Communication breakdown the cause of heart failure in muscular dystrophy

The finding that a breakdown in communication occurs between calcium channels and mitochondria in cardiomyocytes provides new insights into the cause of heart failure in Duchenne muscular dystrophy (DMD).

Researchers from the University of Western Australia and the Victor Chang Cardiac Research Institute in Sydney found that impaired communication between L-type calcium channels and mitochondria in cardiomyocytes from the ventricles of the mdx mouse, a mouse model of DMD, resulted in poor energy production that led to cardiomyopathy.

DMD is a progressive X-linked disease characterised by muscle wasting caused by the absence of the protein dystrophin. It occurs in about 1 in 3500 boys and has no known treatment. About 20% of patients die of dilated cardiomyopathy due to the absence of dystrophin.

The dystrophin protein resides at the inner surface of muscle cells and acts as a shock absorber, stabilising the cells during contraction. Muscle fibres lacking a functional dystrophin are fragile and more vulnerable to breaking than normal muscle fibres.

Dilated cardiomyopathy is associated with cytoskeletal protein disarray, contractile dysfunction and reduced energy production.

Calcium influx through the L-type calcium channel is critical for maintaining excitation and contraction of cardiac muscle cells. It also regulates mitochondrial function and metabolic activity.

When the researchers activated the L-type calcium channel in cardiac cells of the mdx mice there was no corresponding increase in mitochondrial membrane potential and metabolic activity in the cells.

Metabolic function was restored in the cardiac cells when mice were treated with morpholino oligomers to induce skipping of the dystrophin exon 23, which contains a nonsense mutation that gives rise to DMD in this mouse model, or a peptide that blocked the mitochondrial voltage dependent anion channel.

This work clarifies that the absence of dystrophin leads to a disconnect between L-type calcium channels and mitochondria, causing mitochondrial dysfunction that compromises cardiac cell function in the mdx mouse heart.

The study was published in PNAS.