Plenaries Sessions Abstract Books

2014 Journal of Neuromuscular Diseases  
Plenaries Sessions Abstract Books S3 branched phenotype has been reported in vivo in mdx animals or in Duchenne patients, it has been attributed to fusion defects consequent to the cycles of regeneration occurring in dystrophic muscles. Our results rather argue that the defect is intrinsic to the fi bers thus challenging current views on the origin of the pathology of Duchenne Muscular Dystrophy. PLENARY SESSION 01 Adult skeletal muscle homeostasis and regeneration relies on satellite cells.
more » ... ike muscle progenitor cells in the embryo, most adult satellite cells have activated the myogenic determination gene, Myf5, and thus have acquired muscle identity. However, post-transcriptional mechanisms prevent accumulation of myogenic factors so that satellite cells constitute a reserve cell population which can be mobilized in response to muscle damage. Quiescent satellite cells in their niche on the muscle fi bre employ protective strategies against toxins and stress. Once activated, satellite cells proliferate and then begin to differentiate into muscle fi bres. This process is accompanied by major metabolic changes, as the differentiating cells progress from a glycolytic to an oxidative state with extensive mitochondrial biogenesis. This leads to increased production of reactive oxygen species (ROS). We show that Pitx transcription factors, also present in the quiescent cell, regulate ROS levels by directly activating genes in the antioxidant pathway. In Pitx2;Pitx3 double conditional mutant mice, ROS levels are abnormally high leading to DNA damage, satellite cell senescence and impaired regeneration. In Pitx3 single mutants, on the other hand, premature differentiation occurs. By manipulating ROS inhibitors in activated satellite cells we show that a moderate PLENARY SESSION 01 Abstracts S4 level of ROS, acting through the p38 kinase pathway, is necessary for the correct timing of the onset of differentiation. Thus the physiological enhancement of ROS production and mitochondrial content is an essential regulator of muscle fi bre formation, as well as a response to the rising energy demand of regenerating muscle. PLENARY SESSION 01 Abstract not received PLENARY SESSION 01
doi:10.3233/jnd-149001 fatcat:rdfitwnd4jaoxli7okyoet47ui