Exercise combined with corticoid/omega-3 therapy positively affected skeletal and cardiac muscles in middle aged mdx mice

Abstract

Exercise has an important impact on skeletal muscle quality, emerging as an adjuvant therapy to ameliorate muscle inflammation and fibrosis in Duchenne muscular dystrophy (DMD). The aim of the present study was to investigate the benefit of exercise alone or in association with corticoid and omega-3 therapy in the middle aged mdx mouse model of DMD, Mdx mice (12 months of age) performed treadmill exercise (12.4 m/min, for 15 min, twice a week) for 4 weeks. Exercised mdx received deflazacort (1.2 mg/kg; gavage) alone or combined with omega-3 (300 mg/kg; gavage). Sedentary mdx, C57BL/10 and exercised mdx received mineral oil and served as control. At the endpoint (14 months of age), muscle function, respiratory function, electrocardiography (ECG), blood markers of myonecrosis (creatine kinase, CK; alanine aminotransferase, ALT; and aspartate aminotransferase, AST), muscle biomarkers of inflammation and fibrosis (western blot), area of fibrosis and histopathology of tibialis anterior, biceps brachii and diaphragm muscles were evaluated. Exercise and exercise-associated therapies improved behavioural activity (open field), muscle function (grip strength, four limb hanging test, hanging wire test and rotarod), VO₂ consumption, VCO₂ production and ECG. Functional benefits correlated with reduced myonecrosis (decreased CK, ALT, AST) and fibrosis. The muscles studied showed a reduction in inflammation biomarkers (NF-κB, IL-6 and TNF-α) and fibrosis (TGF-β and fibronectin) and an increase in calsequestrin (calcium buffering protein) and PGC1-α (muscle integrity marker). In conclusion, exercise alone or associated with corticosteroid/omega-3 therapy benefited limb, diaphragm and cardiac dystrophic muscles in middle-aged mdx mice.

Keywords: PGC1‐α; TNF‐α; corticoid; dystrophy; exercise; fibronectin; rotarod.