Absence of caspase-3 protects against denervation-induced skeletal muscle atrophy.
The ubiquitin-proteasome system is a key proteolytic pathway activated during skeletal muscle atrophy. The proteasome, however, cannot degrade intact myofibrils or actinomyosin complexes. In rodent models of diabetes mellitus and uremia, caspase-3 is involved in actinomyosin cleavage, generating fragments that subsequently undergo ubiquitin-proteasome-mediated degradation. Here, we demonstrate that caspase-3 also mediates denervation-induced muscle atrophy. At 2 wk after tibial nerve transection, the denervated gastrocnemius of caspase-3-knockout mice weighed more and demonstrated larger fiber-type-specific cross-sectional area than the denervated gastrocnemius of wild-type mice. However, there was no difference between caspase-3-knockout and wild-type denervated muscles in the magnitude or pattern of actinomyosin degradation, as determined by Western blotting for actin and the 14-kDa actin fragment. Similarly, there was no difference between caspase-3-knockout and wild-type denervated muscles in the magnitude of increase in proteasome activity, total protein ubiquitination, or atrogin-1 and muscle-specific ring finger protein 1 transcript levels. In contrast, there was an increase in TdT-mediated dUTP nick end label-positive nuclei in the denervated muscle of wild-type compared with caspase-3-knockout mice. Apoptotic signaling upstream of caspase-3 remained intact, with equivalent mitochondrial Bax translocation and cytochrome c release and caspase-9 activation in the denervated gastrocnemius muscle of wild-type and caspase-3-knockout mice. In contrast, diminished poly(ADP-ribose) polymerase cleavage in the denervated muscle of caspase-3-knockout compared with wild-type mice revealed that apoptotic signaling downstream of caspase-3 was impaired, suggesting that the absence of caspase-3 protects against denervation-induced muscle atrophy by suppressing apoptosis as opposed to ubiquitin-proteasome-mediated protein degradation.
Plant
Pamela J
PJ
Department of Medicine, St. Michael's Hospital, Canada.
Bain
James R
JR
Correa
Judy E
JE
Woo
Minna
M
Batt
Jane
J
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053148:Caspase 3 / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009121:Muscle Denervation / Q000379:methods*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000294:innervation / Q000473:pathology; D009133:Muscular Atrophy / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D011065:Poly(ADP-ribose) Polymerases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D046988:Proteasome Endopeptidase Complex