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Intracellular calcium handling in ventricular myocytes from mdx mice.
. 2007 Feb; 292(2):H846-55.

Abstract

Duchenne muscular dystrophy (DMD) is a lethal degenerative disease of skeletal muscle, characterized by the absence of the cytoskeletal protein dystrophin. Some DMD patients show a dilated cardiomyopathy leading to heart failure. This study explores the possibility that dystrophin is involved in the regulation of a stretch-activated channel (SAC), which in the absence of dystrophin has increased activity and allows greater Ca(2+) into cardiomyocytes. Because cardiac failure only appears late in the progression of DMD, we examined age-related effects in the mdx mouse, an animal model of DMD. Ca(2+) measurements using a fluorescent Ca(2+)-sensitive dye fluo-4 were performed on single ventricular myocytes from mdx and wild-type mice. Immunoblotting and immunohistochemistry were performed on whole hearts to determine expression levels of key proteins involved in excitation-contraction coupling. Old mdx mice had raised resting intracellular Ca(2+) concentration ([Ca(2+)](i)). Isolated ventricular myocytes from young and old mdx mice displayed abnormal Ca(2+) transients, increased protein expression of the ryanodine receptor, and decreased protein expression of serine-16-phosphorylated phospholamban. Caffeine-induced Ca(2+) transients showed that the Na(+)/Ca(2+) exchanger function was increased in old mdx mice. Two SAC inhibitors streptomycin and GsMTx-4 both reduced resting [Ca(2+)](i) in old mdx mice, suggesting that SACs may be involved in the Ca(2+)-handling abnormalities in these animals. This finding was supported by immunoblotting data, which demonstrated that old mdx mice had increased protein expression of canonical transient receptor potential channel 1, a likely candidate protein for SACs. SACs may play a role in the pathogenesis of the heart failure associated with DMD. Early in the disease process and before the onset of clinical symptoms increased, SAC activity may underlie the abnormal Ca(2+) handling in young mdx mice.

Authors+Show Affiliations

Bosch Institute, School of Medical Sciences, University of Sydney F13, NSW 2006 Australia.No affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17012353

Citation

Williams, Iwan A., and David G. Allen. "Intracellular Calcium Handling in Ventricular Myocytes From Mdx Mice." American Journal of Physiology. Heart and Circulatory Physiology, vol. 292, no. 2, 2007, pp. H846-55.
Williams IA, Allen DG. Intracellular calcium handling in ventricular myocytes from mdx mice. Am J Physiol Heart Circ Physiol. 2007;292(2):H846-55.
Williams, I. A., & Allen, D. G. (2007). Intracellular calcium handling in ventricular myocytes from mdx mice. American Journal of Physiology. Heart and Circulatory Physiology, 292(2), H846-55.
Williams IA, Allen DG. Intracellular Calcium Handling in Ventricular Myocytes From Mdx Mice. Am J Physiol Heart Circ Physiol. 2007;292(2):H846-55. PubMed PMID: 17012353.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Intracellular calcium handling in ventricular myocytes from mdx mice. AU - Williams,Iwan A, AU - Allen,David G, Y1 - 2006/09/29/ PY - 2006/10/3/pubmed PY - 2007/3/21/medline PY - 2006/10/3/entrez SP - H846 EP - 55 JF - American journal of physiology. Heart and circulatory physiology JO - Am. J. Physiol. Heart Circ. Physiol. VL - 292 IS - 2 N2 - Duchenne muscular dystrophy (DMD) is a lethal degenerative disease of skeletal muscle, characterized by the absence of the cytoskeletal protein dystrophin. Some DMD patients show a dilated cardiomyopathy leading to heart failure. This study explores the possibility that dystrophin is involved in the regulation of a stretch-activated channel (SAC), which in the absence of dystrophin has increased activity and allows greater Ca(2+) into cardiomyocytes. Because cardiac failure only appears late in the progression of DMD, we examined age-related effects in the mdx mouse, an animal model of DMD. Ca(2+) measurements using a fluorescent Ca(2+)-sensitive dye fluo-4 were performed on single ventricular myocytes from mdx and wild-type mice. Immunoblotting and immunohistochemistry were performed on whole hearts to determine expression levels of key proteins involved in excitation-contraction coupling. Old mdx mice had raised resting intracellular Ca(2+) concentration ([Ca(2+)](i)). Isolated ventricular myocytes from young and old mdx mice displayed abnormal Ca(2+) transients, increased protein expression of the ryanodine receptor, and decreased protein expression of serine-16-phosphorylated phospholamban. Caffeine-induced Ca(2+) transients showed that the Na(+)/Ca(2+) exchanger function was increased in old mdx mice. Two SAC inhibitors streptomycin and GsMTx-4 both reduced resting [Ca(2+)](i) in old mdx mice, suggesting that SACs may be involved in the Ca(2+)-handling abnormalities in these animals. This finding was supported by immunoblotting data, which demonstrated that old mdx mice had increased protein expression of canonical transient receptor potential channel 1, a likely candidate protein for SACs. SACs may play a role in the pathogenesis of the heart failure associated with DMD. Early in the disease process and before the onset of clinical symptoms increased, SAC activity may underlie the abnormal Ca(2+) handling in young mdx mice. SN - 0363-6135 UR - https://www.unboundmedicine.com/medline/citation/17012353/Intracellular_calcium_handling_in_ventricular_myocytes_from_mdx_mice_ L2 - https://journals.physiology.org/doi/10.1152/ajpheart.00688.2006?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -