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As the specific composition of lipids is essential for the maintenance of membrane integrity, enzyme function, ion channels, and membrane receptors, an alteration in lipid composition or metabolism may be one of the crucial changes occurring during skeletal and cardiac myopathies. Although the inheritance (autosomal dominant, autosomal recessive, and X-linked traits) and underlying/defining mutations causing these myopathies are known, the contribution of lipid homeostasis in the progression of these diseases needs to be established. The purpose of this review is to present the current knowledge relating to lipid changes in inherited skeletal muscle disorders, such as Duchenne/Becker muscular dystrophy, myotonic muscular dystrophy, limb-girdle myopathic dystrophies, desminopathies, rostrocaudal muscular dystrophy, and Dunnigan-type familial lipodystrophy. The lipid modifications in familial hypertrophic and dilated cardiomyopathies, as well as Barth syndrome and several other cardiac disorders associated with abnormal lipid storage, are discussed. Information on lipid alterations occurring in these myopathies will aid in the design of improved methods of screening and therapy in children and young adults with or without a family history of genetic diseases.-Saini-Chohan, H.K., R.W. Mitchell, F.M. Vaz, T. Zelinski, and G.M. Hatch. Delineating the role of alterations in lipid metabolism to the pathogenesis of inherited skeletal and cardiac muscle disorders. J. Lipid Res. 2012. 53: 4-27

Persistent pulmonary hypertension of the newborn (PPHN) results in right ventricular (RV) hypertrophy followed by right heart failure and an associated mitochondrial dysfunction. The phospholipid cardiolipin plays a key role in maintaining mitochondrial respiratory and cardiac function via modulation of the activities of enzymes involved in oxidative phosphorylation. In this study, changes in cardiolipin and cardiolipin metabolism were investigated during the development of right heart failure. Newborn piglets (2) environment for 3 days, resulting in the induction of PPHN. Two sets of control piglets were used: 1) newborn or 2) exposed to a normoxic (21% O2) environment for 3 days. Cardiolipin biosynthetic and remodeling enzymes, mitochondrial complex II + III activity, incorporation of [1-14C]linoleoyl-CoA into cardiolipin precursors, and the tetralinoleoyl-cardiolipin pool size were determined in both the RV and left ventricle (LV). PPHN resulted in an increased heart-to-body weight ratio, RV-to-LV plus septum weight ratio, and expression of brain naturetic peptide in RV. In addition, PPHN reduced cardiolipin biosynthesis and remodeling in the RV and LV, which resulted in decreased tetralinoleoyl-cardiolipin levels and reduced complex II + III activity and protein levels of mitochondrial complexes II, III, and IV in the RV. This is the first study to examine the pattern of cardiolipin metabolism during the early development of both the RV and LV of the newborn piglet and to demonstrate that PPHN-induced alterations in cardiolipin biosynthetic and remodeling enzymes contribute to reduced tetralinoleoyl-cardiolipin and mitochondrial respiratory chain function during the development of RV hypertrophy. These defects in cardiolipin may play an important role in the rapid development of RV dysfunction and right heart failure in PPHN.

This study was undertaken to test whether Ca2+-handling abnormalities in cardiomyocytes after ischemia–reperfusion (I/R) are prevented by antioxidants such as N-acetyl l-cysteine (NAC), which is known to reduce oxidative stress by increasing the glutathione redox status, and N-(2-mercaptopropionyl)-glycine (MPG), which scavenges both peroxynitrite and hydroxyl radicals. For this purpose, isolated rat hearts were subjected to 30 min of global ischemia followed by 30 min of reperfusion, and cardiomyocytes were prepared to monitor changes in the intracellular concentration of free Ca2+([Ca2+]i). Marked depression in the left ventricular developed pressure and elevation in the left ventricular end-diastolic pressure in I/R hearts were attenuated by treatment with NAC or MPG. Cardiomyocytes obtained from I/R hearts showed an increase in the basal level of [Ca2+]ias well as augmentation of the low Na+-induced increase in [Ca2+]i, with no change in the KCl-induced increase in [Ca2+]i. These I/R-induced alterations in Ca2+handling by cardiomyocytes were attenuated by treatment of hearts with NAC or MPG. Furthermore, reduction in the isoproterenol-, ATP-, ouabain-, and caffeine-induced increases in [Ca2+]iin cardiomyocytes from I/R hearts were limited by treatment with NAC or MPG. The increases in the basal [Ca2+]i, unlike the KCl-induced increase in [Ca2+]i, were fully or partially prevented by both NAC and MPG upon exposing cardiomyocytes to hypoxia–reoxygenation, H2O2, or a mixture of xanthine and xanthine oxidase. These results suggest that improvement in cardiac function of I/R hearts treated with NAC or MPG was associated with attenuation of changes in Ca2+handling by cardiomyocytes, and the results support the view that oxidative stress due to oxyradical generation and peroxynitrite formation plays an important role in the development of intracellular Ca2+overload in cardiomyocytes as a consequence of I/R injury.

Repletion of Ca2+ in the Ca2+-depleted heart has been shown to produce cardiac dysfunction, myocardial cell damage, intracellular Ca2+ overload, and defects in sarcolemmal and sarcoplasmic reticulum function (Ca2+ paradox). Although these alterations in the Ca2+-paradox heart are associated with a depression in the high-energy phosphate stores, little information regarding changes in mitochondrial oxidative phosphorylation is available. Perfusion of rat hearts with Ca2+-free medium for 5 min followed by reperfusion with a medium containing 1.25 mmol/L Ca2+ for 10 min depressed mitochondrial state 3 respiration, respiratory control index, ADP/O ratio, and rate of oxidative phosphorylation without any change in state 4 respiration. These alterations were partially prevented when the reperfusion was carried out with a medium containing low Ca2+ (0.10–0.50 mmol/L). Treatment of heart with inhibitors of sarcolemmal Ca2+ channels (verapamil and diltiazem) or inhibitors of Na+/Ca2+ exchange (KB-R7943) and Na+/H+ exchange (amiloride) failed to modify changes in mitochondrial function due to Ca2+ paradox. Likewise, antioxidants N-acetylcysteine and N-(2-mercaptopropionyl)-glycine and an oxyradical-scavenging mixture of superoxide dismutase and catalase were ineffective in preventing the mitochondrial alterations in the Ca2+-paradox heart. Incubation of mitochondria with various concentrations of Ca2+ inhibited oxidative phosphorylation; this Ca2+-induced change in mitochondrial function was not affected by different oxyradical-scavenging systems. These observations suggest that defects in mitochondrial function in the Ca2+-paradox heart may be due to the occurrence of intracellular Ca2+ overload rather than the development of oxidative stress.

Cardiolipin (CL) is responsible for modulation of activities of various enzymes involved in oxidative phosphorylation. Although energy production decreases in heart failure (HF), regulation of cardiolipin during HF development is unknown. Enzymes involved in cardiac cardiolipin synthesis and remodeling were studied in spontaneously hypertensive HF (SHHF) rats, explanted hearts from human HF patients, and nonfailing Sprague Dawley (SD) rats. The biosynthetic enzymes cytidinediphosphatediacylglycerol synthetase (CDS), phosphatidylglycerolphosphate synthase (PGPS) and cardiolipin synthase (CLS) were investigated. Mitochondrial CDS activity and CDS-1 mRNA increased in HF whereas CDS-2 mRNA in SHHF and humans, not in SD rats, decreased. PGPS activity, but not mRNA, increased in SHHF. CLS activity and mRNA decreased in SHHF, but mRNA was not significantly altered in humans. Cardiolipin remodeling enzymes, monolysocardiolipin acyltransferase (MLCL AT) and tafazzin, showed variable changes during HF. MLCL AT activity increased in SHHF. Tafazzin mRNA decreased in SHHF and human HF, but not in SD rats. The gene expression of acyl-CoA: lysocardiolipin acyltransferase-1, an endoplasmic reticulum MLCL AT, remained unaltered in SHHF rats. The results provide mechanisms whereby both cardiolipin biosynthesis and remodeling are altered during HF. Increases in CDS-1, PGPS, and MLCL AT suggest compensatory mechanisms during the development of HF. Human and SD data imply that similar trends may occur in human HF, but not during nonpathological aging, consistent with previous cardiolipin studies.

It is commonly held that cardiac remodelling, represented by changes in muscle mass, size, and shape of the heart, explains the progression of congestive heart failure (CHF). However, this concept does not provide any clear information regarding the development of cardiac dysfunction in CHF. Extensive research has revealed that various subcellular organelles such as the extracellular matrix, sarcolemma, sarcoplasmic reticulum, myofibrils, mitochondria, and nucleus undergo varying degrees of changes in their biochemical composition and molecular structure in CHF. This subcellular remodelling occurs due to alterations in cardiac gene expression as well as activation of different proteases and phospholipases in the failing hearts. Several mechanisms including increased ventricular wall stress, prolonged activation of the renin-angiotensin and sympathetic systems, and oxidative stress have been suggested to account for subcellular remodelling in CHF. Furthermore, subcellular remodelling is associated with changes in cardiomyocyte structure, cation homeostasis as well as functional activities of cation channels and transporters, receptor-mediated signal transduction, Ca(2+)-cycling proteins, contractile and regulatory proteins, and energy production during the development of heart failure. The existing evidence supports the view that subcellular remodelling may result in cardiac dysfunction and thus play a critical role in the transition of cardiac hypertrophy to heart failure.

Earlier studies have demonstrated that ouabain-induced increase in [Ca2+]i, as a consequence of sarcolemma (SL) Na+/K+-ATPase inhibition, is associated with activation of both the SL Na+/Ca2+ exchanger and SL Ca2+ channels. In view of the importance of sarcoplasmic reticulum (SR) in the regulation of [Ca2+]i, this study examined the role of SR in ouabain-induced increase in [Ca2+]i in both quiescent and KCl-depolarized cardiomyocytes. For this purpose, adult rat cardiomyocytes were loaded with fura-2 and ouabain-induced changes in [Ca2+]i were monitored upon treatment with or without different agents that are known to influence Ca2+ handling by the intracellular organelles. Ouabain not only increased the basal [Ca2+]i and augmented KCl-induced increase in [Ca2+]i but also produced similar effects on the ATP-induced increase in [Ca2+]i. Treatments of cardiomyocytes with caffeine, ryanodine, or cyclopiazonic acid, which affect SR Ca2+ stores, attenuated the ouabain-induced increase in basal Ca2+ as well as augmentation of the KCl response. Both ryanodine and cyclopiazonic acid produced additional effects, when used in combination with a SL Ca2+ channel inhibitor (verapamil), but not with a Na+/Ca2+ exchange inhibitor (KB-R7943). Inhibitors of Ca2+/calmodulin kinase, protein kinase A, and inositol-3-phosphate receptors were also observed to depress the ouabain-induced increase in [Ca2+]i in cardiomyocytes. On the other hand, mitochondrial Ca2+ transport inhibitors did not exert any effect on the ouabain-induced alterations in [Ca2+]i in cardiomyocytes. Furthermore, ouabain did not show any direct effect on the Ca2+ uptake and Ca2+ release activities of SR or mitochondria. These results suggest an indirect involvement of SR Ca2+ stores in the ouabain-induced increase in [Ca2+]i in cardiomyocytes and indicate the participation of both Ca2+-induced Ca2+ release and regulatory mechanisms in this action.