RESUMO
Centronuclear and myotubular myopathies (CNM) are rare and severe genetic diseases associated with muscle weakness and atrophy as well as intracellular disorganization of myofibres. The main mutated proteins control lipid and membrane dynamics and are the lipid phosphatase myotubularin (MTM1), and the membrane remodelling proteins amphiphysin 2 (BIN1) and dynamin 2 (DNM2). There is no available therapy. Here, to validate a novel therapeutic strategy for BIN1- and DNM2-CNM, we evaluated adeno-associated virus-mediated MTM1 (AAV-MTM1 ) overexpression in relevant mouse models. Early systemic MTM1 overexpression prevented the development of the CNM pathology in Bin1mck-/- mice, while late intramuscular MTM1 expression partially reverted the established phenotypes after only 4 weeks of treatment. However, AAV-MTM1 injection did not change the DNM2-CNM mouse phenotypes. We investigated the mechanism of the rescue of the myopathy in BIN1-CNM and found that the lipid phosphatase activity of MTM1 was essential for the rescue of muscle atrophy and myofibre hypotrophy but dispensable for the rescue of myofibre disorganization including organelle mis-position and T-tubule defects. Furthermore, the improvement of T-tubule organization correlated with normalization of key regulators of T-tubule morphogenesis, dysferlin and caveolin. Overall, these data support the inclusion of BIN1-CNM patients in an AAV-MTM1 clinical trial.
Assuntos
Músculo Esquelético , Miopatias Congênitas Estruturais , Proteínas Tirosina Fosfatases não Receptoras , Animais , Humanos , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Dinamina II/genética , Dinamina II/metabolismo , Lipídeos , Músculo Esquelético/patologia , Atrofia Muscular/patologia , Mutação , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/terapia , Proteínas Nucleares/genética , Fenótipo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Proteínas Tirosina Fosfatases não Receptoras/genética , Terapia GenéticaRESUMO
Amphiphysin-2 is a ubiquitously expressed protein also known as bridging integrator 1 (BIN1), playing a critical role in membrane remodeling, trafficking, and cytoskeleton dynamics in a wide range of tissues. Mutations in the gene encoding BIN1 cause centronuclear myopathies (CNM), and recent evidence has implicated BIN1 in heart failure, underlining its crucial role in both skeletal and cardiac muscle. Furthermore, altered expression of BIN1 is linked to an increased risk of late-onset Alzheimer's disease and several types of cancer, including breast, colon, prostate, and lung cancers. Recently, the first proof-of-concept for potential therapeutic strategies modulating BIN1 were obtained for muscle diseases. In this review article, we discuss the similarities and differences in BIN1's functions in cardiac and skeletal muscle, along with its associated diseases and potential therapies.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Músculo Esquelético , Miocárdio , Proteínas Supressoras de Tumor , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Animais , Miocárdio/metabolismo , Miocárdio/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Mutação , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologiaRESUMO
Remediation of dense non-aqueous phase liquids (DNAPLs) represents a challenging issue because of their persistent behaviour in the environment. This pilot-scale study investigates, by means of in situ experiments and numerical modelling, the feasibility of the pulsed pumping process of a large amount of a DNAPL in an alluvial aquifer. The main compound of the DNAPL is hexachlorobutadiene (HCBD), added in 2015 to the persistent organic pollutants list (POP). A low-permeability keyed enclosure was built at the location of the DNAPL source zone in order to isolate a finite volume of soil and a 3-month pulsed pumping process was applied inside the enclosure to exclusively extract the DNAPL. The water/DNAPL interface elevation at both the pumping well and an observation well was recorded. The cumulated pumped volume of DNAPL was also monitored. A total volume of about 20â¯m3 of pure DNAPL was recovered since no water was extracted during the process. The three-dimensional and multiphase flow simulator TMVOC was used and a conceptual model was elaborated and generated with the pre/post-processing tool mView. Numerical simulations reproduce the pulsed pumping process and show an excellent match between simulated and field data of DNAPL cumulated pumped volume and a reasonable agreement between modelled and observed data for the evolution of the water/DNAPL interface elevations at the two wells. This study offers a new perspective in remediation since DNAPL pumping system optimisation may be performed where a large amount of DNAPL is encountered.