Differential physiological role of BIN1 isoforms in skeletal muscle development, function and regeneration

Abstract

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, 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.

The Physiology and Pathophysiology of T-Tubules in the Heart

“…Early work suggested that the presence of exon 11 is required to induce tubulogenesis ( Lee et al, 2002 ; Kojima et al, 2004 ), and exon 11-containing BIN1 isoforms expressed in rat, sheep, and human myocardium have indeed been observed to induce t-tubule formation ( Caldwell et al, 2014 ; De La Mata et al, 2019 ; Lawless et al, 2019 ; Li L. L. et al, 2020 ). However, other studies have reported that exon 11 is dispensable for t-tubule development ( Prokic et al, 2020 ), and shown that the mouse heart expresses four BIN1 splice variants which do not contain this motif (BIN1, BIN1+13, BIN1+17, and BIN1+13+17) ( Forbes and Sperelakis, 1976 ; Hong et al, 2014 ). In addition to gross t-tubule biogenesis, there may also be isoform-specific roles in determining their fine structure and function.…”

Multi-omics comparisons of different forms of centronuclear myopathies and the effects of several therapeutic strategies

“…27,28 For Bin1, full loss of BIN1 in Bin1 À/À mice is perinatally lethal, preventing the comparison with the other CNM models. 29,30 We recently created a mouse model with a skeletal muscle-specific Bin1 deletion that is viable and faithfully reproduces the decreased muscle force and most histopathological hallmarks of CNM (Bin1 mckÀ/À ; unpublished data). Herein, we focus on omics analysis of Mtm1 À/y , Bin1 mckÀ/À , and Dnm2 SL/+ mice, since they represent faithful models for the three canonical CNM forms and the mice share a similar skeletal muscle organization with patients.…”