Decreased contractility due to energy deprivation in a transgenic rat model of hypertrophic cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is associated with cardiac hypertrophy, diastolic dysfunction, and sudden death. Recently, it has been suggested that inefficient energy utilization could be a common molecular pathway of HCM-related mutations. We have previously generated transgenic Sprague-Dawley rats overexpressing a truncated cardiac troponin T (DEL-TNT) molecule, displaying typical features of HCM such as diastolic dysfunction and an increased susceptibility to ventricular arrhythmias. We now studied these rats using 31P magnetic resonance spectroscopy (MRS). MRS demonstrated that cardiac energy metabolism was markedly impaired, as indicated by a decreased phosphocreatine to ATP ratio (-31%, p < 0.05). In addition, we assessed contractility of isolated cardiomyocytes. While DEL-TNT and control cardiomyocytes showed no difference under baseline conditions, DEL-TNT cardiomyocytes selectively exhibited a decrease in fractional shortening by 28% after 1 h in glucose-deprived medium (p < 0.05). Moreover, significant decreases in contraction velocity and relaxation velocity were observed. To identify the underlying molecular pathways, we performed transcriptional profiling using real-time PCR. DEL-TNT hearts exhibited induction of several genes critical for cardiac energy supply, including CD36, CPT-1/-2, and PGC-1alpha. Finally, DEL-TNT rats and controls were studied by radiotelemetry after being stressed by isoproterenol, revealing a significantly increased frequency of arrhythmias in transgenic animals. In summary, we demonstrate profound energetic alterations in DEL-TNT hearts, supporting the notion that inefficient cellular ATP utilization contributes to the pathogenesis of HCM.

Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression

“…Intracellular Ca 2+ transients of Fura2-AM loaded ARVCMs (2 μmol l −1 for 20 min at 37 °C followed by 20 min incubation to allow for complete de-esterification of the dye) were obtained 24 h after plating and adenoviral infection as described above following a previously published protocol5960. Measurements were carried out using an inverse Olympus microscope (IX70) with a UV filter connected to a monochromator (Polychrome II, T.I.L.L.…”

“…Care and breeding of zebrafish Danio rerio was done under standardized and established conditions6061. The present study was performed under institutional approval, which comply by the Guide for the Care and Use of Laboratory Animals published by the US National Institute of Health (NIHPublication No.…”

“…Functional assessment of cardiac contractility was carried out at the indicated time points post fertilization6061. Ventricular fractional shortening fraction was calculated from the differences of maximum diastole and maximum systole measurements with the help of the zebraFS software (http://www.benegfx.de).…”

Metabolic Modulator Perhexiline Corrects Energy Deficiency and Improves Exercise Capacity in Symptomatic Hypertrophic Cardiomyopathy

“…The observation that patients with HCM manifest impaired myocardial PCr/ATP (Table 1), at least those with sarcomeric mutations, is an expected and likely direct consequence of the biophysical properties of the mutations and accords with previous animal and human studies. 16,17,[25][26][27] Thus, although the pathogenesis of sarcomeric HCM has been varyingly attributed to increased sarcomeric Ca 2ϩ sensitivity, ATPase activity, and aberrant cross-bridge dynamics 6,8 with complications such as oxidative stress 28 and altered sarcomeric phosphorylation, 29,30 a common feature of such studies is the excessive energetic cost of tension generation by sarcomeric mutations. 7,9 In addition to these biophysical considerations, further evidence that the energy deficiency in HCM is a primary event and not a secondary feature of cardiac remodeling (either LV hypertrophy or heart failure) derives from the observation that myocardial high-energy phosphates are even compromised in asymptomatic HCM 16 and prehypertrophic cardiomyopathy.…”

Disease Pathways and Novel Therapeutic Targets in Hypertrophic Cardiomyopathy

“…12,42 In transgenic models of HCM expressing a variety of mutant sarcomeric proteins, impaired energetics precede cardiac pathology. 23,40,43,44 Similarly, HCM patients, irrespective of the presence or absence of hypertrophy, exhibit Ϸ30% reduction in the phosphocreatine-to-ATP ratio, an established marker of cellular energy status. [45][46][47] A reduction in cellular energy charge would be expected to compromise the regulation of membrane potentials and ion currents (regulated by energy-requiring transporters such as Naϩ/Kϩ ATPase and SERCA) and activate cellular energy sensors such as the AMP-activated protein kinase (AMPK) (Figure 2).…”