Mergoud dit Lamarche, Adeline et al. (2015) International Worm Meeting "Toward the identification of genetic pathways involved in muscle aging in Caenorahbditis elegans."

Bessereau, Jean-Louis, Gieseler, Kathrin, Solari, Florence, Mergoud dit Lamarche, Adeline, Molin, Laurent

[International Worm Meeting, 2015]

Aging is accompanied by a progressive loss of muscle mass and function, associated with a loss of muscle quality, termed sarcopenia. In human, sarcopenia is responsible for a decrease in mobility leading to a reduction in the quality of life. Epidemiological studies further suggest that skeletal muscle aging is also a risk factor for the development of several age-related diseases such as diabetes, cancer, Alzheimer's disease, and Parkinson's disease.Several mechanisms have been proposed to be involved in muscle aging including mitochondria default [1], apoptosis [2] and alteration of muscle protein turnover [3]. However the physiological importance of these events in the etiology of sarcopenia remains to be investigated.We are using C. elegans to identify genetic pathways involved in muscle aging. For this purpose we first aimed to identify and characterize biomarkers of muscle aging. Previous studies have shown that worms exhibit loss of mobility [4], myosin filament disorganization and change in muscle nuclei shape with age [5]. More recently, the Xu laboratory reported a functional decline of motor neurons that precedes alteration of muscle contraction [6]. However those studies have not allowed identifying genuine muscle biomarker of sarcopenia.We have defined a time course of events that take place during muscle aging starting from a decrease in the expression of some but not all, muscle genes expression, followed by a change in mitochondria morphology and an impairment of muscular proteostasis.Based on these biomarkers, we have generated transgenic lines, thanks to the CRISPR technics, which express fluorescent reporter that mirror the levels of endogenous muscle gene expression. We are now using those strains to perform a screen in order to identify genes that modulate muscle aging in an extensive manner.[1] Romanello V, et al. EMBO J (2010), 29:1774-1785. [2] Marzetti, E., et al. Gerontology, (2012) , 58:99-106 [3] Masiero E, et al. Autophagy ; (2010) 6:307-9. [4] Huang, C., et al. Proc. Natl. Acad. Sci., (2004). 101, 8084-8089. [5] Herndon, et al. Nature, (2002). 419, 808-814 [6] Liu J, et al. Cell Metab (2013) 18(3):392-402.

MOLIN, L. et al. (2019) International Worm Meeting "Screen for new actors of muscle aging."

Bessereau, JL., ROY, C., SOLARI, F., MOLIN, L.

[International Worm Meeting, 2019]

We previously demonstrated that muscle aging in C. elegans involves a stereotyped sequence of events characterized by a dramatic decrease in the expression of genes encoding proteins required for muscle contraction, followed by a change in mitochondria morphology, and an increase in autophagosome number (Mergoud et al., 2018). To further characterize the mechanisms underlying muscle aging we used CRISPR/CAS9 to generate a transcriptional reporter that mirrors the down-regulation of tnt-2 (troponine T) expression with age. We used CRISPR-CAS9 to generate a knock-in strain, in which tagRFP-T fluorescence in body wall muscles (BWM) and protein level decrease with age. Using this reporter strain we performed a semi-clonal screen after EMS mutagenesis in order to identify genes whose mutation maintains tagRFP-T fluorescence with age. Details of the screening strategy and some preliminary results will be presented. Mergoud dit Lamarche A., Molin L., Pierson L., Mariol MC., Bessereau JL., Gieseler K., Solari F. (2018). UNC-120/SRF independently controls muscle aging and lifespan in Caenorhabditis elegans. Aging Cell. https://doi.org/10.1111/acel.12713