Differential physiological role of BIN1 isoforms in skeletal muscle development, function and regeneration
Résumé
Skeletal muscle developmentand regeneration are tightly regulated processes. How the intracellular organization of muscle fibers is achieved during these steps is unclear. Here we focus on the cellular and physiological roles of amphiphysin 2(BIN1), a membrane remodeling protein mutated in both congenital and adult centronuclear myopathies(CNM),that is ubiquitously expressed and hasskeletal muscle-specific isoforms. We created and characterized constitutive, muscle-specific and inducible Bin1homozygous and heterozygous knockout mice targeting either ubiquitousor muscle-specific isoforms.Constitutive Bin1-deficient mice diedat birth from lack of feeding due to a skeletal muscle defect.T-tubules and other organelles weremisplaced and altered, supporting a general early role of BIN1 on intracellular organization in addition to membrane remodeling.Whereasrestricted deletion of Bin1in unchallenged adult muscles had no impact, the forced switch from the muscle-specificisoformsto the ubiquitousisoformsthrough deletion of the in-frame muscle–specific exon delayed muscle regeneration.Thus, BIN1 ubiquitous function is necessary for muscle development and function while its muscle-specific isoformsfine-tune muscle regenerationinadulthood, supporting that BIN1 centronuclear myopathy with congenital onset are due to developmental defects while later onsetmay be due to regeneration defects.
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