Skeletal muscle as potential central link between sarcopenia and immune senescence.

Skeletal muscle is composed of a large and heterogenous assortment of cell populations that interact with each other to maintain muscle homeostasis and orchestrate regeneration. Although Satellite Cells (SCs) - which are muscle stem cells - are the protagonists of functional muscle repair following damage, several other cells such as inflammatory, vascular and mesenchymal cells coordinate muscle regeneration in a finely tuned process. Fibro-Adipogenic Progenitors (FAPs) are a muscle interstitial mesenchymal cell population, which supports SCs differentiation during tissue regeneration. During the first days following muscle injury FAPs undergo massive expansion, which is followed by their macrophage-mediated clearance and the re-establishment of their steady state pool. It is during this critical time window that FAPs, together with the other cellular components of the muscle stem cell niche, establish a dynamic network of interactions that culminate in muscle repair. A number of different molecules have been recently identified as important mediators of this cross-talk, and its alteration has been associated with different muscle pathologies. In this review, we will focus on the soluble factors that regulate FAPs activity, highlighting their roles in orchestrating the inter-cellular interactions between FAPs and the other cell populations that participate in muscle regeneration.

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Fibro-Adipogenic Progenitors Cross-Talk in Skeletal Muscle: The Social Network.

Biomaterial and stem cell‐based strategies for skeletal muscle regeneration

Fibro/Adipogenic Progenitors (FAPs) are muscle-interstitial progenitors mediating pro-myogenic signals that are critical for muscle homeostasis and regeneration. In myopathies, the autocrine/paracrine constraints controlling FAP adipogenesis are released causing fat infiltrates. Here, by combining pharmacological screening, high-dimensional mass cytometry and in silico network modeling with the integration of single-cell/bulk RNA sequencing data, we highlighted the canonical WNT/GSK/β-catenin signaling as a crucial pathway modulating FAP adipogenesis triggered by insulin signaling. Consistently, pharmacological blockade of GSK3, by the LY2090314 inhibitor, stabilizes β-catenin and represses PPARγ expression abrogating FAP adipogenesis ex vivo while limiting fatty degeneration in vivo. Furthermore, GSK3 inhibition improves the FAP pro-myogenic role by efficiently stimulating, via follistatin secretion, muscle satellite cell (MuSC) differentiation into mature myotubes. Combining, publicly available single-cell RNAseq datasets, we characterize FAPs as the main source of WNT ligands inferring their potential in mediating autocrine/paracrine responses in the muscle niche. Lastly, we identify WNT5a, whose expression is impaired in dystrophic FAPs, as a crucial WNT ligand able to restrain the detrimental adipogenic differentiation drift of these cells through the positive modulation of the β-catenin signaling.

Adipogenesis of skeletal muscle fibro/adipogenic progenitors is affected by the WNT5a/GSK3/β-catenin axis

Normal skeletal muscle functions are affected following trauma, chronic diseases, inherited neuromuscular disorders, aging, and cachexia, hampering the daily activities and quality of life of the affected patients. The maladaptive accumulation of fibrous intramuscular connective tissue and fat are hallmarks of multiple pathologies where chronic damage and inflammation are not resolved, leading to progressive muscle replacement and tissue degeneration. Muscle-resident fibro-adipogenic progenitors are adaptable stromal cells with multilineage potential. They are required for muscle homeostasis, neuromuscular integrity, and tissue regeneration. Fibro-adipogenic progenitors actively regulate and shape the extracellular matrix and exert immunomodulatory functions via cross-talk with multiple other residents and non-resident muscle cells. Remarkably, cumulative evidence shows that a significant proportion of activated fibroblasts, adipocytes, and bone-cartilage cells, found after muscle trauma and disease, descend from these enigmatic interstitial progenitors. Despite the profound impact of muscle disease on human health, the fibrous, fatty, and ectopic bone tissues' origins are poorly understood. Here, we review the current knowledge of fibro-adipogenic progenitor function on muscle homeostatic integrity, regeneration, repair, and aging. We also discuss how scar-forming pathologies and disorders lead to dysregulations in their behavior and plasticity and how these stromal cells can control the onset and severity of muscle loss in disease. We finally explore the rationale of improving muscle regeneration by understanding and modulating fibro-adipogenic progenitors' fate and behavior.

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Evolving Roles of Muscle-Resident Fibro-Adipogenic Progenitors in Health, Regeneration, Neuromuscular Disorders, and Aging.

Chronic muscle injury is characteristics of fatty infiltration and fibrosis. Recently, fibro/adipogenic progenitors (FAPs) were found to be indispensable for muscular regeneration while were also responsible for fibrosis and fatty infiltration in muscle injury. Many myokines have been proven to regulate the adipose or cell proliferation. Because the fate of FAPs is largely dependent on microenvironment and the regulation of myokines on FAPs is still unclear. We screened the potential myokines and found Interleukin-15 (IL-15) may regulate the fatty infiltration in muscle injury. In this study, we investigated how IL-15 regulated FAPs in muscle injury and the effect on muscle regeneration. Cell proliferation assay, western blots, qRT-PCR, immunohistochemistry, flow cytometric analysis were performed to investigate the effect of IL-15 on proliferation and adipogensis of FAPs. Acute muscle injury was induced by injection of glycerol or cardiotoxin to analyze how IL-15 effected on FAPs in vivo and its function on fatty infiltration or muscle regeneration. We identified that the expression of IL-15 in injured muscle was negatively associated with fatty infiltration. IL-15 can stimulate the proliferation of FAPs and prevent the adipogenesis of FAPs in vitro and in vivo. The growth of FAPs caused by IL-15 was mediated through JAK-STAT pathway. In addition, desert hedgehog pathway may participate in IL-15 inhibiting adipogenesis of FAPs. Our study showed IL-15 can cause the fibrosis after muscle damage and promote the myofiber regeneration. Finally, the expression of IL-15 was positively associated with severity of fibrosis and number of FAPs in patients with chronic rotator cuff tear. These findings supported the potential role of IL-15 as a modulator on fate of FAPs in injured muscle and as a novel therapy for chronic muscle injury.

/pdf/interleukin-15-facilitates-muscle-regeneration-through-46kp51vrs0.pdf

Interleukin-15 facilitates muscle regeneration through modulation of fibro/adipogenic progenitors.

Tendon injury repairs are big challenges in sports medicine, and fatty infiltration after tendon injury is very common and hampers tendon injury healing process. Tendon stem cells (TSCs), as precursors of tendon cells, have shown promising effect on injury tendon repair for their tenogenesis and tendon extracellular matrix formation. Adipocytes and lipids accumulation is a landmark event in pathological process of tendon injury, and this may induce tendon rupture in clinical practice. Based on this, it is important to inhibit TSCs adipogenesis and lipids infiltration to restore structure and function of injury tendon. Aspirin, as the representative of non-steroidal anti-inflammatory drugs (NSAIDs), has been widely used in tendon injury for its anti-inflammatory and analgesic actions, but effect of aspirin on TSCs adipogenesis and fatty infiltration is still unclear. Under adipogenesis conditions, TSCs were treated with concentration gradient of aspirin. Oil red O staining was performed to observe changes of lipids accumulation. Next, we used RNA sequencing to compare profile changes of gene expression between induction group and aspirin-treated group. Then, we verified the effect of filtrated signalling on TSCs adipogenesis. At last, we established rat tendon injury model and compared changes of biomechanical properties after aspirin treatment. The results showed that aspirin decreased lipids accumulation in injury tendon and inhibited TSCs adipogenesis. RNA sequencing filtrated PTEN/PI3K/AKT signalling as our target. After adding the signalling activators of VO-Ohpic and IGF-1, inhibited adipogenesis of TSCs was reversed. Still, aspirin promoted maximum loading, ultimate stress and breaking elongation of injury tendon. In conclusion, by down-regulating PTEN/PI3K/AKT signalling, aspirin inhibited adipogenesis of TSCs and fatty infiltration in injury tendon, promoted biomechanical properties and decreased rupture risk of injury tendon. All these provided new therapeutic potential and medicine evidence of aspirin in treating tendon injury and tendinopathy.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jcmm.14622

Aspirin inhibits adipogenesis of tendon stem cells and lipids accumulation in rat injury tendon through regulating PTEN/PI3K/AKT signalling.

Objective To evaluate mid-term effectiveness of manipulation under anesthesia combined with arthroscopic capsular release and subacromial debridement for primary frozen shoulder. Methods Between January 2013 and December 2017, 33 patients of primary frozen shoulder were treated with manipulation under anesthesia combined with 360° arthroscopic capsular release and subacromial debridement. There were 10 males and 23 females, aged from 37 to 65 years, with a mean age of 50.9 years. The affected shoulder on left side in 17 cases and on right side in 16 cases. The disease duration was 6-13 months (mean, 8.4 months). Before and after operation, the visual analogue scale (VAS) score was used to evaluate the shoulder joint pain, Constant score was used to evaluate the shoulder joint function, and the flexion, abduction, and external rotation of shoulder joint were recorded. The internal rotation function was assessed based on the vertebral plane that the thumb could reach after internal rotation of the affected shoulder joint (the rank of internal rotation vertebra). X-ray film was taken to measure the distance of the subacromial space. Results There was no fracture or labrum tear in all patients, and all the incisions healed by first intention. All the 33 patients were followed up 20-31 months, with an average of 24.1 months. During the follow-up, there was no complication such as wound infection and nerve injury. At last follow-up, the range of motion of shoulder flexion, abduction, and external rotation, the rank of internal rotation vertebra, the VAS score, Constant score, and subacromial space were significantly improved when compared with preoperative ones ( P Conclusion Manipulation under anesthesia combined with arthroscopic capsular release and subacromial debridement can achieve a good mid-term effectiveness without complication for primary frozen shoulder.

[Mid-term effectiveness of manipulation under anesthesia combined with arthroscopic capsular release and subacromial debridement for primary frozen shoulder].

Objective To detect the differentially expressed circular RNA (circRNA) in rotator cuff tendinopathy and analyze the potential molecular mechanism of these parental genes. Methods Ten supraspinatus tendons donated from patients who underwent tendon repair surgery between June 2018 and June 2019 were used for RNA-sequence. All rotator cuff tendinopathy and normal tendon samples were confirmed by MRI, histological staining, and observation by arthroscopy. All pathological tendons were matched with tendon samples for patients' age, gender, body mass index, and Bonar score. The bioinformatic analysis was performed based on the differentially expressed circRNA and their parental genes, including gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and competing endogenous RNA (ceRNA) network construction. Results There were 94 differentially expressed circRNAs, including 31 up-regulated and 63 down-regulated, detected between the rotator cuff tendinopathy and normal tendon samples with |log2 fold change (FC)| >2, P<0.05. GO analysis showed that the genes were mostly enriched in response to cyclic adenosine monophosphate (cAMP). KEGG pathway analysis showed that the most genes were enriched in extracellular matrix-receptor interaction, protein digestion and absorption, cell cycle, and nuclear factor κB signaling pathway. ceRNA networks showed the interactions among circRNAs, mRNAs, and miRNAs. And circRNA.8951-has-miR-6089-DNMT3B was the most sum max energy. Conclusion This bioinformatic study reveals several potential therapeutic targets for rotator cuff tendinopathy, which paves the way to better treatment and prevention of this disorder.

Circular RNA expression pattern and competing endogenous RNA network involved in rotator cuff tendinopathy

The present invention relates to the technical field of surgical traction devices and also discloses a shoulder arthroscopy minimally invasive surgery traction device. The shoulder arthroscopy minimally invasive surgery traction device comprises a fixing base, a top part of the fixing base is fixedly connected with a supporting tube, an inner part of the supporting tube is slidably connected witha telescopic rod, a row of threaded holes are arranged in a side wall of the telescopic rod, a limiting screw matching the threaded holes sleeves on a tube wall of the supporting tube, a first U-shaped seat is fixedly connected with a top part of the telescopic rod, the first U-shaped seat is internally rotatably connected with a support rod via a rotating rod, one end of the support rod far awayfrom the telescopic rod is fixedly connected with a connecting plate, the connecting plate is fixedly connected with a traction mechanism by a bolt, the traction mechanism comprises a first threaded rod, a threaded sleeve and a second threaded rod, the first thread rod is connected with the connecting plate by a bolt, and both ends of the threaded sleeve are respectively screwed with the first threaded rod and the second threaded rod. The shoulder arthroscopy minimally invasive surgery traction device can be finely adjusted when a traction rope is used for traction, and avoid secondary injuryto patients' shoulders.

Xiaolong Zheng

Papers

Interleukin-15 facilitates muscle regeneration through modulation of fibro/adipogenic progenitors.

Aspirin inhibits adipogenesis of tendon stem cells and lipids accumulation in rat injury tendon through regulating PTEN/PI3K/AKT signalling.

[Mid-term effectiveness of manipulation under anesthesia combined with arthroscopic capsular release and subacromial debridement for primary frozen shoulder].

Circular RNA expression pattern and competing endogenous RNA network involved in rotator cuff tendinopathy

Shoulder arthroscopy minimally invasive surgery traction device