Apoptosis: a mechanism contributing to remodeling of skeletal muscle in response to hindlimb unweighting

Allen, David L.; Linderman, Jon K.; Roy, Roland R.; Bigbee, A. J.; Grindeland, R. E.; Mukku, Venkat R.; Edgerton, V. Reggie

doi:10.1152/ajpcell.1997.273.2.c579

Cited by 313 publications

(269 citation statements)

References 5 publications

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“…Based on the well-documented increase in circulating TNF-α levels with aging [6][7][8][9][10][11][12][13] and increases in apoptosis of myonuclei in aged skeletal muscles, [18,19,22], we examined whether apoptotic signaling via the extrinsic pathway contributed to sarcopenia. Our data show that pro-and anti-apoptotic proteins in the extrinsic apoptotic pathway are affected by aging in fast (plantaris) and slow (soleus) skeletal muscles of rats.…”

Section: Discussionmentioning

confidence: 99%

“…Apoptosis is an early occurring event that can contribute to muscle atrophy at later time points [22]. Furthermore, nuclear apoptosis is a part of the normal aging process (reviewed in [42][43][44]) and is a contributing mechanism of muscle mass losses with aging.…”

Section: Apoptotic Changes In Aged Skeletal Musclementioning

confidence: 99%

“…The presence of apoptotic nuclei within skeletal myofibers has been welldocumented [18,19,22,23], although the precise signaling mechanisms that result in these nuclear losses are just beginning to be fully understood. Proapoptotic signaling has been shown to arise from mitochondria in aged skeletal muscles [14,15,17,19] and this has been termed the intrinsic apoptotic pathway.…”

Section: Introductionmentioning

confidence: 99%

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Death receptor-associated pro-apoptotic signaling in aged skeletal muscle

2006

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Tumor necrosis factor-alpha (TNF-α) is elevated in the serum as a result of aging and it promotes pro-apoptotic signaling upon binding to the type I TNF receptor. It is not known if activation of this apoptotic pathway contributes to the well-documented age-associated decline in muscle mass (i.e. sarcopenia). We tested the hypothesis that skeletal muscles from aged rodents would exhibit elevations in markers involved in the extrinsic apoptotic pathway when compared to muscles from young adult rodents, thereby contributing to an increased incidence of nuclear apoptosis in these muscles. The plantaris (fast) and soleus (slow) muscles were studied in young adult (5-7 mo, n = 8) and aged (33 mo, n = 8) Fischer 344 × Brown Norway rats. Muscles from aged rats were significantly smaller while exhibiting a greater incidence of apoptosis. Furthermore, muscles from aged rats had higher type I TNF receptor and Fas associated death domain protein (FADD) mRNA, protein contents for FADD, BCL-2 Interacting Domain (Bid), FLICE-inhibitory protein (FLIP), and enzymatic activities of caspase-8 and caspase-3 than muscles from young adult rats. Significant correlations were observed in the plantaris muscle between caspase activity and muscle weight and the apoptotic index, while similar relationships were not found in the soleus. These data demonstrate that pro-apoptotic signaling downstream of the TNF receptor is active in aged muscles. Furthermore, our data extend the previous demonstration that type II fibers are preferentially affected by aging and support the hypothesis that type II fiber containing skeletal muscles may be more susceptible to muscle mass loses via the extrinsic apoptotic pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Apoptotic Changes In Aged Skeletal Musclementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Death receptor-associated pro-apoptotic signaling in aged skeletal muscle

2006

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“…The biological significance of the myonuclear domain is based on the theory that a single myonucleus can sustain necessary gene expression for limited area of cytoplasm. This notion is supported by the observations that new nuclei are incorporated into locomotor skeletal muscle fibers during growth and that nuclei are lost during atrophy (12,14,16). Although it is known that controlled MV decreases protein synthesis and induces proteolysis and myofiber atrophy across all fiber types (6,17,18), it is unknown whether the myonuclear domain of diaphragm myofibers is altered during the fiber atrophy associated with MV.…”

Section: What This Study Adds To the Fieldmentioning

confidence: 92%

“…In addition to myofibrillar protein loss, extracellular matrix expansion, and metabolic enzyme alterations (9)(10)(11), prolonged disuse of skeletal muscle results in the selective loss of myonuclei (12)(13)(14)(15)(16). Myonuclear loss may be a strategy used by the fiber to maintain a constant ratio of cytoplasmic myofiber volume per myonucleus (i.e., myonuclear domain) (16).…”

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confidence: 99%

Caspase-3 Regulation of Diaphragm Myonuclear Domain during Mechanical Ventilation–induced Atrophy

McClung

Kavazis

DeRuisseau

et al. 2007

Am J Respir Crit Care Med

162

178

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Rationale: Unloading the diaphragm via mechanical ventilation (MV) results in rapid diaphragmatic fiber atrophy. It is unknown whether the myonuclear domain (cytoplasmic myofiber volume/ myonucleus) of diaphragm myofibers is altered during MV. Objective: We tested the hypothesis that MV-induced diaphragmatic atrophy is associated with a loss of myonuclei via a caspase-3-mediated, apoptotic-like mechanism resulting in a constant myonuclear domain. Methods: To test this postulate, Sprague-Dawley rats were randomly assigned to a control group or to experimental groups exposed to 6 or 12 h of MV with or without administration of a caspase-3 inhibitor. Measurements and Main Results:After 12 h of MV, type I and type IIa diaphragm myofiber areas were decreased by 17 and 23%, respectively, and caspase-3 inhibition attenuated this decrease. Diaphragmatic myonuclear content decreased after 12 h of MV and resulted in the maintenance of a constant myonuclear domain in all fiber types. Both 6 and 12 h of MV resulted in caspase-3-dependent increases in apoptotic markers in the diaphragm (e.g., number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positive nuclei and DNA fragmentation). Caspase-3-dependent increases in apoptotic markers occurred after 6 h of MV, before the onset of myofiber atrophy. Conclusions: Collectively, these data support the hypothesis that the myonuclear domain of diaphragm myofibers is maintained during prolonged MV and that caspase-3-mediated myonuclear apoptosis contributes to this process. Keywords: muscle atrophy; respiratory muscle; apoptosis; ventilatory weaning Mechanical ventilation (MV) is a clinical intervention for patients who are unable to maintain adequate alveolar ventilation. Recent evidence reveals that controlled MV results in a swift progression of diaphragmatic atrophy and weakness (1-6). It seems that this diaphragmatic atrophy and weakness contributes to difficulty in weaning patients from the ventilator (7). The mechanism(s) responsible for the rapid onset of diaphragmatic atrophy and weakness are not fully understood. Therefore, delineating these mechanisms is a prerequisite for the development of therapeutic strategies to circumvent weaning difficulties. Although mechanical ventilation-induced diaphragm inactivity results in fiber atrophy, it is unknown if prolonged mechanical ventilation is associated with alterations in myonuclear domain via apoptotic mechanisms. What This Study Adds to the FieldOur results reveal that inhibiting caspase-3 activation and myonuclear loss during mechanical ventilation attenuates diaphragmatic muscle atrophy.Mechanical ventilation-induced diaphragmatic atrophy and contractile dysfunction is characterized by oxidative stress and stress-related gene expression in myofibers that occurs within a matter of hours (7,8). In addition to myofibrillar protein loss, extracellular matrix expansion, and metabolic enzyme alterations (9-11), prolonged disuse of skeletal muscle results in the selective loss of myonuclei (12-16). Myonu...

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