Abstract
Decreased cardiac myosin-binding protein C (cMyBPC) expression due to inheritable mutations is thought to contribute to the hypertrophic cardiomyopathy (HCM) phenotype, suggesting that increasing cMyBPC content is of therapeutic benefit. In vitro assays show that cMyBPC N-terminal domains (NTDs) contain structural elements necessary and sufficient to modulate actomyosin interactions, but it is unknown if they can regulate in vivo myocardial function. To test whether NTDs can recapitulate the effects of full-length (FL) cMyBPC in rescuing cardiac function in a cMyBPC-null mouse model of HCM, we assessed the efficacy of AAV9 gene transfer of a cMyBPC NTD that contained domains C0C2 and compared its therapeutic potential with AAV9-FL gene replacement. AAV9 vectors were administered systemically at neonatal day 1, when early-onset disease phenotypes begin to manifest. A comprehensive analysis of in vivo and in vitro function was performed following cMyBPC gene transfer. Our results show that a systemic injection of AAV9-C0C2 significantly improved cardiac function (e.g., 52.24 ± 1.69 ejection fraction in the C0C2-treated group compared with 40.07 ± 1.97 in the control cMyBPC–/– group, P < 0.05) and reduced the histopathologic signs of cardiomyopathy. Furthermore, C0C2 significantly slowed and normalized the accelerated cross-bridge kinetics found in cMyBPC–/– control myocardium, as evidenced by a 32.41% decrease in the rate of cross-bridge detachment (krel). Results indicate that C0C2 can rescue biomechanical defects of cMyBPC deficiency and that the NTD may be a target region for therapeutic myofilament kinetic manipulation.
Highlights
Heart failure (HF) is frequently a result of inherited cardiomyopathies, which are caused by genetic mutations that disrupt cardiomyocyte function [1, 2]
To determine the relative effectiveness of AAV9 gene transfer in cardiac myosin-binding protein C (cMyBPC)–/– mice, cMyBPC expression levels were quantified in AAV9-FL, AAV9-C0C2, or AAV9-GFP–treated cMyBPC–/– myocardium at 6 weeks
Our current study investigated whether gene transfer of the C0C2 N-terminal domains (NTDs) fragment could mitigate the hypertrophic cardiomyopathy (HCM) phenotype in cMyBPC–/– mice by normalizing in vivo contractile function in a manner similar to that of FL cMyBPC
Summary
Heart failure (HF) is frequently a result of inherited cardiomyopathies, which are caused by genetic mutations that disrupt cardiomyocyte function [1, 2]. Since mutations in the MYBPC3 gene, encoding cardiac myosin-binding protein C (cMyBPC), are some of the most frequently implicated in HCM [3], understanding cMyBPC’s role in regulating myocardial contractile function has gained increasing interest in recent years. In rare but severe cases, human patients with homozygous or heterozygous compound MYBPC3 mutations lead to rapid neonatal HF within the first year of life [7, 8]. The idea of increasing cMyBPC expression was proposed as a curative strategy and has since produced promising results in small animal studies [9]. A similar strategy of increasing full-length (FL) cMyBPC expression using a neonatal homozygous cMyBPC-knockin mouse model has been investigated with encouraging results [10]. The striking suppression of pathogenic remodeling in these studies highlights cMyBPC’s indispensable role in regulating sarcomere contractile function
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