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

Cardone, Nastasia; Taglietti, Valentina; Baratto, Serena; Kefi, Kaouthar; Periou, Baptiste; Gitiaux, Ciryl; Barnerias, Christine; Lafuste, Peggy; Pharm, France Leturcq; Pharm, Juliette Nectoux; Panicucci, Chiara; Desguerre, Isabelle; Bruno, Claudio; Authier, François-Jerome; Fiorillo, Chiara; Relaix, Frederic; Malfatti, Edoardo

doi:10.1186/s40478-023-01657-z

Cited by 7 publications

(4 citation statements)

References 49 publications

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“…In this study, we found that individuals diagnosed with dependency exhibit a pro-inflammatory phenotype characterized by the increased expression of Caspase-1, IL-6, IL-1ß, as well as an elevation in the presence of CD68 + inflammatory cells. The senescence secretory profile plays a pivotal role in the initiation and advancement of various myopathies [72,73]. Additionally, we found high levels of protein expression of cell-cycle inhibitor p16 INK4a indicating an increase in senescence cells in sarcopenic muscle from DP.…”

Section: Discussionmentioning

confidence: 59%

NLRP3 Contributes to Sarcopenia Associated to Dependency Recapitulating Inflammatory-Associated Muscle Degeneration

Antuña,

Potes,

Baena-Huerta

et al. 2024

IJMS

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Sarcopenia, a complex and debilitating condition characterized by progressive deterioration of skeletal muscle, is the primary cause of age-associated disability and significantly impacts healthspan in elderly patients. Despite its prevalence among the aging population, the underlying molecular mechanisms are still under investigation. The NLRP3 inflammasome is crucial in the innate immune response and has a significant impact on diseases related to inflammation and aging. Here, we investigated the expression of the NLRP3 inflammasome pathway and pro-inflammatory cytokines in skeletal muscle and peripheral blood of dependent and independent patients who underwent hip surgery. Patients were categorized into independent and dependent individuals based on their Barthel Index. The expression of NLRP3 inflammasome components was significantly upregulated in sarcopenic muscle from dependent patients, accompanied by higher levels of Caspase-1, IL-1β and IL-6. Among older dependent individuals with sarcopenia, there was a significant increase in the MYH3/MYH2 ratio, indicating a transcriptional shift in expression from mature to developmental myosin isoforms. Creatine kinase levels and senescence markers were also higher in dependent patients, altogether resembling dystrophic diseases and indicating muscle degeneration. In summary, we present evidence for the involvement of the NLRP3/ASC/NEK7/Caspase-1 inflammasome pathway with activation of pro-inflammatory SASP in the outcome of sarcopenia in the elderly.

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Section: Discussionmentioning

confidence: 59%

NLRP3 Contributes to Sarcopenia Associated to Dependency Recapitulating Inflammatory-Associated Muscle Degeneration

Antuña,

Potes,

Baena-Huerta

et al. 2024

IJMS

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“…This correlation was even stronger when analyzing samples from the oldest 33-wo mice. A gradual increase in necrosis has been reported in the myo bers of DMD patients with aging, along with decreasing regenerative abilities due to the senescence of satellite cells [71]. Thus, progressive impairment of the surrounding non-supplemented DMD bers with aging may have provided a stronger impact on the remaining dystrophin supplemented-DMD bers.…”

Section: Discussionmentioning

confidence: 98%

Enhanced skeletal muscle fatigue tolerance through cell transplantation-mediated dystrophin supplementation in a mouse model of Duchenne Muscular Dystrophy

Yoshioka,

Takenaka-Ninagawa,

Goto

et al. 2023

Preprint

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Background Duchenne muscular dystrophy (DMD) is an incurable neuromuscular disease leading to progressive skeletal muscle weakness and fatigue. Cell transplantation in murine models have shown promise in supplementing the lack of the dystrophin protein in DMD muscles. However, the establishment of novel, long-term, relevant methods is needed to assess its efficiency on the DMD motor function. By applying newly developed methods, this study aimed to evaluate the functional and molecular effects of cell therapy-mediated dystrophin supplementation on DMD muscles. Methods Dystrophin was supplemented in the gastrocnemius of a 5-week-old immunodeficient DMD mouse model (Dmd-null/NSG) by intramuscular xenotransplantation of healthy human immortalized myoblasts (Hu5/KD3). A long-term time-course comparative study was conducted between wild-type, untreated DMD, and dystrophin supplemented-DMD mouse muscle functions and histology. A novel GO-ATeam2 transgenic DMD mouse model was also generated to assess in vivo real-time ATP levels in gastrocnemius muscles during repeated contractions. Results We found that 10.6% dystrophin supplementation in DMD muscles was sufficient to prevent low values of gastrocnemius maximal isometric contraction torque (MCT) at rest, while muscle fatigue tolerance, assessed by MCT decline after treadmill running, was fully ameliorated in 21-week-old transplanted mice. None of the dystrophin-supplemented fibers were positive for muscle damage markers after treadmill running, with 85.5% demonstrating the utilization of oxidative metabolism. Furthermore, ATP levels in response to repeated muscle contractions tended to improve, and mitochondrial activity was significantly enhanced in dystrophin supplemented-fibers. Conclusions Cell therapy-mediated dystrophin supplementation efficiently improved DMD muscle functions, as evaluated using newly developed evaluation methods. The enhanced muscle fatigue tolerance in 21-week-old mice was associated with the preferential regeneration of damage-resistant and oxidative fibers, highlighting increased mitochondrial activity, after cell transplantation. These findings significantly contribute to a more in-depth understanding of DMD pathogenesis.

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“…They possess self-renewing features and can generate myoblasts. Nevertheless, they lose their regenerative properties during the progression of DMD [ 66 ]. Investigating the miRNA expression profile of satellite cells demonstrated that DMD alters the expression of these molecules.…”

Section: Micrornas In the Pathogenesis Of Duchenne Muscular Dystrophymentioning

confidence: 99%

The Role of MicroRNA in the Pathogenesis of Duchenne Muscular Dystrophy

Kiełbowski,

Bakinowska,

Procyk

et al. 2024

IJMS

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Duchenne muscular dystrophy (DMD) is an X-linked progressive disorder associated with muscle wasting and degeneration. The disease is caused by mutations in the gene that encodes dystrophin, a protein that links the cytoskeleton with cell membrane proteins. The current treatment methods aim to relieve the symptoms of the disease or partially rescue muscle functionality. However, they are insufficient to suppress disease progression. In recent years, studies have uncovered an important role for non-coding RNAs (ncRNAs) in regulating the progression of numerous diseases. ncRNAs, such as micro-RNAs (miRNAs), bind to their target messenger RNAs (mRNAs) to suppress translation. Understanding the mechanisms involving dysregulated miRNAs can improve diagnosis and suggest novel treatment methods for patients with DMD. This review presents the available evidence on the role of altered expression of miRNAs in the pathogenesis of DMD. We discuss the involvement of these molecules in the processes associated with muscle physiology and DMD-associated cardiomyopathy.

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

Cited by 7 publications

References 49 publications

NLRP3 Contributes to Sarcopenia Associated to Dependency Recapitulating Inflammatory-Associated Muscle Degeneration

NLRP3 Contributes to Sarcopenia Associated to Dependency Recapitulating Inflammatory-Associated Muscle Degeneration

Enhanced skeletal muscle fatigue tolerance through cell transplantation-mediated dystrophin supplementation in a mouse model of Duchenne Muscular Dystrophy

The Role of MicroRNA in the Pathogenesis of Duchenne Muscular Dystrophy

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