Apoptosis is a conserved physiological mechanism responsible for the elimination of dysfunctional, damaged, and/or unnecessary cells [1], [2], [3], [4]. Apoptotic signaling is partially mediated by the mitochondria in response to stress stimuli, such as the lack of growth factors, DNA damage, and oxidative stress [1], [2], [3], [4]. At the mitochondrial level, these stimuli lead to dysfunction (i.e., impaired membrane potential, reduced oxidative phosphorylation (OXPHOS), and reduced ATP production) and initiate mitochondrial apoptotic signaling in a multi-step signaling cascade. The BCL2 family, consisting of pro- and anti-apoptotic proteins, plays a major role in regulating mitochondrial apoptotic signaling. Within the BCL2 family, there are generally three categories of proteins: pro-apoptotic initiators, pro-apoptotic effectors, and anti-apoptotic proteins. Pro-apoptotic initiators such as BCL2 binding component 3 (BBC3/PUMA) and BH3 interacting domain death agonist (BID) function to directly activate pro-apoptotic effectors while simultaneously inhibiting anti-apoptotic proteins [5], [6], [7], [8], [9]. This results in a shift towards a pro-apoptotic cellular response. Once stimulated, pro-apoptotic effectors including BCL2-associated X protein (BAX) and BCL2-antagonist/killer 1 (BAK1) translocate to the mitochondria and oligomerize, causing mitochondrial outer membrane permeabilization (MOMP) [5], [6], [7], [8], [9]. Alternatively, mitochondrial permeability transition pores (MPTP) can form in response to oxidative stress or cytosolic ion overload through the assembly of channeling proteins, including voltage-dependent anion channel (VDAC) and adenine nucleotide translocase-1 (ANT1) [3], [10], [11]. MPTP formation can ultimately lead to mitochondrial swelling and mitochondrial membrane rupture [3], [10], [11]. A major consequence of MOMP and outer mitochondrial membrane (OMM) rupture is the release of cytochrome c (CYCS) and second mitochondria-derived activator of caspase (SMAC), which contribute to CASP activation [12], as well as apoptosis inducing factor mitochondria associated 1 (AIFM1) and endonuclease G (ENDOG) [3], [13], which directly causes DNA fragmentation. Importantly, anti-apoptotic effectors including BCL2 and BCL2-like 1 (BCL2L1/BCLXL) function to inhibit mitochondrial apoptotic signaling. Collectively, these events and factors influence the apoptotic signaling cascade (Fig. 1).

Apoptotic signaling plays an important role in several physiological and pathophysiological states. In proliferative tissues, apoptotic signaling is important to maintain a constant number of cells. In contrast, the role of apoptotic signaling in post-mitotic tissues is quite unique, particularly in skeletal muscle. Skeletal muscle fibers are multinucleated cells; thus, DNA fragmentation of nuclei would not necessarily eliminate the entire fiber/cell. Of importance is the concept of the myonuclear domain, which is defined as the amount of cytoplasm supported by a single myonuclei (i.e., ratio of cytosolic area/nucleus), and implies a constant regulation of nuclear number to fiber size [14], [15], [16], [17], [18], [19], [20], [21], [22]. Under atrophic conditions, myonuclei can become fragmented and may be eliminated via myonuclear apoptosis, presumably influencing transcriptional potential, and thereby contributing to muscle atrophy [16], [17], [18], [21], [22]; however, this paradigm has been challenged [23], [24], [25]. Nevertheless, there is ample evidence demonstrating changes in mitochondrial apoptotic signaling in multinucleated myofibers during conditions of skeletal muscle atrophy. In addition, mitochondrial apoptotic signaling has been implicated in myogenic differentiation of mononucleated skeletal muscle cells (i.e., myoblasts) into multinucleated myotubes. This review will highlight the mechanisms of mitochondrial apoptotic signaling in skeletal muscle remodeling, particularly its role in myogenic differentiation and skeletal muscle atrophy.