Abstract
BackgroundCalpain-3 deficiency causes oxidative and nitrosative stress-induced damage in skeletal muscle of LGMD2A patients, but mitochondrial respiratory chain function and anti-oxidant levels have not been systematically assessed in this clinical population previously.MethodsWe identified 14 patients with phenotypes consistent with LGMD2A and performed CAPN3 gene sequencing, CAPN3 expression/autolysis measurements, and in silico predictions of pathogenicity. Oxidative damage, anti-oxidant capacity, and mitochondrial enzyme activities were determined in a subset of muscle biopsies.ResultsTwenty-one disease-causing variants were detected along the entire CAPN3 gene, five of which were novel (c.338 T>C, c.500 T>C, c.1525-1 G>T, c.2115+4 T>G, c.2366 T>A). Protein- and mRNA-based tests confirmed in silico predictions and the clinical diagnosis in 75% of patients. Reductions in antioxidant defense mechanisms (SOD-1 and NRF-2, but not SOD-2), coupled with increased lipid peroxidation and protein ubiquitination, were observed in calpain-3 deficient muscle, indicating a redox imbalance primarily affecting non-mitochondrial compartments. Although ATP synthase levels were significantly lower in LGMD2A patients, citrate synthase, cytochrome c oxidase, and complex I+III activities were not different from controls.ConclusionsDespite significant oxidative damage and redox imbalance in cytosolic/myofibrillar compartments, mitochondrial respiratory chain function is largely maintained in skeletal muscle of LGMD2A patients.
Highlights
Limb-girdle muscular dystrophy (LGMD) are a heterogeneous group of genetic disorders and characterized by progressive weakness and wasting of the proximal limb girdle muscles and dystrophic muscle pathology
Deficiency of CAPN3 is associated with build-up of toxic debris, oxidative damage, degeneration, and necrosis in LGMD2 patients, proving that it is indispensable for the maintenance and function of skeletal muscle
Clinical findings We studied 14 patients (10 males and 4 females [Table 1]) that fulfilled the diagnostic criteria for LGMD2A proposed by the European Neuromuscular Centre Workshop [22], including atrophy and progressive weakness of shoulder/hip girdles, elevated creatine kinase (CK) levels, and muscle biopsies consistent with a dystrophic/ myopathic process
Summary
Limb-girdle muscular dystrophy (LGMD) are a heterogeneous group of genetic disorders and characterized by progressive weakness and wasting of the proximal limb girdle muscles and dystrophic muscle pathology. Primary calpainopathy (LGMD2A, OMIM 253600), caused by mutations in the 40-kb CAPN3 gene (OMIM 114240, mapped to 15q15.1-q21.1), is the most frequent form of recessive LGMD, with a prevalence of 1:15,000–1:150,000 depending on the population [1]. While the majority of the reported ,480 pathological CAPN3 mutations impair autolysis and enzyme activity of calpain-3 (www.dmd.nl), titin-anchorage and substrate binding may be affected [3], which is exemplified by the fact that 20– 30% of LGMD2A patients exhibit normal calpain-3 protein levels and no loss in autolytic activity [12,13,14,15]. Calpain-3 deficiency causes oxidative and nitrosative stress-induced damage in skeletal muscle of LGMD2A patients, but mitochondrial respiratory chain function and anti-oxidant levels have not been systematically assessed in this clinical population previously
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