Rat cardiac troponin T mutation (F72L)-mediated impact on thin filament cooperativity is divergently modulated by α- and β-myosin heavy chain isoforms.
The primary causal link between disparate effects of human hypertrophic cardiomyopathy (HCM)-related mutations in troponin T (TnT) and α- and β-myosin heavy chain (MHC) isoforms on cardiac contractile phenotype remains poorly understood. Given the divergent impact of α- and β-MHC on the NH2-terminal extension (44-73 residues) of TnT, we tested if the effects of the HCM-linked mutation (TnTF70L) were differentially altered by α- and β-MHC. We hypothesized that the emergence of divergent thin filament cooperativity would lead to contrasting effects of TnTF70L on contractile function in the presence of α- and β-MHC. The rat TnT analog of the human F70L mutation (TnTF72L) or the wild-type rat TnT (TnTWT) was reconstituted into demembranated muscle fibers from normal (α-MHC) and propylthiouracil-treated (β-MHC) rat hearts to measure steady-state and dynamic contractile function. TnTF72L-mediated effects on tension, myofilament Ca(2+) sensitivity, myofilament cooperativity, rate constants of cross-bridge (XB) recruitment dynamics, and force redevelopment were divergently modulated by α- and β-MHC. TnTF72L increased the rate of XB distortion dynamics by 49% in α-MHC fibers but had no effect in β-MHC fibers; these observations suggest that TnTF72L augmented XB detachment kinetics in α-MHC, but not β-MHC, fibers. TnTF72L increased the negative impact of strained XBs on the force-bearing XBs by 39% in α-MHC fibers but had no effect in β-MHC fibers. Therefore, TnTF72L leads to contractile changes that are linked to dilated cardiomyopathy in the presence of α-MHC. On the other hand, TnTF72L leads to contractile changes that are linked to HCM in the presence of β-MHC.
Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington murali@vetmed.wsu.edu.
Vikram
V
Chandra
Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington.
Sampath K
SK
Gollapudi
Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington.
Murali
M
Chandra
D000818:Animals; D020013:Calcium Signaling; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D007700:Kinetics; D008297:Male; D053580:Muscle Strength; D009154:Mutation; D009200:Myocardial Contraction / Q000187:drug effects; D009210:Myofibrils / Q000187:drug effects / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000378:metabolism*; D010210:Papillary Muscles / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D010641:Phenotype; D010766:Phosphorylation; D011441:Propylthiouracil / Q000494:pharmacology; D011485:Protein Binding; D017207:Rats, Sprague-Dawley; D020107:Troponin T / Q000235:genetics* / Q000378:metabolism; D016277:Ventricular Function, Left
C000594638:MYH7 protein, rat; D020107:Troponin T; D011441:Propylthiouracil; D018995:Myosin Heavy Chains
contractile dynamics; hypertrophic cardiomyopathy; interplay between troponin T and myosin heavy chain; myosin heavy chain; troponin T