The chemokine receptor CXCR4 regulates satellite cell activation, early expansion, and self-renewal, in response to skeletal muscle injury

Shams, Ahmed S.; Arpke, Robert W.; Gearhart, Micah D.; Weiblen, Johannes; Mai, Ben; Oyler, David; Bosnakovski, Darko; Mahmoud, Omayma M.; Hassan, Gamal M.; Kyba, Michael

doi:10.3389/fcell.2022.949532

Cited by 6 publications

(3 citation statements)

References 65 publications

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“…Next, we wondered if the expression level of chemokines and cytokine receptors as well as adhesion molecules (including CXCR4, VCAM-1, M-cadherin and Il6-r) is altered in SCs upon secondary injury. The chemokine receptor CXCR4 is known to regulate SC activation, migration and early expansion following muscle injury [ 34 ], while M-cadherin expression controls SC adhesion and cell-to-cell interactions as well as myoblast fusion [ 35 ]. Interestingly, RT-qPCR analysis showed significantly higher expression levels of M-cadherin and IL6-r in SCs isolated from muscle at 3 days after the second injury compared to single injury (Additional file 3 : Fig.…”

Section: Resultsmentioning

confidence: 99%

Injury-experienced satellite cells retain long-term enhanced regenerative capacity

Morroni,

Benedetti,

Esposito

et al. 2023

Stem Cell Res Ther

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Background Inflammatory memory or trained immunity is a recently described process in immune and non-immune tissue resident cells, whereby previous exposure to inflammation mediators leads to a faster and stronger responses upon secondary challenge. Whether previous muscle injury is associated with altered responses to subsequent injury by satellite cells (SCs), the muscle stem cells, is not known. Methods We used a mouse model of repeated muscle injury, in which intramuscular cardiotoxin (CTX) injections were administered 50 days apart in order to allow for full recovery of the injured muscle before the second injury. The effect of prior injury on the phenotype, proliferation and regenerative potential of satellite cells following a second injury was examined in vitro and in vivo by immunohistochemistry, RT-qPCR and histological analysis. Results We show that SCs isolated from muscle at 50 days post-injury (injury-experienced SCs (ieSCs)) enter the cell cycle faster and form bigger myotubes when cultured in vitro, compared to control SCs isolated from uninjured contralateral muscle. Injury-experienced SCs were characterized by the activation of the mTORC 1 signaling pathway, suggesting they are poised to activate sooner following a second injury. Consequently, upon second injury, SCs accumulate in greater numbers in muscle at 3 and 10 days after injury. These changes in SC phenotype and behavior were associated with accelerated muscle regeneration, as evidenced by an earlier appearance of bigger fibers and increased number of myonuclei per fiber at day 10 after the second injury. Conclusions Overall, we show that skeletal muscle injury has a lasting effect on SC function priming them to respond faster to a subsequent injury. The ieSCs have long-term enhanced regenerative properties that contribute to accelerated regeneration following a secondary challenge.

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Section: Resultsmentioning

confidence: 99%

Injury-experienced satellite cells retain long-term enhanced regenerative capacity

Morroni,

Benedetti,

Esposito

et al. 2023

Stem Cell Res Ther

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“…Here, we provide a method for muscle stem cell transplantation into the diaphragm with a direct impact on muscle force. We have shown that the pre-injury model consisting of irradiation combined with CTX, widely used for pre-conditioning of hind limbs [ 28 , 47 , 59 , 60 ], can be applied to the diaphragm. The generation of Pax7-ZsGreen–mTmG mice facilitated the process for SC isolation to engraftment detection.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Diaphragm Muscle Function upon Satellite Cell Transplantation in Dystrophic Mice

Azzag,

Gransee,

Magli

et al. 2024

IJMS

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The diaphragm muscle is essential for breathing, and its dysfunctions can be fatal. Many disorders affect the diaphragm, including muscular dystrophies. Despite the clinical relevance of targeting the diaphragm, there have been few studies evaluating diaphragm function following a given experimental treatment, with most of these involving anti-inflammatory drugs or gene therapy. Cell-based therapeutic approaches have shown success promoting muscle regeneration in several mouse models of muscular dystrophy, but these have focused mainly on limb muscles. Here we show that transplantation of as few as 5000 satellite cells directly into the diaphragm results in consistent and robust myofiber engraftment in dystrophin- and fukutin-related protein-mutant dystrophic mice. Transplanted cells also seed the stem cell reservoir, as shown by the presence of donor-derived satellite cells. Force measurements showed enhanced diaphragm strength in engrafted muscles. These findings demonstrate the feasibility of cell transplantation to target the diseased diaphragm and improve its contractility.

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“…Research in Slc44a2 knock-out mice showed that a decrease in muscle mass and tone appeared to increase muscular thyroid hormone content (41,42). Additionally, Shams et al ( 2022) demonstrated the indispensable role of CXCR4 signaling in the early activation, proliferation, and self-renewal of satellite cells for skeletal muscle recovery during acute events (43). These findings suggest an indirect link between the Thr92Ala-DIO2 heterozygosity and muscle mass maintenance, providing a potential mechanistic pathway through which this polymorphism may confer a protective effect in COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Thr92Ala-DIO2 heterozygosity is associated with skeletal muscle mass and myosteatosis in patients with COVID-19

Beltrão,

Carvalhal

et al. 2024

European Thyroid Journal

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Introduction: The type 2 deiodinase and its Thr92Ala-DIO2 polymorphism have been linked to clinical outcomes in acute lung injury and COVID-19. Objective: To identify a potential association between Thr92Ala-DIO2 polymorphism and body composition (appendicular muscle mass, myosteatosis, and fat distribution) and to determine whether they reflect the severity or mortality associated with the disease. Methods: In this prospective cohort study (June-August 2020), 181 patients hospitalized with moderate-to-severe COVID-19 underwent a non-contrast-enhanced computed tomography (CT) of the thorax to assess body composition, laboratory tests, and genotyping for the Thr92Ala-DIO2 polymorphism. Results: 181 consecutive patients were stratified into three subgroups according to the genotype: Thr/Thr (n = 64), Thr/Ala (n = 96), and Ala/Ala (n = 21). The prevalence of low muscle area (MA) (< 92 cm²) was 52.5 %. Low MA was less frequent in Ala/Thr patients (44.8%) than in Thr/Thr (60.9%) or Ala/Ala patients (61.9%) (p = 0.027). Multivariate logistic regression analysis confirmed that the Thr/Ala allele was associated with a reduced risk of low MA (41% to 69%) and myosteatosis (62% to 72%) compared with Thr/Thr + Ala/Ala (overdominant model). Kaplan–Meier curves showed that patients with low muscle mass and homozygosity had lower survival rates than the other groups. Notably, the heterozygotes with MA ≥ 92 cm² exhibited the best survival rate. Conclusion: Thr92Ala-DIO2 heterozygosity is associated with increased skeletal MA and less myosteatosis in patients with COVID-19. The protective effect of Thr92Ala-DIO2 heterozygosity on COVID-19 mortality is restricted to patients with reduced MA.

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The chemokine receptor CXCR4 regulates satellite cell activation, early expansion, and self-renewal, in response to skeletal muscle injury

Cited by 6 publications

References 65 publications

Injury-experienced satellite cells retain long-term enhanced regenerative capacity

Injury-experienced satellite cells retain long-term enhanced regenerative capacity

Enhanced Diaphragm Muscle Function upon Satellite Cell Transplantation in Dystrophic Mice

Thr92Ala-DIO2 heterozygosity is associated with skeletal muscle mass and myosteatosis in patients with COVID-19

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