Pro‐ and Anti‐apoptotic Members of the Bcl‐2 Family in Skeletal Muscle: A Distinct Role for Bcl‐2 in Later Stages of Myogenesis

Dominov, Janice A.; Houlihan-Kawamoto, Caitlin A.; Swap, Clifford J.; Miller, Jeffrey B.

doi:10.1002/1097-0177(2000)9999:9999<::aid-dvdy1088>3.0.co;2-#

Cited by 37 publications

(38 citation statements)

References 49 publications

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“…Postmitotic neurons do not express full-length Bak protein (Sun et al, 2001;Uo et al, 2004), which likely accounts for the singular importance of Bax in the control of developmental neuronal cell death. In contrast, both Bak and Bax are expressed in developing mouse skeletal muscle (Dominov et al, 2001). Thus, we propose that Bax deletion had only minor effects on the perineal muscles, because Bax is redundant with Bak in this tissue.…”

Section: Discussionmentioning

confidence: 99%

Effects of Bax Gene Deletion on Muscle and Motoneuron Degeneration in a Sexually Dimorphic Neuromuscular System

Jacob

Bengston²,

Forger³

2005

Journal of Neuroscience

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Motoneurons in the spinal nucleus of the bulbocavernosus (SNB) and their target muscles in the perineum, bulbocavernosus (BC), and levator ani (LA) normally degenerate in female rodents. Death of the motoneurons and muscles can be prevented by androgen treatments around the time of birth. To identify the intracellular mechanisms underlying hormone-dependent survival of this neuromuscular system, we examined mice with a targeted disruption of the pro-death gene Bax. SNB motoneuron number was increased in female Bax؊/؊ mice, whether measured using immunolabeling for a motoneuron-specific marker or retrograde labeling with the fluorescent tracer Fluoro-Gold. Based on retrograde tracing, the sex difference in SNB cell number is eliminated in Bax؊/؊ mice. Thus, Bax is required for sexually dimorphic motoneuron death in the SNB, and motoneurons rescued by Bax deletion project their axons to the periphery. Mean soma size in the SNB of Bax؊/؊ females is reduced, however, and there is a subpopulation of very small cells in the SNB of female knock-outs. In addition, the BC muscle was not identified in any female, regardless of Bax gene status. All females possessed a small LA muscle, and Bax deletion resulted in a tripling of LA fiber number in females. This increase was small, however, relative to the Ͼ50-fold sex difference in LA muscle fiber number. Thus, the sex difference in the perineal muscles is mostly unaffected by the absence of Bax protein, and SNB motoneuron number is dissociated from target muscle size in Bax؊/؊ animals.

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Section: Discussionmentioning

confidence: 99%

Effects of Bax Gene Deletion on Muscle and Motoneuron Degeneration in a Sexually Dimorphic Neuromuscular System

Jacob

Bengston²,

Forger³

2005

Journal of Neuroscience

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“…We examined satellite cells in Lama2 -/-muscles because both Bax and the MyoD transgene were expressed in proliferating satellite cells, as well as in skeletal muscle cells beginning near the time myofibers first form in embryonic development, and in all multinucleate myofibers in the adult (15,16) (Figure 2B and data not shown). Nonetheless, neither inactivation of Bax nor expression of the Bcl-2 transgene appeared to affect the number of satellite cells in Lama2 -/-muscles, as determined either by counting mononucleate cells found in cross-sections of Lama2 -/-muscles or by determining the number of satellite cells that could be successfully cultured per gram of muscle wet weight (data not shown).…”

Section: Figurementioning

confidence: 96%

Inhibition of apoptosis improves outcome in a model of congenital muscular dystrophy

Girgenrath¹,

Dominov²,

Kostek³

et al. 2004

J. Clin. Invest.

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The most common form of human congenital muscular dystrophy (CMD) is caused by mutations in the laminin-α2 gene. Loss of laminin-α2 function in this autosomal recessive type 1A form of CMD results in neuromuscular dysfunction and, often, early death. Laminin-α2-deficient skeletal muscles in both humans and mice show signs of muscle cell death by apoptosis. To examine the significance of apoptosis in CMD1A pathogenesis, we determined whether pathogenesis in laminin-α2-deficient (Lama2 -/-) mice could be ameliorated by inhibiting apoptosis through either (a) inactivation of the proapoptosis protein Bax or (b) overexpression of the antiapoptosis protein Bcl-2 from a muscle-specific transgene. We found that both of these genetic interventions produced a several-fold increase in the lifespan of Lama2 -/-mice. Bax inactivation also improved postnatal growth rate and myofiber histology and decreased fixed contractures of Lama2 -/-mice. Thus, Bcl-2 family-mediated apoptosis contributes significantly to pathogenesis in the mouse model of CMD1A, and antiapoptosis therapy may be a possible route to amelioration of neuromuscular dysfunction due to laminin-α2 deficiency in humans.

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“…Furthermore, Bcl-2-positive cells co-express markers of early stages of myogenesis such as desmin, MyoD, and Myf5, whereas Bcl-2 was not expressed in differentiated myotubes (Dominov et al 1998). In developing skeletal muscle, Bcl-2 expression was limited to a small group of mononucleate, desmin-positive, and myogenin-negative muscle cells (Dominov et al 2001). Examination of Bcl-2 expression in human myopathies showed that Bcl-2 immunoreactivity was detected not only in regenerating myofibers but also in apparently normal myofibers (Olive and Ferrer 1999).…”

Section: Possible Target Genes and Functions Of Activated Stat3 Proteinmentioning

confidence: 99%

“…In an attempt to investigate regulation of cell death, neonatal muscles of Bcl-2-null mice revealed a reduced myofiber number compared with wild-type mice (Dominov et al 2001), and direct evidence that survival of cultured myoblasts was enhanced by LIF was recently reported (White et al 2001). These observations and the present results, taken together, suggest that one of the target genes of STAT3 in regenerating muscles may be Bcl-2 and that STAT3-induced Bcl-2 may serve to protect against apoptotic cell death of the activated satellite cells, proliferating myoblasts, and surviving myofibers.…”

Section: Possible Target Genes and Functions Of Activated Stat3 Proteinmentioning

confidence: 99%

“…Additional phosphorylation of STAT3 proteins at serine residues has been suggested to enhance transcriptional activity of STAT3 proteins (Taga 1996;Takeda and Akira 2000). Potential target genes of STAT3 have been known to include cyclin D1, c-fos, JunB, Bcl-2, and Bcl-xL (Coffer et al 1995;Fukada et al 1996;Jenab and Morris 1996;Bromberg 2001), which mediate several biological functions such as proliferation, differentiation, and survival of myoblasts (Lassar et al 1989;Rahm et al 1989;Li et al 1992;Rao et al 1994;Skapek et al 1995;Dominov et al 1998Dominov et al ,2001Olive and Ferrer 1999). Therefore, monitoring STAT3 signaling in regenerating muscles may be important to further understand the regulatory mechanism of skeletal muscle regeneration.…”

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confidence: 99%

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In Vivo Activation of STAT3 Signaling in Satellite Cells and Myofibers in Regenerating Rat Skeletal Muscles

Kami

Senba

2002

J Histochem Cytochem.

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S U M M A R YAlthough growth factors and cytokines play critical roles in skeletal muscle regeneration, intracellular signaling molecules that are activated by these factors in regenerating muscles have been not elucidated. Several lines of evidence suggest that leukemia inhibitory factor (LIF) is an important cytokine for the proliferation and survival of myoblasts in vitro and acceleration of skeletal muscle regeneration. To elucidate the role of LIF signaling in regenerative responses of skeletal muscles, we examined the spatial and temporal activation patterns of an LIF-associated signaling molecule, the signal transducer and activator transcription 3 (STAT3) proteins in regenerating rat skeletal muscles induced by crush injury. At the early stage of regeneration, activated STAT3 proteins were first detected in the nuclei of activated satellite cells and then continued to be activated in proliferating myoblasts expressing both PCNA and MyoD proteins. When muscle regeneration progressed, STAT3 signaling was no longer activated in differentiated myoblasts and myotubes. In addition, activation of STAT3 was also detected in myonuclei within intact sarcolemmas of surviving myofibers that did not show signs of necrosis. These findings suggest that activation of STAT3 signaling is an important molecular event that induces the successful regeneration of injured skeletal muscles.

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Pro‐ and Anti‐apoptotic Members of the Bcl‐2 Family in Skeletal Muscle: A Distinct Role for Bcl‐2 in Later Stages of Myogenesis

Cited by 37 publications

References 49 publications

Effects of Bax Gene Deletion on Muscle and Motoneuron Degeneration in a Sexually Dimorphic Neuromuscular System

Effects of Bax Gene Deletion on Muscle and Motoneuron Degeneration in a Sexually Dimorphic Neuromuscular System

Inhibition of apoptosis improves outcome in a model of congenital muscular dystrophy

In Vivo Activation of STAT3 Signaling in Satellite Cells and Myofibers in Regenerating Rat Skeletal Muscles

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