O-Mannosylation of alpha-dystroglycan is required to prevent stress-induced cardiac muscle fiber damage and heart failure

Abstract

Mutations in glycosyltransferases involved in the O-mannosyl processing and formation of matriglycan on alpha-dystroglycan (αDG) constitute a subset of limb girdle muscular dystrophies referred to as dystroglycanopathies. Patients exhibit a range of cardiac phenotypes, including progressive disease leading to heart failure and acute events that can result in death. The goal of the present study was to investigate the factors that provoke heart pathology in a mouse model of dystroglycanopathy. We disrupted O-mannosylation of αDG in vivo by designing a striated muscle-specific protein O-mannosyltransferase 1 knockout mouse line. Hearts from conditional knockout mice appeared histologically and functionally similar to littermate controls up to 60-weeks-of-age. Acute pharmacological-induced contractile stress resulted in large patches of damaged cardiomyofibers and was associated with bradycardia, as determined by electrocardiography, in knockout mice twenty-four hours following the stressor. In hearts from littermate control mice, stress-induced cardiac muscle damage was limited to small patches or individual fibers and did not cause cardiac dysfunction. The contraction-induced cardiac muscle fiber damage observed in the knockout mice led to aberrant remodeling that developed into extensive ventricular fibrosis when examined twenty-eight days later, an effect that was not observed in control hearts. These data indicate that cardiomyopathy due to improper glycosylation of αDG can be instigated by a short-lived increase in workload. Cardiovascular Institutional Research Fellowship -- National Institutes of Health (5T32HL007121-45); Paul D. Wellstone Muscular Dystrophy Specialized Research Center (1U54NS053672); Howard Hughes Medical Institute This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.