4.5 Article

Differential physiological roles for BIN1 isoforms in skeletal muscle development, function and regeneration

期刊

DISEASE MODELS & MECHANISMS
卷 13, 期 11, 页码 -

出版社

COMPANY BIOLOGISTS LTD
DOI: 10.1242/dmm.044354

关键词

Myotubular myopathy; Centronuclear myopathy; XLMTM; SH3 domain; BAR domain; Myotonic dystrophy; Triad; Dynamin; Myoblast fusion; Animal model

资金

  1. Institut National de la Santeet de la Recherche Medicale, Centre National de la Recherche Scientifique, Universite de Strasbourg
  2. Agence Nationale de la Recherche [ANR-08-GENOPAT-005, ANR-10-LABX-0030-INRT, ANR-10-IDEX-0002-02]
  3. Agence Nationale de la Recherche [Reseau National des Genopoles]
  4. Agence Nationale de la Recherche [Fondation Maladies Rares]
  5. Agence Nationale de la Recherche [Fondation pour la Recherche Medicale] [20071210538]
  6. Agence Nationale de la Recherche [Association Francaise contre les Myopathies] [13304, 14058, 15352, 17088, 20323]
  7. Agence Nationale de la Recherche [MyoNeurALP] [5.3.4.4]

向作者/读者索取更多资源

Skeletal muscle development and 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 centro nuclear myopathies (CNM), that is ubiquitously expressed and has skeletal muscle-specific isoforms. We created and characterized constitutive muscle-specific and inducible Bin1 homozygous and heterozygous knockout mice targeting either ubiquitous or muscle-specific isoforms. Constitutive Bin1-deficient mice died at birth from lack of feeding due to a skeletal muscle defect. T-tubules and other organelles were misplaced and altered, supporting a general early role for BIN1 in intracellular organization, in addition to membrane remodeling. Although restricted deletion of Bin1 in unchallenged adult muscles had no impact, the forced switch from the muscle-specific isoforms to the ubiquitous isoforms through deletion of the in-frame muscle-specific exon delayed muscle regeneration. Thus, ubiquitous BIN1 function is necessary for muscle development and function, whereas its muscle-specific isoforms fine tune muscle regeneration in adulthood, supporting that BIN1 CNM with congenital onset are due to developmental defects, whereas later onset may be due to regeneration defects.

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