|Des Rosiers, Christine|
Submitted to: Journal of Molecular and Cellular Cardiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/14/2007
Publication Date: 5/24/2007
Citation: Khairallah, M., Khairallah, R., Young, M.E., Dyck, J.R.B., Petrof, B.J., Des Rosiers, C. 2007. Metabolic and signaling alterations in dystrophin-deficient hearts precede overt cardiomyopathy. Journal of Molecular and Cellular Cardiology. 43:119-129. Interpretive Summary: Muscular dystrophy patients develop severe heart disease. Therefore, understanding the events leading to heart disease development may improve therapies for these patients. The present study investigated some of the events occurring before and after heart disease development in an animal model of muscular dystrophy. The results show marked alterations in metabolism and signaling in the heart, prior to heart disease development.
Technical Abstract: The cytoskeletal protein dystrophin has been implicated in hereditary and acquired forms of cardiomyopathy. However, much remains to be learned about the role of dystrophin in the heart. We hypothesized that the dystrophin-deficient heart displays early alterations in energy metabolism that precede overt cardiomyopathy. We evaluated the metabolic and functional phenotype of dystrophin-deficient mdx mouse hearts at 10-12 weeks, when no major histological or echocardiographic abnormalities are reported. Ex vivo working mdx heart perfusions with stable isotopes revealed a marked shift in substrate fuel selection from fatty acids to carbohydrates associated with enhanced oxygen consumption. They also unmasked in the mdx heart: (i) compromised cardiac contractile function and efficiency, (ii) reduced cellular integrity, and (iii) exacerbated alterations in mitochondrial citric acid cycle-related parameters and in nutrient signaling pathways related to Akt. The observed shift in substrate selection cannot be explained by metabolic gene remodeling. However, mdx mice hearts showed an increased expression of the atrial natriuretic factor (anf) gene, an activator of the nitric oxide (NO)/cGMP signaling pathway and marker of cardiac remodeling, and, only as the cardiomyopathy progresses (at 25 weeks of age), an increased expression of the alpha(1) subunit of soluble guanylate cyclase, which is known to negatively correlate with the activity NO/cGMP pathway. Collectively, our results highlight early metabolic and signaling alterations in the dystrophin-deficient heart, which may predispose these hearts to contractile dysfunction and sarcolemmal fragility. They also suggest the presence of a "sub-clinical" defect in the NO/cGMP pathway, which in vivo, at an early age, may be compensated by enhanced anf gene expression.