Abstract：
:Duchenne muscular dystrophy (DMD) is characterized by muscle degeneration and progressive weakness. There is considerable inter-patient variability in disease onset and progression, which can confound the results of clinical trials. Here we show that a common null polymorphism (R577X) in ACTN3 results in significantly reduced muscle strength and a longer 10 m walk test time in young, ambulant patients with DMD; both of which are primary outcome measures in clinical trials. We have developed a double knockout mouse model, which also shows reduced muscle strength, but is protected from stretch-induced eccentric damage with age. This suggests that α-actinin-3 deficiency reduces muscle performance at baseline, but ameliorates the progression of dystrophic pathology. Mechanistically, we show that α-actinin-3 deficiency triggers an increase in oxidative muscle metabolism through activation of calcineurin, which likely confers the protective effect. Our studies suggest that ACTN3 R577X genotype is a modifier of clinical phenotype in DMD patients.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Hogarth MW,Houweling PJ,Thomas KC,Gordish-Dressman H,Bello L,Cooperative International Neuromuscular Research Group (CINRG).,Pegoraro E,Hoffman EP,Head SI,North KNdoi
10.1038/ncomms14143subject
Has Abstractpub_date
2017-01-31 00:00:00pages
14143issn
2041-1723pii
ncomms14143journal_volume
8pub_type
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