HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 9/2/103    most recent 00099.2001v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (11) Citing Articles via Google Scholar Google Scholar Articles by Michele, D. E. Articles by Metzger, J. M. Search for Related Content PubMed PubMed Citation Articles by Michele, D. E. Articles by Metzger, J. M.

Divergent abnormal muscle relaxation by hypertrophic cardiomyopathy and nemaline myopathy mutant tropomyosins

Department of Physiology, University of Michigan, Ann Arbor, Michigan 48109-0622

Mutations in tropomyosin (Tm) have been linked to distinct inherited diseases of cardiac and skeletal muscle, hypertrophic cardiomyopathy (HCM), and nemaline myopathy (NM). How HCM and NM mutations in nearly identical Tm proteins produce the vastly divergent clinical phenotypes of heightened, prolonged cardiac muscle contraction in HCM and skeletal muscle weakness in NM is currently unknown. We report here a direct comparison of the effects of HCM (A63V) and NM (M9R) mutant Tm on membrane-intact myocyte contractile function as assessed by adenoviral gene transfer to fully differentiated cardiac muscle cells. Wild-type, and mutant HCM, and mutant NM proteins were expressed at similar levels in myocytes and incorporated into sarcomeres. Interestingly, HCM mutant Tm produced significantly longer contractions by slowing relaxation, whereas NM mutant Tm produced the opposite effect of accelerated muscle relaxation. We propose slowed relaxation caused by HCM mutant Tm can directly contribute to diastolic dysfunction seen in HCM even without secondary cardiac remodeling. Conversely, hastening of relaxation by NM mutant Tm may shift the force-frequency relationship in skeletal muscle and contribute to muscle weakness seen in NM. Together, these results implicate divergent, abnormal "turning off" of muscle contraction as a cellular basis for the differential pathogenesis of mutant Tm-associated HCM and NM.

tropomyosin; nemaline myopathy; hypertrophic cardiomyopathy; calcium; muscle

This article has been cited by other articles:

				P. B. Chase Tropomyosin in the groove? Molecular insights into an inherited myopathy J. Physiol., June 15, 2007; 581(3): 889 - 889. [Full Text] [PDF]

				P. Coutu, C. N. Bennett, E. G. Favre, S. M. Day, and J. M. Metzger Parvalbumin Corrects Slowed Relaxation in Adult Cardiac Myocytes Expressing Hypertrophic Cardiomyopathy-Linked {alpha}-Tropomyosin Mutations Circ. Res., May 14, 2004; 94(9): 1235 - 1241. [Abstract] [Full Text] [PDF]

				M. J. Heller, M. Nili, E. Homsher, and L. S. Tobacman Cardiomyopathic Tropomyosin Mutations That Increase Thin Filament Ca2+ Sensitivity and Tropomyosin N-domain Flexibility J. Biol. Chem., October 24, 2003; 278(43): 41742 - 41748. [Abstract] [Full Text] [PDF]

				S. B. Marston, J. S. Ingwall, and S. B. Glueck Calcium, contractions, and tropomyosin Focus on "Divergent abnormal muscle relaxation by hypertrophic cardiomyopathy and nemaline myopathy mutant tropomyosins" Physiol Genomics, May 10, 2002; 9(2): 57 - 58. [Full Text] [PDF]