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.
Highlights
Duchenne muscular dystrophy (DMD) is characterized by muscle degeneration and progressive weakness
The ACTN3 577X allele was associated with poorer muscle performance; ACTN3 577RX patients display significantly less strength across the quantitative muscle testing (QMT) and took significantly longer to complete the 10 m walk test compared with patients with ACTN3 577RR genotype
We show a marked (2-fold) upregulation in the expression of regulator of calcineurin 1.4 (RCAN 1.4) in double knockout model (dKO) mice compared with control mdx (Fig. 6a,b); this was not associated with an increase in the expression of utrophin or a shift in fibre type at baseline (Supplementary Fig. 3)
Summary
Duchenne muscular dystrophy (DMD) is characterized by muscle degeneration and progressive weakness. A single nucleotide polymorphism (SNP) in SPP1, resulting in reduced gene expression, was associated with greater muscle weakness and earlier loss of ambulation (LoA)[5] The mechanism underlying this effect on DMD phenotype has not yet been determined, but SPP1 expression is known to affect muscle regeneration[6] and is upregulated in DMD patients[7]. The modifier effect on LoA has since been replicated for both of these genes in a large patient cohort, but only when the cohort was stratified for both ethnicity and corticosteroid treatment, highlighting the difficulty associated with identifying genetic modifiers Both SPP1 and LTBP4 map to the TGF-b pathway, a key driver of failed regeneration and the development of fibrosis in DMD Actn[3] knockout (KO) mice mimic the phenotype seen in a-actinin-3 deficient humans; Actn[3] KO mice have reduced muscle mass and strength[18], but display increased endurance capacity, fatigue resistance and response to training[19,20]
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