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Concept

Dystrophie musculaire

Résumé

Les dystrophies musculaires sont un groupe de myopathies génétiques héréditaires qui ont en commun de provoquer une faiblesse des muscles de l'organisme. La faiblesse progressive des muscles squelettiques est consécutive à un défaut quantitatif ou qualitatif de certaines protéines qui conduit à la mort des cellules et du tissu musculaires. Chez les humains, neuf maladies sont traditionnellement classées parmi les dystrophies musculaires :

Dystrophie musculaire de Duchenne
Dystrophie musculaire de Becker ou dystrophie musculaire bénigne pseudohypertrophique
Dystrophie musculaire des ceintures
Dystrophie musculaire congénitale
Dystrophie facio-scapulo-humérale
Dystrophie myotonique
Dystrophie musculaire oculo-pharyngée
Dystrophie musculaire distale
Dystrophie musculaire d'Emery-Dreifuss

Plus de 100 autres maladies ont des similitudes avec les dystrophies musculaires. La plupart des types de dystrophies musculaires sont des affections multi-systémiques qui touchent d

Source officielle

https://fr.wikipedia.org/wiki/Dystrophie_musculaire

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Concepts associés (18)

La myopathie de Duchenne (DMD) est la plus grave des manifestations en rapport avec un déficit de la dystrophine qui permet aux muscles de résister à l'effort : sans elle, les fibres musculaires dégé

Les muscles squelettiques sont les muscles sous contrôle volontaire du système nerveux central. Le corps humain comprend environ 570 muscles présents chez tous les individus sains. Leur corps conti

L'électromyographie (EMG) est une technique médicale qui permet d'étudier la fonction des nerfs et des muscles = le système nerveux périphérique, les muscles et la jonction neuromusculaire, et donc

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Cours associés (5)

The theoretical part of this course covers classical genetics and contemporary genomics. Because bioinformatics has become important for genomic research, the course also includes practical applications to genomic analyses using Python, including group projects.

The course starts with fundamentals of electrical - and chemical signaling in neurons. Students then learn how neurons in the brain receive and process sensory information, and how other neurons control the behavior of an animal. Furthermore, memory, learning, and brain disorders will be introduced.

The course covers the fundaments of bioelectronics and integrated microelectronics for biomedical and implantable systems. Issues and trade-offs at the circuit and systems levels of invasive microelectronic systems as well as their eluding designs, methods and classical implementations are discussed

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Séances de cours associées (6)

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Duchenne muscular dystrophy (DMD), caused by the mutation of dystrophin gene, is an X-linked disorder that affects 1 in 3500 males, leading to progressive muscle degeneration and eventually resulting in premature death. Increasing evidence indicates that DMD and age-related sarcopenia share clinical hallmarks, such as decreased metabolic activity of both myofibers and muscle stem cells (MuSCs), which results in defective MuSC function and impaired muscle regeneration. In my Ph.D. thesis, I focused on manipulating mitochondrial function, such as mitophagy, and lipid metabolism, particularly sphingolipid metabolic pathways, to restore muscle and MuSC functions in DMD and age-associated sarcopenia. My thesis consists of three projects: Rescue of mitophagy improves muscle function in DMD. In this project, we identified defective mitophagy as a hallmark of muscular dystrophy. Rescue of dysfunctional mitophagy by dietary supplementation of Urolithin A (UA), a metabolite present in fruit extracts and a potent activator of mitophagy, improved muscle function in mdx mice. The beneficial effects of mitophagy restoration observed in dystrophic animals were attributed to the improvement in mitochondrial function, structural integrity of muscles, restoration of MuSC activity, and reduction in general inflammation and fibrosis. Sphingolipid depletion improves muscle regeneration during ageing. We first established the link between sphingolipid metabolism and ageing by demonstrating that sphingolipids accumulate in skeletal muscle upon aging. We reduced skeletal muscle sphingolipid accumulation by treating aged mice with myriocin, a selective inhibitor of serine pamitoyltransferase (SPT), the first and rate-limiting enzyme of sphingolipid de novo synthesis pathway. Sphingolipid depletion increased MuSC regenerative ability through enhancing the proliferation and differentiation capacities of MuSCs, ultimately leading to the prevention of age-related decline in muscle mass and function. Inhibition of sphingolipid synthesis reverts muscular dystrophy. By studying skeletal muscle transcript profiles of human muscular dystrophies, we identified upregulation of sphingolipid biosynthetic pathway as a universal feature of human patients affected with muscular dystrophy. To rescue the aberrant sphingolipid metabolism, we treated mdx mice with myriocin and showed that inhibition of sphingolipid generation enhanced muscle function, leading to amelioration of DMD. Furthermore, we uncovered a novel role of sphingolipid depletion in macrophage polarization and in reconstruction of the mdx MuSC niche, resulting in improved regenerative capacity of MuSCs. In summary, our work establishes the essential roles of mitophagy and sphingolipid metabolism in maintaining muscle and MuSC function. Restoration of mitophagy and blockade of sphingolipid generation could therefore be attractive treatment strategies to delay the progression of DMD and age-related sarcopenia.

EPFL2020

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BET1 variants establish impaired vesicular transport as a cause for muscular dystrophy with epilepsy

Matteo Dal Peraro, Mykola Dergai

BET1 is required, together with its SNARE complex partners GOSR2, SEC22b, and Syntaxin-5 for fusion of endoplasmic reticulum-derived vesicles with the ER-Golgi intermediate compartment (ERGIC) and the cis-Golgi. Here, we report three individuals, from two families, with severe congenital muscular dystrophy (CMD) and biallelic variants in BET1 (P1 p.(Asp68His)/p.(Ala45Valfs*2); P2 and P3 homozygous p.(Ile51Ser)). Due to aberrant splicing and frameshifting, the variants in P1 result in low BET1 protein levels and impaired ER-to-Golgi transport. Since in silico modeling suggested that p.(Ile51Ser) interferes with binding to interaction partners other than SNARE complex subunits, we set off and identified novel BET1 interaction partners with low affinity for p.(Ile51Ser) BET1 protein compared to wild-type, among them ERGIC-53. The BET1/ERGIC-53 interaction was validated by endogenous co-immunoprecipitation with both proteins colocalizing to the ERGIC compartment. Mislocalization of ERGIC-53 was observed in P1 and P2's derived fibroblasts; while in the p.(Ile51Ser) P2 fibroblasts specifically, mutant BET1 was also mislocalized along with ERGIC-53. Thus, we establish BET1 as a novel CMD/epilepsy gene and confirm the emerging role of ER/Golgi SNAREs in CMD.

WILEY2021

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Molecular and cell-based therapies for muscle degenerations: a road under construction

Marco Cassano, Stefania Crippa

Despite the advances achieved in understanding the molecular biology of muscle cells in the past decades, there is still need for effective treatments of muscular degeneration caused by muscular dystrophies and for counteracting the muscle wasting caused by cachexia or sarcopenia. The corticosteroid medications currently in use for dystrophic patients merely help to control the inflammatory state and only slightly delay the progression of the disease. Unfortunately, walkers and wheel chairs are the only options for such patients to maintain independence and walking capabilities until the respiratory muscles become weak and the mechanical ventilation is needed. On the other hand, myostatin inhibition, IL6 antagonism and synthetic ghrelin administration are examples of promising treatments in cachexia animal models. In both dystrophies and cachectic syndrome the muscular degeneration is extremely relevant and the translational therapeutic attempts to find a possible cure are well defined. In particular, molecular-based therapies are common options to be explored in order to exploit beneficial treatments for cachexia, while gene/cell therapies are mostly used in the attempt to induce a substantial improvement of the dystrophic muscular phenotype. This review focuses on the description of the use of molecular administrations and gene/stem cell therapy to treat muscular degenerations. It reviews previous trials using cell delivery protocols in mice and patients starting with the use of donor myoblasts, outlining the likely causes for their poor results and briefly focusing on satellite cell studies that raise new hope. Then it proceeds to describe recently identified stem/progenitor cells, including pluripotent stem cells and in relationship to their ability to home within a dystrophic muscle and to differentiate into skeletal muscle cells. Different known features of various stem cells are compared in this perspective, and the few available examples of their use in animal models of muscular degeneration are reported. Since non coding RNAs, including microRNAs (miRNAs), are emerging as prominent players in the regulation of stem cell fates we also provides an outline of the role of microRNAs in the control of myogenic commitment. Finally, based on our current knowledge and the rapid advance in stem cell biology, a prediction of clinical translation for cell therapy protocols combined with molecular treatments is discussed.

Frontiers Research Foundation2014

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EPFL2020

Molecular and cell-based therapies for muscle degenerations: a road under construction

Marco Cassano, Stefania Crippa

Frontiers Research Foundation2014