Myopathologic trajectory in Duchenne muscular dystrophy (DMD) reveals lack of regeneration due to senescence in satellite cells

Acta Neuropathologica Communications

Research

Serena Baratto¹  Chiara Panicucci¹  Claudio Bruno²  Chiara Fiorillo³  Ciryl Gitiaux⁴  Christine Barnerias⁵  Isabelle Desguerre⁵  France Leturcq Pharm⁶  Juliette Nectoux Pharm⁶  Nastasia Cardone⁷  Valentina Taglietti⁷  Frederic Relaix⁷  Peggy Lafuste⁷  Kaouthar Kefi⁷  Edoardo Malfatti⁸  Baptiste Periou⁸  François-Jerome Authier⁸ 

[1] Centre of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, Genoa, Italy;Centre of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, Genoa, Italy;Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health-DINOGMI, University of Genova, Genoa, Italy;Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health-DINOGMI, University of Genova, Genoa, Italy;Child Neuropsychiatry, IRCCS Istituto Giannina Gaslini, Genoa, Italy;Neurophysiologie clinique pédiatrique, Centre de référence des maladies neuromusculaires Hôpital universitaire Necker-Enfants Malades-Paris, Centre de Référence de Pathologie Neuromusculaire Nord-Est-Ile-de-France, Henri Mondor Hospital, Université Paris Est, U955 INSERM, IMRB, APHP, Creteil, France;Reference Center for Neuromuscular Disorders, Filnemus, EuroNMD, Assistance Publique-Hôpitaux de Paris (APHP) Necker Enfants Malades Hospital, Paris, France;Reference Center for Neuromuscular Disorders, Filnemus, EuroNMD, Assistance Publique-Hôpitaux de Paris (APHP) Necker Enfants Malades Hospital, Paris, France;Service de Médecine Génomique, Maladies de Système et d’Organe - Fédération de Génétique et de Médecine Génomique, DMU BioPhyGen, APHP Centre-Université Paris Cité - Hôpital Cochin, Paris, France;Univ Paris Est Creteil, INSERM, IMRB, 94010, Creteil, France;Univ Paris Est Creteil, INSERM, IMRB, 94010, Creteil, France;APHP, Filnemus, EuroNMD, Centre de Référence de Pathologie Neuromusculaire Nord-Est-Ile-de-France, Henri Mondor Hospital, Paris, France;

关键词: Duchenne muscular dystrophy;    Fibrosis;    FAPs;    Muscle regeneration;    Cellular senescence;   

DOI  :  10.1186/s40478-023-01657-z

 received in 2023-08-11, accepted in 2023-09-19,  发布年份 2023

来源: Springer

【 摘 要 】

Duchenne muscular dystrophy (DMD) is a devastating X-linked muscular disease, caused by mutations in the DMD gene encoding Dystrophin and affecting 1:5000 boys worldwide. Lack of Dystrophin leads to progressive muscle wasting and degeneration resulting in cardiorespiratory failure. Despite the absence of a definitive cure, innovative therapeutic avenues are emerging. Myopathologic studies are important to further understand the biological mechanisms of the disease and to identify histopathologic benchmarks for clinical evaluations. We conducted a myopathologic analysis on twenty-four muscle biopsies from DMD patients, with particular emphasis on regeneration, fibro-adipogenic progenitors and muscle stem cells behavior. We describe an increase in content of fibro-adipogenic progenitors, central orchestrators of fibrotic progression and lipid deposition, concurrently with a decline in muscle regenerative capacity. This regenerative impairment strongly correlates with compromised activation and expansion of muscle stem cells. Furthermore, our study uncovers an early acquisition of a senescence phenotype by DMD-afflicted muscle stem cells. Here we describe the myopathologic trajectory intrinsic to DMD and establish muscle stem cell senescence as a pivotal readout for future therapeutic interventions.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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