Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin

Duchenne muscular dystrophy is a fatal X-linked disease characterized by the absence of dystrophin. Approximately 20% of boys will die of dilated cardiomyopathy that is associated with cytoskeletal protein disarray, contractile dysfunction, and reduced energy production. However, the mechanisms for altered energy metabolism are not yet fully clarified. Calcium influx through the L-type Ca 2+ channel is critical for maintaining cardiac excitation and contraction. The L-type Ca 2+ channel also regulates mitochondrial function and metabolic activity via transmission of movement of the auxiliary beta subunit through intermediate filament proteins. Here, we find that activation of the L-type Ca 2+ channel is unable to induce increases in mitochondrial membrane potential and metabolic activity in intact cardiac myocytes from the murine model of Duchenne muscular dystrophy (mdx) despite robust increases recorded in wt myocytes. Treatment of mdx mice with morpholino oligomers to induce exon skipping of dystrophin exon 23 (that results in functional dystrophin accumulation) or application of a peptide that resulted in block of voltage-dependent anion channel (VDAC) "rescued" mitochondrial membrane potential and metabolic activity in mdx myocytes. The mitochondrial VDAC coimmunoprecipitated with the L-type Ca 2+ channel. We conclude that the absence of dystrophin in the mdx ventricular myocyte leads to impaired functional communication between the L-type Ca 2+ channel and mitochondrial VDAC. This appears to contribute to metabolic inhibition. These findings provide new mechanistic and functional insight into cardiomyopathy associated with Duchenne muscular dystrophy.ion channels | structure | cytoskeleton D uchenne muscular dystrophy affects 1:3,500 males, and in addition to skeletal muscle damage and atrophy, boys also develop a dilated cardiomyopathy due to the absence of expression of dystrophin. This pathology involves myocyte remodelling, disorganization of cytoskeletal proteins, and contractile dysfunction (1, 2). Early metabolic and signaling alterations have been reported in 10-to 12-wk-old murine model of Duchenne muscular dystrophy (mdx) hearts before the development of overt contractile dysfunction (2). However, the mechanisms by which absence of dystrophin leads to mitochondrial dysfunction and compromised cardiac function in mdx hearts are not fully clarified yet.Cytoskeletal proteins stabilize cell structure. In mature muscle, intermediate filaments form a 3D scaffold that extend from the Z disks to the plasma membrane and traverse cellular organelles such as t-tubules, sarcoplasmic reticulum, and mitochondria (3). Intermediate filaments and microtubules interact directly with mitochondria by binding to outer mitochondrial membrane proteins. In addition to a physical association, cytoskeletal proteins also regulate the function of proteins in the plasma membrane and within the cell (4). The L-type Ca 2+ channel (I Ca-L ) or dihydropyridine receptor (DHPR) is anchored to F-actin networks by subsarcolemmal sta...

Background: Antisense oligonucleotides (AOs) can interfere with exon recognition and intron removal during pre-mRNA processing, and induce excision of a targeted exon from the mature gene transcript. AOs have been used in vitro and in vivo to redirect dystrophin pre-mRNA processing in human and animal cells. Targeted exon skipping of selected exons in the dystrophin gene transcript can remove nonsense or frame-shifting mutations that would otherwise have lead to Duchenne Muscular Dystrophy, the most common childhood form of muscle wasting.