scholarly journals Cellular senescence-mediated exacerbation of Duchenne muscular dystrophy

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Hidetoshi Sugihara ◽  
Naomi Teramoto ◽  
Katsuyuki Nakamura ◽  
Takanori Shiga ◽  
Taku Shirakawa ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Body Weight ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Strength ◽  
Progenitor Cells ◽  
Satellite Cells ◽  
Muscle Regeneration ◽  
Mesenchymal Progenitor Cells

Abstract Duchenne muscular dystrophy (DMD) is a progressive disease characterised by chronic muscle degeneration and inflammation. Our previously established DMD model rats (DMD rats) have a more severe disease phenotype than the broadly used mouse model. We aimed to investigate the role of senescence in DMD using DMD rats and patients. Senescence was induced in satellite cells and mesenchymal progenitor cells, owing to the increased expression of CDKN2A, p16- and p19-encoding gene. Genetic ablation of p16 in DMD rats dramatically restored body weight and muscle strength. Histological analysis showed a reduction of fibrotic and adipose tissues invading skeletal muscle, with increased muscle regeneration. Senolytic drug ABT263 prevented loss of body weight and muscle strength, and increased muscle regeneration in rats even at 8 months—the late stage of DMD. Moreover, senescence markers were highly expressed in the skeletal muscle of DMD patients. In situ hybridization of CDKN2A confirmed the expression of it in satellite cells and mesenchymal progenitor cells in patients with DMD. Collectively, these data provide new insights into the integral role of senescence in DMD progression.

scholarly journals Isometric resistance training increases strength and alters histopathology of dystrophin-deficient mouse skeletal muscle

2019 ◽  
Vol 126 (2) ◽  
pp. 363-375 ◽  
Author(s):  
Angus Lindsay ◽  
Alexie A. Larson ◽  
Mayank Verma ◽  
James M. Ervasti ◽  
Dawn A. Lowe
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Muscle Strength ◽  
Exercise Training ◽  
Satellite Cells ◽  
Eccentric Contraction ◽  
Deficient Mouse ◽  
Isometric Training ◽  
Isometric Torque ◽  
Edl Muscle

Mutation to the dystrophin gene causes skeletal muscle weakness in patients with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD). Deliberation continues regarding implications of prescribing exercise for these patients. The purpose of this study was to determine whether isometric resistance exercise (~10 tetanic contractions/session) improves skeletal muscle strength and histopathology in the mdx mouse model of DMD. Three isometric training sessions increased in vivo isometric torque (22%) and contractility rates (54%) of anterior crural muscles of mdx mice. Mice expressing a BMD-causing missense mutated dystrophin on the mdx background showed comparable increases in torque (22%), while wild-type mice showed less change (11%). Increases in muscle function occurred within 1 h and peaked 3 days posttraining; however, the adaptation was lost after 7 days unless retrained. Six isometric training sessions over 4 wk caused increased isometric torque (28%) and contractility rates (22–28%), reduced fibrosis, as well as greater uniformity of fiber cross-sectional areas, fewer embryonic myosin heavy-chain-positive fibers, and more satellite cells in tibialis anterior muscle compared with the contralateral untrained muscle. Ex vivo functional analysis of isolated extensor digitorum longus (EDL) muscle from the trained hindlimb revealed greater absolute isometric force, lower passive stiffness, and a lower susceptibility to eccentric contraction-induced force loss compared with untrained EDL muscle. Overall, these data support the concept that exercise training in the form of isometric tetanic contractions can improve contractile function of dystrophin-deficient muscle, indicating a potential role for enhancing muscle strength in patients with DMD and BMD. NEW & NOTEWORTHY We focused on adaptive responses of dystrophin-deficient mouse skeletal muscle to isometric contraction training and report that in the absence of dystrophin (or in the presence of a mutated dystrophin), strength and muscle histopathology are improved. Results suggest that the strength gains are associated with fiber hypertrophy, reduced fibrosis, increased number of satellite cells, and blunted eccentric contraction-induced force loss in vitro. Importantly, there was no indication that the isometric exercise training was deleterious to dystrophin-deficient muscle.

scholarly journals Role of satellite cells in skeletal muscle plasticity: Beyond muscle regeneration

2017 ◽  
Vol 6 (2) ◽  
pp. 89-93
Author(s):  
Kotaro Tamura ◽  
Yasuro Furuichi ◽  
Yasuko Manabe ◽  
Nobuharu L. Fujii
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cells ◽  
Muscle Regeneration ◽  
Muscle Plasticity

scholarly journals Skeletal muscle secretome in Duchenne muscular dystrophy: a pivotal anti-inflammatory role of adiponectin

2017 ◽  
Vol 74 (13) ◽  
pp. 2487-2501 ◽  
Author(s):  
S. Lecompte ◽  
M. Abou-Samra ◽  
R. Boursereau ◽  
L. Noel ◽  
S. M. Brichard
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Anti Inflammatory

scholarly journals Co-Transplantation of Bone Marrow-MSCs and Myogenic Stem/Progenitor Cells from Adult Donors Improves Muscle Function of Patients with Duchenne Muscular Dystrophy

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1119
Author(s):  
Aleksandra Klimczak ◽  
Agnieszka Zimna ◽  
Agnieszka Malcher ◽  
Urszula Kozlowska ◽  
Katarzyna Futoma ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Bone Marrow ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Progenitor Cells ◽  
Muscle Function ◽  
Progenitor Cell ◽  
Genetic Disorder ◽  
Cell Populations ◽  
Muscle Fibres

Duchenne muscular dystrophy (DMD) is a genetic disorder associated with a progressive deficiency of dystrophin that leads to skeletal muscle degeneration. In this study, we tested the hypothesis that a co-transplantation of two stem/progenitor cell populations, namely bone marrow-derived mesenchymal stem cells (BM-MSCs) and skeletal muscle-derived stem/progenitor cells (SM-SPCs), directly into the dystrophic muscle can improve the skeletal muscle function of DMD patients. Three patients diagnosed with DMD, confirmed by the dystrophin gene mutation, were enrolled into a study approved by the local Bioethics Committee (no. 79/2015). Stem/progenitor cells collected from bone marrow and skeletal muscles of related healthy donors, based on HLA matched antigens, were expanded in a closed MC3 cell culture system. A simultaneous co-transplantation of BM-MSCs and SM-SPCs was performed directly into the biceps brachii (two patients) and gastrocnemius (one patient). During a six-month follow-up, the patients were examined with electromyography (EMG) and monitored for blood kinase creatine level. Muscle biopsies were examined with histology and assessed for dystrophin at the mRNA and protein level. A panel of 27 cytokines was analysed with multiplex ELISA. We did not observe any adverse effects after the intramuscular administration of cells. The efficacy of BM-MSC and SM-SPC application was confirmed through an EMG assessment by an increase in motor unit parameters, especially in terms of duration, amplitude range, area, and size index. The beneficial effect of cellular therapy was confirmed by a decrease in creatine kinase levels and a normalised profile of pro-inflammatory cytokines. BM-MSCs may support the pro-regenerative potential of SM-SPCs thanks to their trophic, paracrine, and immunomodulatory activity. Both applied cell populations may fuse with degenerating skeletal muscle fibres in situ, facilitating skeletal muscle recovery. However, further studies are required to optimise the dose and timing of stem/progenitor cell delivery.

Characterisation of dystrophin during development of human skeletal muscle

Development ◽  
1992 ◽  
Vol 114 (2) ◽  
pp. 395-402 ◽  
Author(s):  
A. Clerk ◽  
P.N. Strong ◽  
C.A. Sewry
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Human Skeletal Muscle ◽  
Gradual Increase ◽  
Differential Staining ◽  
Relative Molecular Mass ◽  
Adult Tissue ◽  
Dmd Gene

Dystrophin, the 427 × 10(3) Mr product of the Duchenne muscular dystrophy (DMD) gene, was studied in human foetal skeletal muscle from 9 to 26 weeks of gestation. Dystrophin could be detected from at least 9 weeks of gestation at the sarcolemmal membrane of most myotubes, though there was differential staining with antibodies raised to various regions of the protein. Dystrophin immunostaining increased and became more uniform with age and by 26 weeks of gestation there was intense sarcolemmal staining of all myotubes. On a Western blot, a doublet of smaller relative molecular mass than that seen in adult tissue was detected in all foetuses studied. There was a gradual increase in abundance of the upper band from 9 to 26 weeks, and the lower band, although present in low amounts in young foetuses, increased significantly between 20 and 26 weeks of gestation. These data indicate that there are several specific isoforms of dystrophin present in developing skeletal muscle, though the role of these is unknown.

Reparative dysfunction during muscle regeneration in Duchenne muscular dystrophy: therapeutic approaches to modulating the muscle environment and muscle stem cells

2019 ◽  
Author(s):  
◽  
Michael Everette Nance
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Regeneration ◽  
Genetic Mutation ◽  
Critical Determinant ◽  
Muscle Stem Cells ◽  
Dystrophin Protein

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Duchenne muscular dystrophy (DMD) is a lethal muscular dystrophy resulting from functional loss of the dystrophin protein, a critical sub-sarcolemmal protein involved in membrane stability. While reparative dysfunction is thought to be a critical determinant of disease progression in humans, regeneration is not significantly impaired in the murine muscular dystrophy (mdx) model. Furthermore, it is not well understood if reparative dysfunction is related to inherent defects in stem cells or chronic alterations in the muscle environment due to disease related remodeling. To address these observed discrepancies, we adapted a whole muscle transplant model to study the in vivo regeneration of intact pieces of skeletal muscle from normal and dystrophic dogs (cDMD), a physiological and clinically relevant model to humans. Regeneration in cDMD muscle grafts was significantly attenuated compared to normal and predisposed to the development of skeletal muscle tumors. We used an adeno-associated virus (AAV) expressing a micro-dystrophin protein to specifically rescue the muscle environment by preventing fiber damage while retaining dystrophin-null SCs. AAV.micro-dystrophin rescued the environment by improving fibrosis, stiffness, and fiber orientation, which significantly improved early muscle regeneration but not late regeneration (2 greater than and less than 4 months post-transplant) via enhancing muscle stem cells differentiation. We next developed Cre- and CRISPR-cas9 gene editing strategies to test the ability of AAV serotype 9 to transduce and treat the genetic mutation in muscle stem cells. We observed efficient SC transduction when used as a single vector expressing Cre. Dual-vector CRISPR-cas9 SC transduction was inefficient and likely related to the requirement for two vectors, promoter usage, and mechanistic differences between Cre-recombination and CRISPR genome editing.

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