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Aging is associated with a decline in the cardiovascular and muscular systems with an increased prevalence of heart failure (HF), age-related muscle atrophy (sarcopenia) and increased fat-to-muscle ratio (sarcopenic obesity). In previous years, we studied a conditional KO of the SRF transcription factor that regulates muscle genes and whose changes in activity were involved in cardiovascular aging. We also pursued our studies on the role of intermediate filaments (IFs) in muscle through the generation of a new KO model for synemin (Syn), a partner of vimentin (Vim) and desmin (Des) that plays a key role in the structuration of cytoskeleton and mitochondria. We studied extensively the molecular mechanisms underlying the pathogenesis of dilated cardiomyopathy (DCM) and HF, angiogenesis and muscle dystrophy in these models. Two main themes will be developed. The first one is based on transcriptome analyses of the SRF cardiac KO, pointing to alterations in the expression of genes involved in cytoskeleton organization and energy metabolism. Specifically, we initiate a new theme on the role of a kinase involved in the biosynthesis of NAD, Nmrk2, which is overexpressed in the SRF KO and other HF models. NAD acts not only as a cofactor for oxidation of energetic substrates but also as a signaling molecule used by enzymes like the Sirtuins and the PARPs involved in chromatin remodeling, energy metabolism and resistance to oxidative stress. We generated transgenic and KO models to determine the role of Nmrk2 and NAD signaling in the pathogenesis of DCM/HF and aging process. A second axis of research will focus on the role of IF in the balance between energy production and consumption and in skeletal muscle growth. Indeed, we found that old Des, Vim and Syn KO mice stay leaner than controls. Moreover Des and Vim KO are fully resistant to obesity induced by a high fat diet, while Syn KOs develop exaggerated muscle hypertrophy. The role of endurance exercise and pharmaceutical mimetics as a counter measure to sarcopenic obesity will be studied. We will focus on the molecular mechanisms linked to IF expression/organization and transcription factor activity. All the mouse models are present in the animal facility of the Charles Foix Institute for Longevity (Ivry sur Seine) dedicated to longterm longitudinal studies in mice. | |
