title: Impaired contractile function due to decreased cardiac myosin binding protein C content in the sarcomere.
abstract: Mutations in cardiac myosin binding protein C (MyBP-C) are a common cause of familial hypertrophic cardiomyopathy (FHC). The majority of MyBP-C mutations are expected to reduce MyBP-C expression; however, the consequences of MyBP-C deficiency on the regulation of myofilament function, Ca²⁺ homeostasis, and in vivo cardiac function are unknown. To elucidate the effects of decreased MyBP-C expression on cardiac function, we employed MyBP-C heterozygous null (MyBP-C+/-) mice presenting decreases in MyBP-C expression (32%) similar to those of FHC patients carrying MyBP-C mutations. The levels of MyBP-C phosphorylation were reduced 53% in MyBP-C+/- hearts compared with wild-type hearts. Skinned myocardium isolated from MyBP-C+/- hearts displayed decreased cross-bridge stiffness at half-maximal Ca²⁺ activations, increased steady-state force generation, and accelerated rates of cross-bridge recruitment at low Ca²⁺ activations (<15% and <25% of maximum, respectively). Protein kinase A treatment abolished basal differences in rates of cross-bridge recruitment between MyBP-C+/- and wild-type myocardium. Intact ventricular myocytes from MyBP-C+/- hearts displayed abnormal sarcomere shortening but unchanged Ca²⁺ transient kinetics. Despite a lack of left ventricular hypertrophy, MyBP-C+/- hearts exhibited elevated end-diastolic pressure and decreased peak rate of LV pressure rise, which was normalized following dobutamine infusion. Furthermore, electrocardiogram recordings in conscious MyBP-C+/- mice revealed prolonged QRS and QT intervals, which are known risk factors for cardiac arrhythmia. Collectively, our data show that reduced MyBP-C expression and phosphorylation in the sarcomere result in myofilament dysfunction, contributing to contractile dysfunction that precedes compensatory adaptations in Ca²⁺ handling, and chamber remodeling. Perturbations in mechanical and electrical activity in MyBP-C+/- mice could increase their susceptibility to cardiac dysfunction and arrhythmia.
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Cheng
authors.forename: X
authors.initials: X
authors.lastname: Wan
authors.forename: T A
authors.initials: TA
authors.lastname: McElfresh
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: K S
authors.initials: KS
authors.lastname: Gresham
authors.forename: D S
authors.initials: DS
authors.lastname: Rosenbaum
authors.forename: M P
authors.initials: MP
authors.lastname: Chandler
authors.forename: J E
authors.initials: JE
authors.lastname: Stelzer
mesh_terms: D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D006321:Heart / Q000502:physiology; D006339:Heart Rate; D006352:Heart Ventricles / Q000166:cytology; D006579:Heterozygote; D051379:Mice; D009119:Muscle Contraction; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D012518:Sarcomeres / Q000378:metabolism* / Q000502:physiology; D014158:Transcription, Genetic; D000099163:Myosin Binding Protein C
chemical_list: D002118:Calcium; D002352:Carrier Proteins; D000099163:Myosin Binding Protein C
keywords: cardiomyopathy; contractile function; cross-bridge kinetics; myocardium; myosin binding protein C