A novel mechanism of myocyte degeneration involving the Ca2+-permeable growth factor–regulated channel

Abstract

Disruption of the dystrophin–glycoprotein complex caused by genetic defects of dystrophin or sarcoglycans results in muscular dystrophy and/or cardiomyopathy in humans and animal models. However, the key early molecular events leading to myocyte degeneration remain elusive. Here, we observed that the growth factor–regulated channel (GRC), which belongs to the transient receptor potential channel family, is elevated in the sarcolemma of skeletal and/or cardiac muscle in dystrophic human patients and animal models deficient in dystrophin or δ-sarcoglycan. However, total cell GRC does not differ markedly between normal and dystrophic muscles. Analysis of the properties of myotubes prepared from δ-sarcoglycan–deficient BIO14.6 hamsters revealed that GRC is activated in response to myocyte stretch and is responsible for enhanced Ca2+ influx and resultant cell damage as measured by creatine phosphokinase efflux. We found that cell stretch increases GRC translocation to the sarcolemma, which requires entry of external Ca2+. Consistent with these findings, cardiac-specific expression of GRC in a transgenic mouse model produced cardiomyopathy due to Ca2+ overloading, with disease expression roughly parallel to sarcolemmal GRC levels. The results suggest that GRC is a key player in the pathogenesis of myocyte degeneration caused by dystrophin–glycoprotein complex disruption.

A Multidisciplinary Evaluation of the Effectiveness of Cyclosporine A in Dystrophic Mdx Mice

“…42,50,51 The CsA treatment did not ameliorate the alteration of calcium homeostasis that is a typical hallmark of dystrophic fibers and is worsened by exercise. 2,4,29 CsA per se may even lead to a further increase in calcium mobilization; 52 thus our finding leads to two main considerations: the first one is that the alteration in calcium homeostasis is rather independent on the inflammatory reaction. The second is that CsA acts on the sensitive parameters independently or downstream the alteration of calcium homeostasis.…”

“…This leads to a complex and still not fully understood network of interconnected pathogenic events responsible for progressive muscle degeneration; these events involve the increased entrance of calcium, the activation of proteases, and the occurrence of a functional ischemic state. [1][2][3][4] Recent evidence suggests that a chronic inflammatory state is a secondary reaction that strongly contributes to the progression of the pathology. A significant overexpression of inflammatory and immune response genes has been described by microarray in muscle of dystrophic subjects.…”

PI3-kinase promotes TRPV2 activity independently of channel translocation to the plasma membrane

“…Different reports have shown that heat above 52°C, hypo-osmolarity, membrane stretch or PI3-kinase regulated membrane insertion of the channel could be implicated in the regulation of TRPV2 activity [10,12,13,22]. However, some of these observations have proved difficult to reproduce.…”

“…Other TRPV2 activation mechanisms have also been proposed. In myocytes, TRPV2 channels behave as mechano-and osmo-gated channels and could be involved in the regulation of vascular tone or in myocyte degeneration [12,13].…”

Probenecid Improves Cardiac Function in Patients With Heart Failure With Reduced Ejection Fraction In Vivo and Cardiomyocyte Calcium Sensitivity In Vitro

“…Expression of the transient receptor potential vanilloid 2 (TRPV2) channel was noted in abundance in murine myocardial tissue, specifically in the left ventricle 14. Iwata et al initially described that cardiac‐specific overexpression of TRPV2 resulted in chamber dilation of all cavities of the murine heart,15 while our laboratory recently demonstrated increased expression of TRPV2 in diseased hearts 16. Related studies by our laboratory demonstrated that stimulation of the channel with probenecid in isolated cardiomyocytes resulted in increased cytosolic calcium concentrations with improved contractility and relaxation, independently of the β‐adrenergic signaling pathway 17.…”