates apoptosis.

Figure 3

Molecular regulation of mitophagy in skeletal muscle. The priming of mitochondria to degradation can occur via Parkin-dependent or-independent pathways. Following mitochondrial depolarization, PTEN-induced putative kinase 1 (PINK1) accumulates on the mitochondrial surface, leading to the recruitment of Parkin, which ubiquitinates proteins located in the outer mitochondrial membrane. Ubiquitination of the presenilin-associated rhomboid-like (PARL) protease promotes the execution of mitophagy by preventing PINK1 degradation. Ubiquitin-tagged mitochondria bind to p62, which assists in the recruitment of autophagosomal membranes to mitochondria. Parkin can also interact with activating molecule in Beclin1-regulated autophagy (Ambra1), which stimulates the activity of the class III phosphatidylinositol 3-kinase (PI3K) complex required for phagophore formation. In the Parkin-independent pathway, FUN14 domain-containing protein 1 (FUNDC1) is engaged, followed by the recruitment of microtubule-associated protein 1 light chain 3 (LC3) to mitochondria. In addition, upon mitochondrial depolarization, SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1) targets mitochondria to mitophagy via the ubiquitination of mitochondrial proteins. Finally, Bcl2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and Nip3-like protein X (NIX) can trigger mitophagy by mitochondrial depolarization, competitive disruption of the inhibitory interaction between Bcl-2 and Beclin1, and direct interaction with LC3. Mitochondria-derived ROS and AMP-activated protein kinase (AMPK) activation by ATP depletion converge on Forkhead box O3 (FoxO3) to induce mitophagy. AMPK and FoxO3 also relieve autophagy inhibition by mammalian target of rapamycin (mTOR). For a detailed description of the molecular mechanisms and regulation of mitophagy, the reader is referred to specialized reviews on the subject (for instance, Youle and Narendra, 2011; Ding and Yin, 2012).

Figure 4

The mitochondrial apoptotic machinery in skeletal muscle. Release of pro-apoptotic factors from the mitochondrial intermembrane space occurs as a result of an imbalance between pro- (e.g., Bax and Bid) and anti-apoptotic (e.g., Bcl-2 and Bcl-X_L) members of the Bcl-2 family of proteins and/or following mitochondrial permeability transition pore (mPTP) opening. Mitochondrial caspase-dependent apoptosis is initiated by the cytosolic release of cytochrome c (Cyto c), which associates with apoptotic protease-activating factor-1 (Apaf-1), dATP and procaspase-9. The resulting apoptosome activates caspase-9, followed by the engagement of caspase-3, which performs protein breakdown and DNA fragmentation via a caspase-activated DNase (CAD). Second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with low pI (Smac/DIABLO) and heat requirement A2 protein (Omi/HtrA2), block the activity of inhibitor of apoptosis proteins (IAPs). Mitochondrial caspase-independent apoptosis is executed by apoptosis-inducing factor (AIF) and endonuclease G (EndoG). Crosstalk between tumor necrosis factor-α (TNF-α)-mediated and mitochondria-driven apoptosis can occur via cleavage and activation of Bid by caspase-8, which is recruited by the death-inducing signaling complex associated with tumor necrosis factor receptor 1 (TNF-R1).