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Cellular Biology |
From the Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor.
Correspondence to Joseph M. Metzger, PhD, 7730 Med Sci II, 1301 E Catherine St, Ann Arbor, MI 48109-0622. E-mail metzgerj{at}umich.edu
Inherited restrictive cardiomyopathy (RCM) is a debilitating disease characterized by a stiff heart with impaired ventricular relaxation. Mutations in cardiac troponin I (cTnI) were identified as causal for RCM. Acute genetic engineering of adult cardiac myocytes was used to identify primary structure/function effects of mutant cTnI. Studies focused on R193H cTnI owing to the poor prognosis of this allele. Compared with wild-type cTnI, R193H mutant cTnI more effectively incorporated into the sarcomere, where it exerted dose-dependent effects on basal and dynamic contractile function. Under loaded conditions, permeabilized myocyte Ca2+ sensitivity of tension was increased, whereas the passive tensionextension relationship was not altered by R193H cTnI. Normal rod-shaped myocyte morphology acutely transitioned to a "short-squat" phenotype in concert with progressive stoichiometric incorporation of R193H in the absence of altered diastolic Ca2+. The specific myosin inhibitor blebbistatin fully blocked this transition. Heightened Ca2+ buffering by the R193H myofilaments, and not alterations in Ca2+ handling by the sarcoplasmic reticulum, slowed the decay rate of the Ca2+ transient. Incomplete mechanical relaxation conferred by R193H was exacerbated at increasing pacing frequencies independent of elevated diastolic Ca2+. R193H cTnIdependent mechanical tone caused acute remodeling to a quasicontracted state not elicited by other Ca2+-sensitizing proteins and is a direct correlate of the stiff heart characteristic of RCM in vivo. These results point toward targets downstream of Ca2+ handling, notably thin filament regulation and actinmyosin interaction, in designing therapeutic strategies to redress the primary cell morphological and mechanical underpinnings of RCM.
Key Words: cardiomyopathy troponin contraction
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