BIN1 modulation in vivo rescues dynamin-related myopathy

Abstract

The mechanoenzyme dynamin 2 (DNM2) is crucial for intracellular organization and trafficking. DNM2 is mutated in dominant centronuclear myopathy (DNM2-CNM), a muscle disease characterized by defects in organelle positioning in myofibers. It remains unclear how the in vivo functions of DNM2 are regulated in muscle. Moreover, there is no therapy for DNM2-CNM to date. Here, we overexpressed human amphiphysin 2 (BIN1), a membrane remodeling protein mutated in other CNM forms, in Dnm2RW/+ and Dnm2RW/RW mice modeling mild and severe DNM2-CNM, through transgenesis or with adeno-associated virus (AAV). Increasing BIN1 improved muscle atrophy and main histopathological features of Dnm2RW/+ mice and rescued the perinatal lethality and survival of Dnm2RW/RW mice. In vitro experiments showed that BIN1 binds and recruits DNM2 to membrane tubules, and that the BIN1-DNM2 complex regulates tubules fission. Overall, BIN1 is a potential therapeutic target for dominant centronuclear myopathy linked to DNM2 mutations.

Uncovering the BIN1-SH3 interactome underpinning centronuclear myopathy

“…At last, we tested whether the natural variants impacting the affinity interactome of BIN1 are capable to recruit DNM2 to BIN1-induced membrane invaginations. We co-transfected Cos-1 cells with GFP-BIN1 (FL, isoform 8) and Myc-DNM2 (FL) as described previously (Lionello et al , 2022) (Figure 6B-C, Figure S6). We performed membrane tubulation assay with WT BIN1, with the likely benign Q540H variant, as well as with the three variants that displayed perturbed affinity interactomes.…”

“…These observations indicate the critical role of the SH3 domain of BIN1 and its mediated protein-protein interactions in CNM. At last, molecular characterization of the SH3 domain-mediated interactions of BIN1 and their molecular functions are of particular importance, as exogenous expression of BIN1 is a promising therapeutic approach to treat CNM (Lionello et al , 2022) (Lionello et al , 2019).…”

Cellular and structural insight into dynamin function during endocytic vesicle formation: a tale of 50 years of investigation

“…BIN1, which interacts with dynamin, is also linked to some ADCNM cases. Moreover, it recruits dynamin2 to membrane tubules and regulates tubules fission and its overexpression improves muscle atrophy in dynamin2 ADCNM mouse models [170], linking these two scission proteins in a complex phenotype. Whether or not this phenotype is directly linked to scission activity remains to be established.…”

Mutations in proteins involved in E-C coupling and SOCE and congenital myopathies

“…Given the functional interplay between BIN1, DNM2, and MTM1, a correct balance in their reciprocal expression levels has been shown to be important for muscle physiology. Indeed, overexpression of BIN1 in Dnm2 R465W/WT and Dnm2 R465W/R465W mice improved muscle atrophy and rescued the perinatal lethality and survival of Dnm2 R465W/R465W mice ( Lionello et al, 2022 ). Moreover, the use of antisense oligonucleotides against Dnm2 in Bin1 knockout mice improved muscle force and intracellular architecture ( Silva-Rojas et al, 2022 ).…”