title: Loss of cIAP1 attenuates soleus muscle pathology and improves diaphragm function in mdx mice.
abstract: The cellular inhibitor of apoptosis 1 (cIAP1) protein is an essential regulator of canonical and noncanonical nuclear factor κB (NF-κB) signaling pathways. NF-κB signaling is known to play important roles in myogenesis and degenerative muscle disorders such as Duchenne muscular dystrophy (DMD), but the involvement of cIAP1 in muscle disease has not been studied directly. Here, we asked whether the loss of cIAP1 would influence the pathology of skeletal muscle in the mdx mouse model of DMD. Double-mutant cIAP1(-/-);mdx mice exhibited reduced muscle damage and decreased fiber centronucleation in the soleus, compared with single-mutant cIAP1(+/+);mdx mice. This improvement in pathology was associated with a reduction in muscle infiltration by macrophages and diminished expression of inflammatory cytokines such as IL-6 and tumor necrosis factor-α. Furthermore, the cIAP1(-/-);mdx mice exhibited reduced serum creatine kinase, and improved exercise endurance associated with improved exercise resilience by the diaphragm. Mechanistically, the loss of cIAP1 was sufficient to drive constitutive activation of the noncanonical NF-κB pathway, which led to increased myoblast fusion in vitro and in vivo. Collectively, these results show that the loss of cIAP1 protects skeletal muscle from the degenerative pathology resulting from systemic loss of dystrophin.
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Emeka K
authors.initials: EK
authors.lastname: Enwere
authors.forename: Louise
authors.initials: L
authors.lastname: Boudreault
authors.forename: Janelle
authors.initials: J
authors.lastname: Holbrook
authors.forename: Kristen
authors.initials: K
authors.lastname: Timusk
authors.forename: Nathalie
authors.initials: N
authors.lastname: Earl
authors.forename: Eric
authors.initials: E
authors.lastname: LaCasse
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Renaud
authors.forename: Robert G
authors.initials: RG
authors.lastname: Korneluk
mesh_terms: D000818:Animals; D003402:Creatine Kinase / Q000097:blood; D003964:Diaphragm / Q000378:metabolism / Q000503:physiopathology; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D018101:Mice, Inbred mdx; D024510:Muscle Development / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000503:physiopathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010807:Physical Endurance / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016189:Dystrophin; D051034:Inhibitor of Apoptosis Proteins; D015850:Interleukin-6; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D003402:Creatine Kinase