Downregulation and functional deactivation of the transcriptional coactivator PGC-1alpha has been implicated in heart failure pathogenesis. We hypothesized that the estrogen-related receptor alpha (ERRalpha), which recruits PGC-1alpha to metabolic target genes in heart, exerts protective effects in the context of stressors known to cause heart failure. ERRalpha(-/-) mice subjected to left ventricular (LV) pressure overload developed signatures of heart failure including chamber dilatation and reduced LV fractional shortening. (31)P-NMR studies revealed abnormal phosphocreatine depletion in ERRalpha(-/-) hearts subjected to hemodynamic stress, indicative of a defect in ATP reserve. Mitochondrial respiration studies demonstrated reduced maximal ATP synthesis rates in ERRalpha(-/-) hearts. Cardiac ERRalpha target genes involved in energy substrate oxidation, ATP synthesis, and phosphate transfer were downregulated in ERRalpha(-/-) mice at baseline or with pressure overload. These results demonstrate that the nuclear receptor ERRalpha is required for the adaptive bioenergetic response to hemodynamic stressors known to cause heart failure.

The calcium͞calmodulin-dependent protein phosphatase calcineurin stimulates cardiac hypertrophy in response to numerous stimuli. Calcineurin activity is suppressed by association with modulatory calcineurin-interacting protein (MCIP)1͞DSCR1, which is up-regulated by calcineurin signaling and has been proposed to function in a negative feedback loop to modulate calcineurin activity. To investigate the involvement of MCIP1 in cardiac hypertrophy in vivo, we generated MCIP1 null mice and subjected them to a variety of stress stimuli that induce cardiac hypertrophy. In the absence of stress, MCIP1 ؊/؊ animals exhibited no overt phenotype. However, the lack of MCIP1 exacerbated the hypertrophic response to activated calcineurin expressed from a musclespecific transgene, consistent with a role of MCIP1 as a negative regulator of calcineurin signaling. Paradoxically, however, cardiac hypertrophy in response to pressure overload or chronic adrenergic stimulation was blunted in MCIP1 ؊/؊ mice. These findings suggest that MCIP1 can facilitate or suppress cardiac calcineurin signaling depending on the nature of the hypertrophic stimulus. These opposing roles of MCIP have important implications for therapeutic strategies to regulate cardiac hypertrophy through modulation of calcineurin-MCIP activity.

Cantu syndrome (CS) is caused by gain-of-function (GOF) mutations in genes encoding pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) K ATP channel subunits. We show that patients with CS, as well as mice with constitutive (cGOF) or tamoxifen-induced (icGOF) cardiac-specific Kir6.1 GOF subunit expression, have enlarged hearts, with increased ejection fraction and increased contractility. Whole-cell voltage-clamp recordings from cGOF or icGOF ventricular myocytes (VM) show increased basal L-type Ca 2+ current (LTCC), comparable to that seen in WT VM treated with isoproterenol. Mice with vascularspecific expression (vGOF) show left ventricular dilation as well as less-markedly increased LTCC. Increased LTCC in K ATP GOF models is paralleled by changes in phosphorylation of the pore-forming α 1 subunit of the cardiac voltage-gated calcium channel Cav1.2 at Ser1928, suggesting enhanced protein kinase activity as a potential link between increased K ATP current and CS cardiac pathophysiology.C antu syndrome (CS), characterized by hypertrichosis, osteochondrodysplasia, and multiple cardiovascular abnormalities (1), is caused by gain-of-function (GOF) mutations in the genes encoding the pore-forming (Kir6.1, KCNJ8) and regulatory (SUR2, ABCC9) subunits of the predominantly cardiovascular isoforms of the K ATP channel (2-5). Because the same disease features arise from mutations in either of these subunits, it is concluded that CS arises from increased K ATP channel activity, as opposed to any nonelectrophysiologic function of either subunit.However, this conclusion does not provide immediate explanation for many CS features. In the myocardium, for example, acute activation of K ATP channels results in shortening of the action potential (AP), with concomitant reduction of both calcium entry and contractility (6). The naïve prediction in CS would therefore be that K ATP GOF mutations should shorten the AP, reduce contractility, and reduce cardiac output. We previously reported high cardiac output with low systemic vascular resistance in CS (7). Cantu syndrome cardiac pathology is therefore opposite to prediction, and also unlike classical hypertrophic or dilated cardiomyopathies, in that the ventricle is dilated, but there is increased cardiac output. Here we characterize CS cardiac pathology in patients, and explore the mechanistic basis using mice that express K ATP GOF mutant subunits in the heart and vasculature. ResultsLow Blood Pressure in CS Patients. Eleven CS individuals (five male, six female, aged 17 mo to 47 y), all harboring ABCC9 mutations (Table S1), participated in CS research clinics at St. Louis Children's Hospital. Five had been previously followed at this institution (7) and the remainder were enrolled via the CS Interest Group (www.cantu-syndrome.org). Patient demographic data, genotype, and available cardiac historical, physical, and test information are summarized in Table S1. Most patients had no recalled cardiac symptomatology, although prior office notes revealed episodes of chest pain, f...

Lysosomal storage diseases (LSD) are metabolic disorders characterized by accumulation of undegraded material. The mucopolysaccharidoses (MPS) are LSDs defined by the storage of glycosaminoglycans. Previously, we hypothesized that cells affected with LSD have increased energy expenditure for biosynthesis because of deficiencies of raw materials sequestered within the lysosome. Thus, LSDs can be characterized as diseases of deficiency as well as overabundance (lysosomal storage). In this study, metabolite analysis identified deficiencies in simple sugars, nucleotides, and lipids in the livers of MPSI mice. In contrast, most amino acids, amino acid derivatives, dipeptides, and urea were elevated. These data suggest that protein catabolism, perhaps because of increased autophagy, is at least partially fulfilling intermediary metabolism. Thus, maintaining glycosaminoglycan synthesis in the absence of recycled precursors results in major shifts in the energy utilization of the cells. A high fat diet increased simple sugars and some fats and lowered the apparent protein catabolism. Interestingly, autophagy, which is increased in several LSDs, is responsive to dietary intervention and is reduced in MPSVII and MPSI mice fed a high fat diet. Although long term dietary treatment improved body weight in MPSVII mice, it failed to improve life span or retinal function. In addition, the ventricular hypertrophy and proximal aorta dilation observed in MPSVII mice were unchanged by a high fat, simple sugar diet. As the mechanism of this energy imbalance is better understood, a more targeted nutrient approach may yet prove beneficial as an adjunct therapy to traditional approaches. Lysosomal storage disease (LSD)2 typically results from a genetic deficiency of an acid hydrolase (1). The material usually degraded by the enzyme now accumulates in the lysosomes of cells throughout the body. In normal cells, some proportion of the degraded material is exported to the cytosol for reuse, thereby reducing the energy burden on the cell (2, 3). In the case of LSDs, more energy must be diverted to the synthesis of raw material because of the impaired recycling. Thus, this class of disorders presents with an energy imbalance caused by a simultaneous excess of stored material and a deficiency of raw material (4).Deficiencies in lysosomal enzymes involved in glycosaminoglycan (GAG) catabolism result in the mucopolysaccharidoses (MPS) (5). The biochemical, histological, and clinical phenotypes of MPS are likely due to a combination of the adaptations to both lysosomal storage and a deficiency of recycled monosaccharides. Maintaining a normal rate of GAG biosynthesis would require newly imported or synthesized monosaccharides, irrespective of the adaptations to stored material. The increased demand for GAG precursors is likely to be considerable. It has been shown previously in cultured cells that reutilization of catabolites from lysosomal GAG degradation is substantial (2). Therefore, the increased energy burden required for de novo synthesis...