Cardiac Hypertrophy in the Dog and Rat Induced by Oxfenicine, an Agent Which Modifies Muscle Metabolism

Greaves, Peter; Martín, Juana Robledo; Michel, Mary Ellen; Mompon, P.

doi:10.1007/978-3-642-69132-4_103

Cited by 37 publications

(25 citation statements)

References 5 publications

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“…Humans with inborn errors in mitochondrial FAO cycle enzymes often develop ventricular hypertrophy in the absence of stimuli (such as hypertension) known to induce cardiac hypertrophy (17). Further, cardiac hypertrophy develops in rodents fed drugs that inhibit fatty acid import into the mitochondrion (18)(19)(20). Taken together with the results of studies demonstrating that fatty acid utilization is reduced during pressure overload-induced hypertrophy, these findings suggest that regulatory pathways involved in myocardial lipid metabolism are coupled to cardiac hypertrophic growth.…”

Section: Introductionsupporting

confidence: 63%

A role for Sp and nuclear receptor transcription factors in a cardiac hypertrophic growth program

Sack

Disch

Rockman

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

193

131

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During cardiac hypertrophy, the chief myocardial energy source switches from fatty acid ␤-oxidation (FAO) to glycolysis-a reversion to fetal metabolism. The expression of genes encoding myocardial FAO enzymes was delineated in a murine ventricular pressure overload preparation to characterize the molecular regulatory events involved in the alteration of energy substrate utilization during cardiac hypertrophy. Expression of genes involved in the thioesterification, mitochondrial import, and ␤-oxidation of fatty acids was coordinately down-regulated after 7 days of right ventricular (RV) pressure overload. Results of RV pressure overload studies in mice transgenic for the promoter region of the gene encoding human medium-chain acyl-CoA dehydrogenase (MCAD, which catalyzes a rate-limiting step in the FAO cycle) fused to a chloramphenicol acetyltransferase reporter confirmed that repression of MCAD gene expression in the hypertrophied ventricle occurred at the transcriptional level. Electrophoretic mobility-shift assays performed with MCAD promoter fragments and nuclear protein extracts prepared from hypertrophied and control RV identified pressure overload-induced protein͞DNA interactions at a regulatory unit shown previously to confer control of MCAD gene transcription during cardiac development. Antibody ''supershift'' studies demonstrated that members of the Sp (Sp1, Sp3) and nuclear hormone receptor [chicken ovalbumin upstream promoter transcription factor (COUP-TF)͞erbA-related protein 3] families interact with the pressure overload-responsive unit. Cardiomyocyte transfection studies confirmed that COUP-TF repressed the transcriptional activity of the MCAD promoter. The DNA binding activities and nuclear expression of Sp1͞3 and COUP-TF in normal fetal mouse heart were similar to those in the hypertrophied adult heart. These results identify a transcriptional regulatory mechanism involved in the reinduction of a fetal metabolic program during pressure overload-induced cardiac hypertrophy.Fatty acid oxidation (FAO) is the major source of energy in the adult mammalian heart (1). The chief myocardial energy source switches from glucose and pyruvate in the fetal period to fatty acids after birth (1, 2). Studies in a variety of mammalian species, including humans, have shown that with cardiac hypertrophy, myocardial glucose utilization increases and FAO decreases: a reinduction of the fetal energy metabolic program (3-8). Myocardial energy utilization pathways also undergo alterations during cardiac hypertrophy, as evidenced by the re-expression of the fetal isoforms of a variety of ATPases involved in contractile function (e.g., myosin heavy chains) and ion homeostasis (e.g., Ca 2ϩ -and Na ϩ -K ϩ ATPases) (9-16). Accordingly, reactivation of fetal gene regulatory programs in the hypertrophied heart may serve to reduce ATP and oxygen consumption requirements, albeit at a cost of diminished energy-producing capacity and contractile reserve. Little is known about the molecular regulatory mechanisms involved in...

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Section: Introductionsupporting

confidence: 63%

A role for Sp and nuclear receptor transcription factors in a cardiac hypertrophic growth program

Sack

Disch

Rockman

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

193

131

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“…For example, enlargement of cardiac muscle fibers is reported in dogs and rats after prolonged administration of oxfenicine, a modifying agent for muscle metabolism (Greaves et al, 1984). Cardiac hypertrophy also occurs secondarily by an adoptive response to chemical exposure that affects vascular resistance and oxygen delivery.…”

Section: Discussionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor .ALPHA. (PPAR.ALPHA.) agonist, WY-14,643, increased transcription of myosin light chain-2 in cardiomyocytes.

et al. 2001

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Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that can be activated by xenobiotics and natural fatty acids. To assess the potential physiological activity of PPAR ligands on cardiac muscular cells, the effects of PPAR agonist, WY-14,643, on both rat hearts and a rat cardiomyocyte cell line (H9c2 cells) were investigated. Male F344 rats were fed a diet containing WY-14,643 at a concentration of 100 ppm for 26 weeks. Cardiac muscular hypertrophy was revealed by morphometric analysis in which the diameter of the muscular fibers in WY-14,643-treated rats was larger than those of control rats. Using H9c2 cells in vitro, the protein content per cell was increased in a dosedependent manner with the treatment of WY-14,643. The transcription of myosin light chain-2 (MLC-2), a parameter of myocardial hypertrophy, was increased in H9c2 cells transfected with the rat MLC-2/luciferase fusion gene by WY-14,643 as well as other peroxisome proliferators, clofibrate and di(2-ethylhexyl) phthalate. In addition, accumulation of myosin light chain protein was confirmed in H9c2 cells treated with WY-14,643 at 10 g/ml for 7 days or more by immunohistochemistry. These results suggest that PPAR ligands have a potential to regulate MLC-2, which is a contractile protein in cardiomyocytes and may play a part of role in the pathogenesis of cardiac hypertrophy.

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“…Decreased hepatic gluconeogenesis as a result of liver Cpt1 inhibition may have effects on whole-body insulin response independent of muscle (18,22). Furthermore, Cpt1 inhibition is associated with both cardiac hypertrophy and hepatic steatosis (24)(25)(26). There have been attempts to inhibit the muscle isoform, Cpt1b (23), specifically; however, long-term risks of cardiac hypertrophy and mortality (27) suggest that pharmacological strategies must target specifically skeletal muscle.…”

mentioning

confidence: 99%

Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

Wicks

Vandanmagsar

Haynie

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

107

134

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The correlations between intramyocellular lipid (IMCL), decreased fatty acid oxidation (FAO), and insulin resistance have led to the hypothesis that impaired FAO causes accumulation of lipotoxic intermediates that inhibit muscle insulin signaling. Using a skeletal muscle-specific carnitine palmitoyltransferase-1 KO model, we show that prolonged and severe mitochondrial FAO inhibition results in increased carbohydrate utilization, along with reduced physical activity; increased circulating nonesterified fatty acids; and increased IMCLs, diacylglycerols, and ceramides. Perhaps more importantly, inhibition of mitochondrial FAO also initiates a local, adaptive response in muscle that invokes mitochondrial biogenesis, compensatory peroxisomal fat oxidation, and amino acid catabolism. Loss of its major fuel source (lipid) induces an energy deprivation response in muscle coordinated by signaling through AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) to maintain energy supply for locomotion and survival. At the whole-body level, these adaptations result in resistance to obesity.carnitine palmitoyltransferase | muscle | fatty acid | lipid | carbohydrate C onsiderable evidence suggests that when oversupply of dietary fat exceeds the storage capacity of adipose tissue, ectopic lipids accumulate in skeletal muscle, leading to "metabolic stress" that induces insulin resistance. One prevailing theory is that impaired skeletal muscle fatty acid oxidation (FAO) (1-4) leads to cytosolic accumulation of lipotoxic intermediates that are directly linked to defects in insulin signaling (5-11). Recent findings counter this premise because they have shown that models of insulin resistance consistently exhibit enhanced (not reduced) FAO, as demonstrated by elevated incomplete β-oxidation and accumulation of excess lipid-derived acylcarnitines (12, 13). Supporting evidence was obtained using a whole-body genetic approach to elevate levels of the endogenous carnitine palmitoyltransferase-1 (Cpt1) inhibitor, malonyl-CoA (12). These studies have led to the contrasting theory that lipid overload and incomplete FAO within the mitochondria accelerate the progression of insulin resistance (14). Faced with a plethora of studies supporting both hypotheses, a crucial question remains: "Is inhibition of mitochondrial FAO in skeletal muscle sufficient to initiate development of insulin resistance?" Cpt1 is essential for long-chain acyl-CoA transport into the mitochondria, and lies at the nexus of both the lipotoxicity and the mitochondrial overload hypotheses. If decreased FAO is a root cause of lipotoxicity, then muscle-specific ablation of Cpt1b activity should lead to impaired FAO, intramyocellular lipid (IMCL) accumulation, and insulin resistance. In stark contrast, the mitochondrial overload hypothesis suggests that decreased Cpt1b activity would preserve insulin sensitivity by preventing unbalanced overfueling of β-oxidation. Characterization of the rare genetic disorders o...

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Cardiac Hypertrophy in the Dog and Rat Induced by Oxfenicine, an Agent Which Modifies Muscle Metabolism

Cited by 37 publications

References 5 publications

A role for Sp and nuclear receptor transcription factors in a cardiac hypertrophic growth program

A role for Sp and nuclear receptor transcription factors in a cardiac hypertrophic growth program

Peroxisome proliferator-activated receptor .ALPHA. (PPAR.ALPHA.) agonist, WY-14,643, increased transcription of myosin light chain-2 in cardiomyocytes.

Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

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