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1 VCAPP, Washington State University, Pullman, WA, USA
2 Department of Physiology and Biophysics, Albert Einstein College of Medicine, New York, NY, USA
* To whom correspondence should be addressed. E-mail: murali{at}vetmed.wsu.edu.
How different mutations in cardiac troponin T (cTnT) lead to distinct secondary downstream cellular remodeling in familial hypertrophic cardiomyopathy (FHC) remains elusive. To explore the molecular basis for the distinct impact of different mutations in cTnT on cardiac myocytes, we studied mechanical activity of detergent-skinned muscle fiber bundles from different lines of transgenic (TG) mouse hearts that express wild type cTnT (WTTG), R92W cTnT, R92L cTnT and Delta-160 cTnT (deletion of amino acid 160). The amount of mutant cTnT is ~50% of the total myocellular cTnT in both R92W and R92L TG mouse hearts and ~ 35% in Delta-160 TG mouse hearts. Myofilament Ca2+ sensitivity was enhanced in all mutant cTnT TG cardiac muscle fibers. When compared to the WTTG fibers, Ca2+ sensitivity increased significantly at short sarcomere length (SL) of 1.9 µm (p < 0.001) in R92W TG fibers by 2.2-fold, in R92L by 2.1-fold and in Delta-160 by 1.3-fold. At long SL of 2.3 µm, Ca2+ sensitivity increased significantly (p < 0.01) in a similar manner (R92W, 2.5-fold; R92L, 2.0-fold and Delta-160, 1.3-fold). Ca2+ activated maximal tension remained unaltered in all TG muscle fibers. However, tension-dependent ATP consumption increased significantly in Delta-160 TG muscle fibers at both short SL (23%, p < 0.005) and long SL (37%, p < 0.0001), suggesting a mutation-induced change in crossbridge detachment rate constant. Chronic stresses on relative cellular ATP level in cardiac myocytes may cause a strain on energy-dependent Ca2+ homeostatic mechanisms. This may result in pathological remodeling that we observed in Delta-160 TG cardiac myocytes where the ratio of SERCA2/PLB decreased significantly. Our results suggest that different type of stresses imposed on cardiac myocytes would trigger distinct cellular signaling, which leads to remodeling that may be unique to some mutants.
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