Molecular mechanism of pH sensitivity of muscle contraction : investigation using site-directed mutagenesis

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The Ca^<2+> sensitivity of contraction in vertebrate striated muscles is modified by a variety of agents such as protons, inorganic phosphate and caffeine. Proton, which is believed to contribute to the inhibited contractility during skeletal muscle fatigue and myocardial ischemia, has a profound depressant effect on the Ca^<2+> sensitivity of the skinned fibres prepared from vertebrate striated muscles, depending on the muscle types in the order of cardiac > fast skeletal > slow skeletal. In this project, we have examined the contributions of the isoforms of troponin subunits to the differential pH dependence of Ca^<2+> sensitivity in striated muscles, by exchanging endogenous TnI and TnC in cardiac skinned fibres with all possible combinations of the corresponding isoforms prepared from fast and s1ow skeletal and cardiac muscles. The results demonstrated that, unlike the findings of early studies by other investigators, the difference in the pH sensitivities of the fast skeletal and cardiac muscles solely depends on the TnC isoforms and also demonstrated that the highest resistibility to the acidic pH of slow skeletal muscle is a manifestation of the unique properties of slow skeletal TnI isoform. Further studies to clarify the site(s) or region(s) in troponin subunit molecules that determines these pH sensitivity are now in progress using site-direct mutagenesis.