title: Dystrophic cardiomyopathy: role of TRPV2 channels in stretch-induced cell damage.
abstract: OBJECTIVE
  Duchenne muscular dystrophy (DMD), a degenerative pathology of skeletal muscle, also induces cardiac failure and arrhythmias due to a mutation leading to the lack of the protein dystrophin. In cardiac cells, the subsarcolemmal localization of dystrophin is thought to protect the membrane from mechanical stress. The absence of dystrophin results in an elevated stress-induced Ca2+ influx due to the inadequate functioning of several proteins, such as stretch-activated channels (SACs). Our aim was to investigate whether transient receptor potential vanilloid channels type 2 (TRPV2) form subunits of the dysregulated SACs in cardiac dystrophy.
  
  
  RESULTS
  We defined the role of TRPV2 channels in the abnormal Ca2+ influx of cardiomyocytes isolated from dystrophic mdx mice, an established animal model for DMD. In dystrophic cells, western blotting showed that TRPV2 was two-fold overexpressed. While normally localized intracellularly, in myocytes from mdx mice TRPV2 channels were translocated to the sarcolemma and were prominent along the T-tubules, as indicated by immunocytochemistry. Membrane localization was confirmed by biotinylation assays. Furthermore, in mdx myocytes pharmacological modulators suggested an abnormal activity of TRPV2, which has a unique pharmacological profile among TRP channels. Confocal imaging showed that these compounds protected the cells from stress-induced abnormal Ca2+ signals. The involvement of TRPV2 in these signals was confirmed by specific pore-blocking antibodies and by small-interfering RNA ablation of TRPV2.
  
  
  CONCLUSIONS
  Together, these results establish the involvement of TRPV2 in a stretch-activated calcium influx pathway in dystrophic cardiomyopathy, contributing to the defective cellular Ca2+ handling in this disease.
authors.affiliation: Department of Physiology, University of Bern, Buehlplatz 5, 3012 Bern, Switzerland.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Lorin
authors.affiliation: Department of Physiology, University of Bern, Buehlplatz 5, 3012 Bern, Switzerland.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Vögeli
authors.affiliation: Department of Physiology, University of Bern, Buehlplatz 5, 3012 Bern, Switzerland niggli@pyl.unibe.ch.
authors.forename: Ernst
authors.initials: E
authors.lastname: Niggli
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology*; D009202:Cardiomyopathies / Q000473:pathology / Q000503:physiopathology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D020388:Muscular Dystrophy, Duchenne / Q000473:pathology / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000473:pathology*; D009995:Osmosis / Q000502:physiology; D012508:Sarcolemma / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013314:Stress, Mechanical; D050916:TRPV Cation Channels / Q000502:physiology*
chemical_list: D015220:Calcium Channels; D050916:TRPV Cation Channels; C485717:Trpv2 protein, mouse; D002118:Calcium
keywords: Calcium; Dystrophy; SACs; TRPV2 channels; mdx cardiomyocytes