Sarcoglycan, the heart, and skeletal muscles: new treatment, old drug?

leagues describe important findings regarding the development of dilated cardiomyopathy (DCM) and a potential therapeutic option that can alleviate the cardiomyopathic phenotype (1). Using mouse models of cardiomyopathy in which they ablate two of the sarcoglycan complex members, β-sarcoglycan and δsarcoglycan, and thereby disrupt the muscle cytoskeleton and the sarcoglycan-sarcospan complex in vascular smooth muscle (2), the authors demonstrate improvement of the signs and symptoms using the calcium channel blocker/vasodilator verapamil (1). This improvement includes normalization of the myocardial morphology and serum cardiac troponin I levels. As proof of concept, the authors also show that interruption of verapamil therapy leads to vascular dysfunction, acute myocardial necrosis, and elevation of serum troponin I. Importantly, verapamil therapy in dystrophin-deficient mdx mice, which have an intact sarcoglycan complex, was unable to prevent cardiac muscle pathology. These data suggest that verapamil therapy in patients with certain forms of cardiomyopathy, particularly those caused by sarcoglycan mutations or associated with secondary sarcoglycan deficiency, could be effective in alleviating the signs, symptoms, and devastating outcome of patients with cardiomyopathies. How does this animal model study impact human patients? Let us evaluate the importance of this work. Over the past several years, multiple genes have been reported to cause DCM, including dystrophin (X-linked DCM) (3), actin (4), desmin (5), lamin A/C (6, 7), and, most recently, δ-sarcoglycan (8). These genes not only appear to contribute to structural support of the myocyte, but also appear to link the sarcomere to the sarcolemma and ECM. Dystrophin plays a major role by connecting to the sarcomere via the actin cytoskeleton at the NH2-terminal end of dystrophin and to the sarcolemma at the COOH-terminal through its interaction with the oligomeric membrane complex known as the dystrophin-associated protein complex (DAPC), which includes the sarcoglycan (α, β, γ, δ, ε) and dystroglycan (α, β) subcomplexes (9) (Figure 1). Interestingly, all of the known DCM-causing genes have been previously shown to cause skeletal myopathy, and mutations in the DAPC proteins are important causes of skeletal muscle disease (8, 10). Mouse models with defective sarcoglycan genes have all shown associated cardiomyopathy and skeletal myopathy (limb-girdle muscular dystrophy in mice and humans), while patients with sarcoglycan deficiency have associated DCM in about 30% of cases (11). In the δ-sarcoglycan–deficient mouse, abnormalities of the coronary arteries were also found, resulting in ischemia (2). The mechanism has been speculated to be disruption of the sarcoglycan-sarcospan complex in vascular smooth muscle. In contradistinction, patients with heterozygous δ-sarcoglycan mutations resulting in autosomal dominant DCM or sporadic DCM had normal coronary