Cardiac and skeletal muscle adaptations in health and disease
Year: 2009
Type: dissertation
Abstract: Contractility is a fundamental feature of skeletal and cardiac muscles. \nAn indispensable step in the cellular signal for contraction is a \ntransient elevation in cytoplasmic free [Ca2+] ([Ca2+]i). Both the \nproduction of contractile force and Ca2+ handling processes are highly \nenergy demanding. Mitochondrial ATP production from the respiratory chain \nis thus of pivotal importance for muscle cell function. Moreover, the \nmitochondria are also directly involved in Ca2+ signaling and are the \nforemost source of reactive oxygen species (ROS). Mutations in the \ngenomes encoding for the mitochondrial respiratory chain, either the \nnuclear or the mitochondrial (mtDNA) genome, can give rise to primary \nmitochondrial diseases. Mitochondrial dysfunction is also implicated in \nother diseases, such as heart failure, obesity and diabetes. \n \n \n \nPaper I and II investigate two mouse models of primary mitochondrial \nmyopathy (Tfam KO) and cardiomyopathy (Mterf3 KO). Furthermore, the \nobese, pre-diabetic ob/ob mouse was studied in papers III and IV. \nSkeletal and cardiac muscle cells were studied primarily with respect to \ncontractility, [Ca2+]i and mitochondrial ROS production. \n \n \n \nSkeletal muscle fibers of myopathy Tfam KO mice produce less force \ncompared to control mice. This was explained by reduced tetanic [Ca2+]i, \ndecreased SR Ca2+ release and reduced SR Ca2+ storage via calsequestrin \n2. Moreover, Tfam KO but not control fibers, displayed a markedly \nincreased mitochondrial [Ca2+] during fatigue, partly through a \ncyclosporin A-sensitive mechanism. Elevated [Ca2+] in the mitochondria \ncan trigger cellular damage. Thus, reducing mitochondrial Ca2+ with \ncyclosporin A may provide one way for treatment of mitochondrial \nmyopathy. \n \n \n \nMterf3 KO mice develop hypertrophic cardiomyopathy and die suddenly. \nCardiomyocytes from these mice display elevated SR Ca2+ cycling, \nincreased SR Ca2+ load and aberrant pro-arrhythmic Ca2+ releases \ncompatible with that seen in sympathetic stimulation. In support of this, \nelectrocardiography revealed signs of elevated catecholaminergic drive. \nMoreover, in the moribund stage Mterf3 KO mice develop terminal AV-block \nand bradycardia. \n \n \n \nAcutely exposing WT cardiomyocytes to an excess of the saturated fatty \nacid palmitate caused dissipation of the mitochondrial membrane potential \nand a large increase in mitochondrial ROS production. In turn, this ROS \nincrease impaired the cellular Ca2+ cycling and contractility. However in \nob/ob cardiomyocytes, palmitate did not cause increased ROS production \nand the function of ob/ob cardiomyocytes was in fact improved by \npalmitate. This suggests that the ob/ob heart has adapted to a high fat \nenvironment and metabolizes fatty acids without the producing large \namounts of mitochondrial ROS. \n \n \n \nIn WT cardiomyocytes, application of the beta-adrenergic agonist \nisoproterenol (ISO) stimulated mitochondrial ROS production. Concomitant \napplication of the ROS scavenger N-acetylcysteine (NAC) diminished the \ninotropic effect of ISO on cardiomyocyte [Ca2+]i transients and \ncontractility. On the other hand, ob/ob cardiomyocytes failed to increase \nROS production when exposed to ISO and NAC did not alter the effect of \nISO on [Ca2+]i transients. Hence, mitochondrial ROS is integrated in, but \nnot essential to, the inotropic mechanism of beta-adrenergic stimulation. \n \n \n \nIn all the studied disease models, neither an increase in mitochondrial \nROS production nor signs of oxidative damage were found. \n \n \n \nIn conclusion, dysfunctional mitochondria cause long-term \nadaptive/maladaptive changes in Ca2+ handling as seen in the Tfam and \nMterf3 KO mice. Mitochondrial functions can influence cellular Ca2+ \nhandling also in the short term. This is evident by the effects of \npalmitate and ISO-stimulated mitochondrial ROS production.
Source: Figshare
Author: Daniel Andersson
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1485116840