Mending a Broken Heart: The Role of Sarcospan in Duchenne Muscular Dystrophy–Associated Cardiomyopathy

D uchenne muscular dystrophy (DMD) is the most severe and most common form of X-linked muscular diseases. It has been known for over 25 years that DMD is caused by a gene mutation leading to the near total absence of functional dystrophin protein. Transcription of the gene is controlled by 3 independent promoters of which the muscle (M) promoter drives high expression of dystrophin in skeletal and cardiac muscle. Dystrophin is associated with a cytoskeletal lattice commonly referred to as a costamere. It has been shown that dystrophin, through the membrane-spanning region, physically links the extracellular matrix to the actin cytoskeleton. The costameres physically couple the sarcolemmal membrane with the Z disk region and as a result, dystrophin stabilizes the sarcolemma against the mechanical forces produced during the contraction process. The importance of dystrophin in the structural support of the sarcolemma has been clearly shown in data from the mdx mouse, a model of DMD. In this mouse, dystrophin and/or select dystrophin domains have been deleted and the resulting striated muscle cells demonstrate markedly increased fragility, disorganization of the costameres, and necrosis. This knowledge led to the “mechanical hypothesis” in which the lack of dystrophin leads to increased membrane fragility and the progressive cellular necrosis characteristic of the disease. Studies published in the 1990s using cultured myotubes and isolated mature muscle fibers showed that DMD and mdx myotubes were more susceptible to hypo-osmotic shock than control cells, indicating that mdxderived cells were fragile and prone to mechanical injury. Interestingly, the membrane fragility/mechanical injury hypothesis had first been hypothesized in the 1980s in experimental model systems as the underlying mechanism of ischemia/reperfusion injury as well as the calcium paradox. Subsequent groups confirmed that inhibition of contraction at the onset of reperfusion prevented and/or substantially reduced cell death in experimental systems. At the subsarcolemmal location, dystrophin is incorporated into a larger complex of proteins known as the dystrophinassociated protein complex containing dystrophin, dystroglycans, sarcoglycans, sarcospan, dystrobrevins, and syntrophin, which is commonly referred to as the dystroglycan complex (DGC). In addition to its role in structural support of the sarcolemmal membrane, the DGC has been proposed to constitute a potential cellular signaling complex by virtue of the scaffolding nature of dystrophin and the association of many putative cellular signaling molecules into the DGC, raising the possibility that the DGC may be capable of transmitting extracellular-mediated signals to the inside of the cell through the cytoskeleton. Indeed, b-dystroglycan has been shown to interact with mitogen activated protein kinase (MEK) and extracellular signal-regulated kinase (ERK), suggesting that dystroglycan can influence the ERK-mitogen activated protein kinase (MAPK) cascade through such a scaffolding interaction. Laminin also interacts with dystroglycan and is capable of recruiting signaling complexes (eg, Grg2-Sos1) to dystroglycan. Recent experimental studies from Vander Heide have shown that cytoskeletal-based signaling is important in cellular protection in cardiac ischemia–reperfusion injury. These studies imply that the necrosis characteristic of DMD may be in part due to interruption and/or quenching of important cell survival signals involving the proteins present in the DGC complex. The sarcoglycan complex is composed of 4 isoforms (a, b, c, d) and sarcospan (SSPN). SSPN consists of 4 membranespanning segments, while sarcoglycans contain 1 membranespanning region. It has been suggested that the function of the sarcoglycan complex is to strengthen the interaction of bdystroglycan with a-dystroglycan and dystrophin. Mutations in any of the 4 transmembrane proteins result in autosomal recessive limb-girdle muscular dystrophy. Several studies on sarcoglycans have yielded clues that they may also play an important role in intracellular signal transduction. In addition, The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Department of Pathology, Louisiana State University Health Science Center, New Orleans, LA. Correspondence to: Richard Vander Heide, MD, PhD, Department of Pathology, Louisiana State University Health Sciences Center, 1901 Perdido St, New Orleans, LA 70112. E-mail: [email protected] J Am Heart Assoc. 2015;4:e002928 doi: 10.1161/JAHA.115.002928. a 2015 The Author. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.