SMAC-expression in denervated human skeletal muscle as a potential inhibitor of coexpressed inhibitor-of-apoptosis proteins.
In multinucleated skeletal muscle fibers, apoptotic muscle fiber loss is mediated by a consecutive disassembly of single fiber segments. During this period of time, proapoptotic and antiapoptotic factors compete for promotion or inhibition of apoptotic fiber degradation. In 16 patients with a neurogenic muscular atrophy, we studied the immunohistochemical expression of the inhibitor-of-apoptosis proteins (IAP) survivin, cIAP1, and XIAP and also of second mitochondria-derived activator of caspase (SMAC), which is released during apoptosis and binds to IAPs to prevent them from inhibiting caspases. Although normal control muscle fibers show no expression of SMAC and IAPs, there was a distinct sarcoplasmic expression of SMAC (12.0%+/-3.5%), survivin (10.2%+/-4.0%), cIAP1 (9.0%+/-3.1%), and XIAP (11.0%+/-4.6%) in varying numbers of muscle fibers in neurogenic muscular atrophy. Coexpression of SMAC and IAPs varied. Some denervated muscle fibers displayed up-regulation of either SMAC or IAPs. Other groups of atrophic muscle fibers showed coexpression of SMAC and IAPs. All factors were exclusively up-regulated in atrophic muscle fibers. These findings indicate that IAPs may inhibit apoptotic degradation of denervated muscle fibers. However, IAPs are finally insufficient to counterbalance and prevent muscle fiber apoptosis, as up-regulated expression of SMAC can antagonize this antiapoptotic potential and promote apoptotic muscle fiber disassembly and loss. The interplay between IAPs and SMAC may represent a threshold for muscle fiber-degrading caspase activities. If this bears a therapeutic potential in the prevention of loss of denervated muscle fibers, it remains highly speculative.
Tews
Dominique S
DS
Neurological (Edinger-) Institute, Johann Wolfgang Goethe University-Hospital, Frankfurt/M, Germany. dominique-suzanne.tews@kgu.de
Behrhof
Wera
W
Schindler
Susanne
S
D000368:Aged; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000378:metabolism*; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000294:innervation / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000378:metabolism* / Q000473:pathology
D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins