Cardiac failure is the most common cause of mortality in Friedreich's ataxia (FRDA), a mitochondrial disease characterized by neurodegeneration, hypertrophic cardiomyopathy and diabetes. FRDA is caused by reduced levels of frataxin (FXN), an essential mitochondrial protein involved in the biosynthesis of iron-sulfur (Fe-S) clusters. Impaired mitochondrial oxidative phosphorylation, bioenergetics imbalance, deficit of Fe-S cluster enzymes and mitochondrial iron overload occur in the myocardium of individuals with FRDA. No treatment exists as yet for FRDA cardiomyopathy. A conditional mouse model with complete frataxin deletion in cardiac and skeletal muscle (Mck-Cre-Fxn(L3/L-) mice) recapitulates most features of FRDA cardiomyopathy, albeit with a more rapid and severe course. Here we show that adeno-associated virus rh10 vector expressing human FXN injected intravenously in these mice fully prevented the onset of cardiac disease. Moreover, later administration of the frataxin-expressing vector, after the onset of heart failure, was able to completely reverse the cardiomyopathy of these mice at the functional, cellular and molecular levels within a few days. Our results demonstrate that cardiomyocytes with severe energy failure and ultrastructure disorganization can be rapidly rescued and remodeled by gene therapy and establish the preclinical proof of concept for the potential of gene therapy in treating FRDA cardiomyopathy.

The function of the majority of genes in the mouse and human genomes remains unknown. The mouse ES cell knockout resource provides a basis for characterisation of relationships between gene and phenotype. The EUMODIC consortium developed and validated robust methodologies for broad-based phenotyping of knockouts through a pipeline comprising 20 disease-orientated platforms. We developed novel statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no prior functional annotation. We captured data from over 27,000 mice finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. Novel phenotypes were uncovered for many genes with unknown function providing a powerful basis for hypothesis generation and further investigation in diverse systems.

Abstract-The injured mammalian heart is particularly susceptible to tissue deterioration, scarring, and loss of contractile function in response to trauma or sustained disease. We tested the ability of a locally acting insulin-like growth factor-1 isoform (mIGF-1) to recover heart functionality, expressing the transgene in the mouse myocardium to exclude endocrine effects on other tissues. supplemental mIGF-1 expression did not perturb normal cardiac growth and physiology. Restoration of cardiac function in post-infarct mIGF-1 transgenic mice was facilitated by modulation of the inflammatory response and increased antiapoptotic signaling. mIGF-1 ventricular tissue exhibited increased proliferative activity several weeks after injury. The canonical signaling pathway involving Akt, mTOR, and p70S6 kinase was not induced in mIGF-1 hearts, which instead activated alternate PDK1 and SGK1 signaling intermediates. The robust response achieved with the mIGF-1 isoform provides a mechanistic basis for clinically feasible therapeutic strategies for improving the outcome of heart disease. (Circ Res. 2007;100:1732-1740.)Key Words: cardiac muscle Ⅲ insulin-like growth factor-1 Ⅲ regeneration Ⅲ wound healing T he insulin/insulin-like growth factor signaling pathway arose early in the evolution and is highly conserved among invertebrates and vertebrates. 1 Mammalian IGF-1 acts predominately as a growth, survival, and differentiation factor. The pleiotropic functions of IGF-1 are reflected in the complicated structure and regulation of Igf-1 gene. 2 The products include variable amino-terminal signal peptides and different carboxy-terminal E peptides, the precise function of which is still unclear. Injury of mammalian tissues induces transient production of locally acting IGF-1 isoforms that control growth, survival, and differentiation. 3 By contrast, high levels of circulating IGF-1, produced by the liver, has been implicated in the restriction of lifespan 1 and predisposition to neoplasia. 4 When expressed as transgenes, different IGF-1 isoforms have contrasting effects on the mouse heart. Transgenic mice generated with a minor human IGF-1 cDNA under the control of the rat ␣-myosin heavy chain (␣-MHC) promoter showed no striking differences in size and cell volume when compared with control mice, but harbored an increased number of cardiomyocytes, coupling IGF-1 overexpression with myocyte proliferation. 5 The hearts of these animals responded to coronary ligation with attenuated diastolic wall stress, cardiac weight, ventricular dilatation, and hypertrophy, attributable mainly to a prevention of cardiac cell death. 6 In another report, cardiac expression of a modified human IGF-1 cDNA produced no hyperplasia but instead induced physiologic, then pathologic, cardiac hypertrophy in transgenic mice. 7 Here, we have used the mIGF-1 isoform, comprising a Class 1 signal peptide and a C-terminal Ea extension peptide. 8 This isoform is expressed at high levels in neonatal tissues and in the adult liver, but decreases during aging ...

Mutation of 5-HT(2B) receptor leads to a cardiomyopathy without hypertrophy and a disruption of intercalated disks. 5-HT(2B) receptor is required for cytoskeleton assembly to membrane structures by its regulation of N-cadherin expression. These results constitute, for the first time, strong genetic evidence that serotonin, via the 5-HT(2B) receptor, regulates cardiac structure and function.