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 centronuclear 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 of BIN1 on intracellular organization in addition to membrane remodeling. Whereas 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, BIN1 ubiquitous function is necessary for muscle development and function while its muscle-specific isoforms fine-tune muscle regeneration in adulthood, supporting that BIN1 centronuclear myopathy with congenital onset are due to developmental defects while later onset may be due to regeneration defects.

中文翻译：

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BIN1 亚型在骨骼肌发育、功能和再生中的不同生理作用。


骨骼肌的发育和再生是受到严格调控的过程。在这些步骤中如何实现肌纤维的细胞内组织尚不清楚。在这里，我们重点关注两性蛋白 2 (BIN1) 的细胞和生理作用，这是一种在先天性和成人中心核肌病 (CNM) 中发生突变的膜重塑蛋白，广泛表达并具有骨骼肌特异性亚型。我们创建并表征了针对普遍存在或肌肉特异性亚型的组成型、肌肉特异性和可诱导性Bin1纯合和杂合敲除小鼠。 Bin1缺陷型小鼠在出生时因骨骼肌缺陷而缺乏喂养而死亡。 T 管和其他细胞器被错位和改变，支持 BIN1 除了膜重塑之外对细胞内组织的一般早期作用。虽然在未受挑战的成年肌肉中限制性删除Bin1没有影响，但通过删除框内肌肉特异性外显子强制从肌肉特异性亚型转换为普遍存在的亚型会延迟肌肉再生。因此，BIN1普遍存在的功能对于肌肉的发育和功能是必要的，而其肌肉特异性亚型则可以微调成年后的肌肉再生，这支持先天性发病的BIN1中心核肌病是由于发育缺陷引起的，而后来发病的可能是由于再生缺陷引起的。