Respiratory Function in the Mdx Mouse Model of Duchenne Muscular Dystrophy: Role of Hypoxia, Stress and Immune Factors

Abstract

Duchenne muscular dystrophy (DMD) is a genetic disease caused by defects in the dystrophin gene. Patients have severe progressive respiratory muscle dysfunction due to progressive weakness and fibrosis culminating in hypoxaemic periods due to hypoventilation. We examined respiratory function in young adult male Mdx (dystrophin deficient) mice (C57BL/10ScSnMdx/J, n=11) and wild type (WT) controls (C57BL/10ScSn, n=10). During normoxic breathing, Mdx mice had significantly reduced breathing frequency, tidal volume and minute ventilation compared to WT. Mdx mice had a significantly increased ventilatory response to acute hypoxic challenge. We also determined that young adult Mdx mice have reduced diaphragm functional capacity compared to WT, with significant decreases in tetanic force, work and power. Interestingly, Mdx diaphragm displayed tolerance to an acute (6hr) in vivo hypoxic stress, which was not observed in WT. In separate studies, co‐treatment with a monoclonal IL‐6 receptor antibody (MR1‐61; 0.3mg/kg) and the CRFR2 agonist, Urocortin 2 (30µg/kg) both administered by 6 subcutaneous injections over 2 weeks completely rescued Mdx diaphragm muscle force loss compared to saline treatment. Mdx mice have pronounced respiratory muscle dysfunction and impaired normoxic ventilation suggestive of hypoventilation. Enhanced hypoxic chemosensitivity and respiratory muscle tolerance of hypoxic stress are suggestive of adaptation to chronic hypoxaemia in young adult life. Hypoxia, stress and immune factors are implicated in diaphragm dysfunction in the Mdx mouse model of DMD.The MR1‐61 antibody was gifted by Chugai Pharmaceuticals, Tokyo, Japan.