Abstract
Progressive cardiomyopathy is a major cause of death in Duchenne muscular dystrophy (DMD) patients. Coupling between Ca2+ handling and contractile properties in dystrophic hearts is poorly understood. It is also not clear whether developing cardiac failure is dominated by alterations in Ca2+ pathways or more related to the contractile apparatus. We simultaneously recorded force and Ca2+ transients in field-stimulated papillary muscles from young (10–14 weeks) wild-type (wt) and dystrophic mdx mice. Force amplitudes were fivefold reduced in mdx muscles despite only 30 % reduction in fura-2 ratio amplitudes. This indicated mechanisms other than systolic Ca2+ to additionally account for force decrements in mdx muscles. pCa-force relations revealed decreased mdx myofibrillar Ca2+ sensitivity. ‘In vitro’ motility assays, studied in mdx hearts here for the first time, showed significantly slower sliding velocities. mdx MLC/MHC isoforms were not grossly altered. Dystrophic hearts showed echocardiography signs of early ventricular wall hypertrophy with a significantly enlarged end-diastolic diameter ‘in vivo’. However, fractional shortening was still comparable to wt mice. Changes in the contractile apparatus satisfactorily explained force drop in mdx hearts. We give first evidence of early hypertrophy in mdx mice and possible mechanisms for already functional impairment of cardiac muscle in DMD.
Highlights
Duchenne muscular dystrophy is a progressive, wasting muscle disease that originates from numerous point mutations in the X-chromosomal DMD gene
Force-Ca2+ transients in papillary muscles from young mdx mice stolic diameter in mdx (n =4) over wt (n = 3) mice. At this stage of the disease, fractional shortening of the hearts was not yet compromised. It is still not known which cellular events precede the morphological hypertrophic/dilative changes and to which extent force output is compromised at early stages before the fibrotic onset
Intracellular Ca2+ overload has been linked to amplified positive feedback loops between mitochondrial dysfunction, ROS production and cell death that could explain the progressive ongoing fibrotic remodelling during ageing [18]
Summary
Duchenne muscular dystrophy is a progressive, wasting muscle disease that originates from numerous point mutations in the X-chromosomal DMD gene. Only few studies addressed contractile properties of cardiac muscle from mdx mice, where specific force in young (8–14 weeks) animals was compromised [8, 9]. There are even less studies that have addressed the frequency response of Ca2+ dynamics or force responses in stimulated dystrophic cardiac muscle [8] This is important to know, as diastole progressively shortens with heart rate and may compromise intracellular Ca2+ removal. Ca2+ transients showed a different behaviour: absolute fura-2 ratio amplitudes were about 40% reduced in mdx papillary muscles, their frequency dependence was rather flat, whereas in wt they showed a positive bell shape (Fig. 1C). The steady-state pCa-force relations from 8 wt and 20 mdx preparations clearly showed a marked right shift towards smaller pCa values for papillary muscles from dystrophic mice in the early pre-fibrotic phase (Fig. 2). Details on the statistical analysis are given in the supporting information (SI Methods)
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