Mitochondria in Skeletal Muscle: Rheostats of Apoptotic Susceptibility
Mitochondria in Skeletal Muscle: Rheostats of Apoptotic Susceptibility
Apoptosis is an essential process that plays a critical role in both tissue development and maintenance. Apoptosis has been shown to be involved in skeletal muscle atrophy resulting from chronic muscular disuse, sarcopenia, and mitochondrial myopathies. Exercise may attenuate some of the proapoptotic adaptations that occur during these conditions. This review will focus on the factors influencing mitochondrially mediated apoptosis in skeletal muscle.
Overview of Morphological Features of Apoptosis. Apoptosis is an evolutionarily conserved form of cell death responsible for removing cells from tissues. It is an important process that is necessary for normal development and tissue homeostasis in a wide variety of organisms. Morphological features typically manifested after apoptotic induction include plasma membrane blebbing, nuclear breakdown, chromosomal fragmentation, and the bundling of cellular contents into apoptotic bodies that are marked for phagocytosis. These unique morphological and biochemical characteristics of apoptosis clearly distinguish it from necrotic cell death. This review will focus primarily on the molecular mechanisms and pathways of mitochondrially mediated apoptosis in skeletal muscle. In addition, a description of the physiological and pathophysiological conditions that have been shown to alter apoptosis in skeletal muscle will be examined. Our hypothesis is that chronic muscle disuse leads to an increase in mitochondrial apoptotic susceptibility, which results in an elevated rate of muscle atrophy.
Apoptotic Signal Transduction. Apoptosis can be activated by either external or internal stimuli. The external pathway occurs via ligand-mediated activation (e.g., via tumor necrosis factor α;), whereas the internal pathway originates within the mitochondrion. Although most of the research thus far on skeletal muscle has focused on the internal mitochondrially mediated pathway, many of the external apoptotic stimuli activate signaling pathways that also converge on the mitochondria to initiate cell death. Thus, mitochondria play a central role in apoptosis within skeletal muscle.
Muscle-Specific Apoptotic Distinctions. Evidence accumulated over the last several years has shown that apoptosis is a significant contributor to muscle degeneration. However, apoptosis in skeletal muscle is unique for several reasons. First, skeletal muscle is multinucleated. Thus, the decay of one myonucleus by apoptosis will not produce "wholesale" muscle cell death, but it does result in a loss of gene expression within the local myonuclear domain, potentially leading to cellular atrophy. Second, muscle contains two morphologically and biochemically distinct subfractions of mitochondria (subsarcolemmal (SS) and intermyofibrillar (IMF)) that exist in different regions of the fiber. This could produce regional differences in the sensitivity to apoptotic stimuli within the cell. Third, skeletal muscle is a malleable tissue capable of changing its mitochondrial content and/or composition in response to chronic alterations in muscle use or disuse. Such variations in mitochondrial content and/or composition can undoubtedly influence the degree of organelle-directed apoptotic signaling in skeletal muscle.
Apoptosis-Associated Degradation Pathways: Proteasome and Autophagy. Although apoptotic signaling and induction are initiated by the mitochondria, the subsequent degradation pathways that discard fragments of myonuclei are less well established. However, apoptosis-induced myonuclear debris removal likely involves the ubiquitin-proteasome pathway, as well as autophagy. Literature relating to how the ubiquitin-proteasome and autophagy pathways are associated with apoptosis in muscle is currently scarce, and further investigation in this area is warranted.
Apoptosis is an essential process that plays a critical role in both tissue development and maintenance. Apoptosis has been shown to be involved in skeletal muscle atrophy resulting from chronic muscular disuse, sarcopenia, and mitochondrial myopathies. Exercise may attenuate some of the proapoptotic adaptations that occur during these conditions. This review will focus on the factors influencing mitochondrially mediated apoptosis in skeletal muscle.
Overview of Morphological Features of Apoptosis. Apoptosis is an evolutionarily conserved form of cell death responsible for removing cells from tissues. It is an important process that is necessary for normal development and tissue homeostasis in a wide variety of organisms. Morphological features typically manifested after apoptotic induction include plasma membrane blebbing, nuclear breakdown, chromosomal fragmentation, and the bundling of cellular contents into apoptotic bodies that are marked for phagocytosis. These unique morphological and biochemical characteristics of apoptosis clearly distinguish it from necrotic cell death. This review will focus primarily on the molecular mechanisms and pathways of mitochondrially mediated apoptosis in skeletal muscle. In addition, a description of the physiological and pathophysiological conditions that have been shown to alter apoptosis in skeletal muscle will be examined. Our hypothesis is that chronic muscle disuse leads to an increase in mitochondrial apoptotic susceptibility, which results in an elevated rate of muscle atrophy.
Apoptotic Signal Transduction. Apoptosis can be activated by either external or internal stimuli. The external pathway occurs via ligand-mediated activation (e.g., via tumor necrosis factor α;), whereas the internal pathway originates within the mitochondrion. Although most of the research thus far on skeletal muscle has focused on the internal mitochondrially mediated pathway, many of the external apoptotic stimuli activate signaling pathways that also converge on the mitochondria to initiate cell death. Thus, mitochondria play a central role in apoptosis within skeletal muscle.
Muscle-Specific Apoptotic Distinctions. Evidence accumulated over the last several years has shown that apoptosis is a significant contributor to muscle degeneration. However, apoptosis in skeletal muscle is unique for several reasons. First, skeletal muscle is multinucleated. Thus, the decay of one myonucleus by apoptosis will not produce "wholesale" muscle cell death, but it does result in a loss of gene expression within the local myonuclear domain, potentially leading to cellular atrophy. Second, muscle contains two morphologically and biochemically distinct subfractions of mitochondria (subsarcolemmal (SS) and intermyofibrillar (IMF)) that exist in different regions of the fiber. This could produce regional differences in the sensitivity to apoptotic stimuli within the cell. Third, skeletal muscle is a malleable tissue capable of changing its mitochondrial content and/or composition in response to chronic alterations in muscle use or disuse. Such variations in mitochondrial content and/or composition can undoubtedly influence the degree of organelle-directed apoptotic signaling in skeletal muscle.
Apoptosis-Associated Degradation Pathways: Proteasome and Autophagy. Although apoptotic signaling and induction are initiated by the mitochondria, the subsequent degradation pathways that discard fragments of myonuclei are less well established. However, apoptosis-induced myonuclear debris removal likely involves the ubiquitin-proteasome pathway, as well as autophagy. Literature relating to how the ubiquitin-proteasome and autophagy pathways are associated with apoptosis in muscle is currently scarce, and further investigation in this area is warranted.
Source...