Why Is there a Limit to the Changes in Myofilament Ca2+-Sensitivity Associated with Myopathy Causing Mutations?

Abstract

Mutations in striated muscle contractile proteins have been found to be the cause of a number of inherited muscle diseases; in most cases the mechanism proposed for causing the disease is derangement of the thin filament-based Ca2+-regulatory system of the muscle. When considering the results of experiments reported over the last 15 years, one feature has been frequently noted, but rarely discussed: the magnitude of changes in myofilament Ca2+-sensitivity due to myopathy-causing mutations in skeletal or heart muscle seems to be always in the range 1.5–3x EC50. Such consistency suggests it may be related to a fundamental property of muscle regulation; in this article we will investigate whether this observation is true and consider why this should be so. A literature search found 71 independent measurements of HCM mutation-induced change of EC50 ranging from 1.15 to 3.8-fold with a mean of 1.87 ± 0.07 (sem). We also found 11 independent measurements of increased Ca2+-sensitivity due to mutations in skeletal muscle proteins ranging from 1.19 to 2.7-fold with a mean of 2.00 ± 0.16. Investigation of dilated cardiomyopathy-related mutations found 42 independent determinations with a range of EC50 wt/mutant from 0.3 to 2.3. In addition we found 14 measurements of Ca2+-sensitivity changes due skeletal muscle myopathy mutations ranging from 0.39 to 0.63. Thus, our extensive literature search, although not necessarily complete, found that, indeed, the changes in myofilament Ca2+-sensitivity due to disease-causing mutations have a bimodal distribution and that the overall changes in Ca2+-sensitivity are quite small and do not extend beyond a three-fold increase or decrease in Ca2+-sensitivity. We discuss two mechanism that are not necessarily mutually exclusive. Firstly, it could be that the limit is set by the capabilities of the excitation-contraction machinery that supplies activating Ca2+ and that striated muscle cannot work in a way compatible with life outside these limits; or it may be due to a fundamental property of the troponin system and the permitted conformational transitions compatible with efficient regulation.

Pathogenic troponin T mutants with opposing effects on myofilament Ca2+ sensitivity attenuate cardiomyopathy phenotypes in mice

“…Myofilament Ca 2+ sensitivity has been previously shown to be essential in the manifestation of DCM pathophysiology [32–35]. To note, the TnT R141W mutation showed significantly Ca 2+ desensitization and also displayed an increase in Ca 2+ transient amplitudes as a consequence [12].…”

Troponin structure and function: a view of recent progress

“…A large number of mutations in troponin subunits have been found to be associated with cardiomyopathies and have been extensively studied. Mutations in TNNNT2 and TNNI3 genes are significant causes of hypertrophic cardiomyopathy and dilated cardiomyopathy, whilst mutations in in TNNC1 are rare causes of these cardiomyopathies, Functionally the HCM mutations all seem to increase myofilament Ca 2+− sensitivity by about twofold (Marston 2011(Marston , 2016 and this is proposed to be disease-causing (Spudich 2014). In contrast, the effect of DCM mutations on Ca 2+ sensitivity is variable (Marston 2011;Memo et al 2013).…”

Investigations into the Sarcomeric Protein and Ca2+-Regulation Abnormalities Underlying Hypertrophic Cardiomyopathy in Cats (Felix catus)

“…It has been reported that HCM mutations in MYBPC3, MYH7 , and MYL2 cause enhanced myofibrillar Ca 2+ -sensitivity in muscle strips (see Marston, 2016). This was presumed to be due to allosteric interactions between the thick and thin filaments, however the results with the cat samples indicates that troponin is itself altered secondary to the HCM mutations in another gene.…”