title: Hypertrophic cardiomyopathy-related beta-myosin mutations cause highly variable calcium sensitivity with functional imbalances among individual muscle cells.
abstract: Disease-causing mutations in cardiac myosin heavy chain (beta-MHC) are identified in about one-third of families with hypertrophic cardiomyopathy (HCM). The effect of myosin mutations on calcium sensitivity of the myofilaments, however, is largely unknown. Because normal and mutant cardiac MHC are also expressed in slow-twitch skeletal muscle, which is more easily accessible and less subject to the adaptive responses seen in myocardium, we compared the calcium sensitivity (pCa(50)) and the steepness of force-pCa relations (cooperativity) of single soleus muscle fibers from healthy individuals and from HCM patients of three families with selected myosin mutations. Fibers with the Arg723Gly and Arg719Trp mutations showed a decrease in mean pCa(50), whereas those with the Ile736Thr mutation showed slightly increased mean pCa(50) with higher active forces at low calcium concentrations and residual active force even under relaxing conditions. In addition, there was a marked variability in pCa(50) between individual fibers carrying the same mutation ranging from an almost normal response to highly significant differences that were not observed in controls. While changes in mean pCa(50) may suggest specific pharmacological treatment (e.g., calcium antagonists), the observed large functional variability among individual muscle cells might negate such selective treatment. More importantly, the variability in pCa(50) from fiber to fiber is likely to cause imbalances in force generation and be the primary cause for contractile dysfunction and development of disarray in the myocardium.
authors.affiliation: Molecular and Cell Physiology, Medical School Hannover, Germany.
authors.forename: Sebastian E
authors.initials: SE
authors.lastname: Kirschner
authors.forename: Edgar
authors.initials: E
authors.lastname: Becker
authors.forename: Massimo
authors.initials: M
authors.lastname: Antognozzi
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Kubis
authors.forename: Antonio
authors.initials: A
authors.lastname: Francino
authors.forename: Francisco
authors.initials: F
authors.lastname: Navarro-López
authors.forename: Nana
authors.initials: N
authors.lastname: Bit-Avragim
authors.forename: Andreas
authors.initials: A
authors.lastname: Perrot
authors.forename: Mirsaid M
authors.initials: MM
authors.lastname: Mirrakhimov
authors.forename: Karl-Josef
authors.initials: KJ
authors.lastname: Osterziel
authors.forename: William J
authors.initials: WJ
authors.lastname: McKenna
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brenner
authors.forename: Theresia
authors.initials: T
authors.lastname: Kraft
mesh_terms: D002118:Calcium / Q000378:metabolism*; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D018995:Myosin Heavy Chains / Q000235:genetics*; D010766:Phosphorylation; D017354:Point Mutation
chemical_list: D018995:Myosin Heavy Chains; D002118:Calcium