Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances

Abstract

Centronuclear myopathies (CNM) are rare congenital disorders characterized by muscle weakness and structural defects including fiber hypotrophy and organelle mispositioning. The main CNM forms are caused by mutations in: the MTM1 gene encoding the phosphoinositide phosphatase myotubularin (myotubular myopathy), the DNM2 gene encoding the mechanoenzyme dynamin 2, the BIN1 gene encoding the membrane curvature sensing amphiphysin 2, and the RYR1 gene encoding the skeletal muscle calcium release channel/ryanodine receptor. MTM1, BIN1, and DNM2 proteins are involved in membrane remodeling and trafficking, while RyR1 directly regulates excitation-contraction coupling (ECC). Several CNM animal models have been generated or identified, which confirm shared pathological anomalies in T-tubule remodeling, ECC, organelle mispositioning, protein homeostasis, neuromuscular junction, and muscle regeneration. Dynamin 2 plays a crucial role in CNM physiopathology and has been validated as a common therapeutic target for three CNM forms. Indeed, the promising results in preclinical models set up the basis for ongoing clinical trials. Another two clinical trials to treat myotubular myopathy by MTM1 gene therapy or tamoxifen repurposing are also ongoing. Here, we review the contribution of the different CNM models to understanding physiopathology and therapy development with a focus on the commonly dysregulated pathways and current therapeutic targets.

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

“…Although it is easy to understand that mutations in RYR1 or CACNA1S can be found in patients with MH or CCD and that mutations in STIM1 or ORAI1 are associated with TAM/Stormorken syndrome, less obvious are the cases where mutations in genes not involved in Ca 2+ -handling pathways, such as MYH7 , TTN , or MEGF10 , are detected in patients presenting with clinical symptoms and histopathological alterations like those present in RYR1- related myopathies. This apparent incongruency can be rationalized by evidence that, at least in some cases, mutations in genes apparently not directly connected with Ca 2+ signaling may indirectly affect regulation of Ca 2+ homeostasis, as proposed for SEPN1 ( Chernorudskiy et al, 2020 ) or BIN1 , MTM1 , or DNM2 ( Gómez-Oca et al, 2021 ). However, more work is needed in this direction to explain how genes not known to affect Ca 2+ signaling mat induce a myopathy.…”

“…Recessive mutations in RYR1 are the most common cause of autosomal recessive CNM, accounting for ∼15% of patients. At clinical presentation, autosomal CNM most frequently shows delayed motor milestones, nonprogressive muscle weakness and hypotonia, ptosis, ophthalmoplegia, and mild to severe respiratory impairment ( Jungbluth et al, 2008 ; Wilmshurst et al, 2010 ; Bevilacqua et al, 2011 ; Romero and Bitoun, 2011 ; Gòmez-Oca et al, 2021 ). From a histological point of view, CNM shows centralized and internalized nuclei, peripheral halos depleted of oxidative activity, and cores, although based on which gene is mutated, the histological patterns may vary ( Nicot et al, 2007 ; Bevilacqua et al, 2011 ; Gomez-Oca et al, 2021 ).…”

“…At clinical presentation, autosomal CNM most frequently shows delayed motor milestones, nonprogressive muscle weakness and hypotonia, ptosis, ophthalmoplegia, and mild to severe respiratory impairment ( Jungbluth et al, 2008 ; Wilmshurst et al, 2010 ; Bevilacqua et al, 2011 ; Romero and Bitoun, 2011 ; Gòmez-Oca et al, 2021 ). From a histological point of view, CNM shows centralized and internalized nuclei, peripheral halos depleted of oxidative activity, and cores, although based on which gene is mutated, the histological patterns may vary ( Nicot et al, 2007 ; Bevilacqua et al, 2011 ; Gomez-Oca et al, 2021 ). RYR1 -related CNM often presents as a mixed phenotype between CNM and core myopathies, with the presence of multiple central nuclei and core-like structures with no limited boundaries ( Abath Neto et al, 2017 ).…”

“…RYR1 -related CNM often presents as a mixed phenotype between CNM and core myopathies, with the presence of multiple central nuclei and core-like structures with no limited boundaries ( Abath Neto et al, 2017 ). These forms are normally caused by compound heterozygous mutations in RYR1 , where one of the two mutations usually cause premature termination of the transcript, resulting in a decrease in RYR1 protein expression levels ( Gòmez-Oca et al, 2021 ). Mutations in MTM1 account for >50% of CNM cases.…”

Centronuclear Myopathy Caused by Defective Membrane Remodelling of Dynamin 2 and BIN1 Variants

“…BIN1 - and DNM2 -associated CNM patients show normal or slightly elevated levels of serum creatine kinase and slowly progressive muscle weakness [ 8 , 9 , 10 , 11 ]. This review will overview the functions of dynamin 2 and BIN1 in T-tubule biogenesis and discuss possible pathogenic mechanisms of CNM caused by their membrane remodelling defects, aiming for compensating other excellent reviews [ 2 , 12 , 13 , 14 , 15 , 16 ].…”