Pathogenetic role of the sarcoglycan-sarcospan complex in cardiomyopathies

Cardiomyopathy is a multifactorial disease and one of the leading causes of heart failure in the industrial world. The dystrophin-glycoprotein complex has been implicated in the pathogenesis of both hereditary and acquired forms of cardiomyopathy. Clinical features of cardiomyopathy have been reported in patients with mutations in dystrophin and the sarcoglycan genes. We have developed mouse models of cardiomyopathy by ablation of genes encoding components of the sarcoglycan complex. Interestingly, mice deficient for α-sarcoglycan (Sgca-null) exhibit a progressive muscular dystrophy but do not develop cardiomyopathy, despite a disruption of the sarcoglycan-sarcospan complex. In marked contrast, mice deficient for β- and δ-sarcoglycan (Sgcb- and Sgcd-null, respectively) display a more severe muscular dystrophy and develop cardiomyopathy. In addition to perturbation of the sarcoglycan-sarcospan complex in striated muscle, both animal models show an additional disruption of the sarcoglycan-sarcospan complex in vascular smooth muscle. This leads to perturbation of vascular function as shown by multiple microvascular constrictions. Moreover, Sgcb- and Sgcd-null mice show a disruption of a distinct ε-sarcoglycan containing complex in striated muscle. Taken together, perturbation of vascular function together with disruption of the cardiac muscle sarcoglycan-sarcospan complex represent a novel mechanism in the pathogenesis of cardiomyopathies associated with limb-girdle muscular dystrophy types 2E and F. Characterization of this novel mechanism will ultimately lead to new pharmacological and gene therapeutic approaches targeted not only towards striated muscle but also towards the dysfunction of the vascular system.