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 systemof
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 independentmeasurements of HCMmutation-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 show
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.