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.

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

Screw fixation is a typical technique for isolated talonavicular arthrodesis (TNA), however, no consensus has been reached on how to select most suitable inserted position and direction. The study aimed to present a new fixation technique and to evaluate the clinical outcome of individual headless compression screws (HCSs) applied with three-dimensional (3D) image processing technology to isolated TNA. From 2007 to 2014, 69 patients underwent isolated TNA by using double Acutrak HCSs. The preoperative three-dimensional (3D) insertion model of double HCSs was applied by Mimics, Catia, and SolidWorks reconstruction software. One HCS oriented antegradely from the edge of dorsal navicular tail where intersected interspace between the first and the second cuneiform into the talus body along the talus axis, and the other one paralleled the first screw oriented from the dorsal-medial navicular where intersected at the medial plane of the first cuneiform. The anteroposterior and lateral X-ray examinations certified that the double HCSs were placed along the longitudinal axis of the talus. Postoperative assessment included the American Orthopaedic Foot & Ankle Society hindfoot (AOFAS), the visual analogue scale (VAS) score, satisfaction score, imaging assessments, and complications. At the mean 44-months follow-up, all patients exhibited good articular congruity and solid bone fusion at an average of 11.26 ± 0.85 weeks (range, 10 ~ 13 weeks) without screw loosening, shifting, or breakage. The overall fusion rates were 100%. The average AOFAS score increased from 46.62 ± 4.6 (range, 37 ~ 56) preoperatively to 74.77 ± 5.4 (range, 64–88) at the final follow-up (95% CI: −30.86 ~ −27.34; p < 0.001). The mean VAS score decreased from 7.01 ± 1.2 (range, 4 ~ 9) to 1.93 ± 1.3 (range, 0 ~ 4) (95% CI: 4.69 ~ 5.48; p < 0.001). One cases (1.45%) and three cases (4.35%) experienced wound infection and adjacent arthritis respectively. The postoperative satisfaction score including pain relief, activities of daily living, and return to recreational activities were good to excellent in 62 (89.9%) cases. Individual 3D reconstruction of HCSs insertion model can be designed with three-dimensional image processing technology in TNA. The technology is safe, effective, and reliable to isolated TNA method with high bone fusion rates, low incidences of complications.

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Individual headless compression screws fixed with three-dimensional image processing technology improves fusion rates of isolated talonavicular arthrodesis

Objective To analyze the clinical outcomes of triple arthrodesis with osteotomy in the treatment of Stage ⅡB and Stage Ⅲ adult-acquired flatfoot. Methods The authors reviewed 10 cases of adult-acquired flatfoot, including 3 cases of stage ⅡB adult-acquired flatfoot and 7 cases of stage Ⅲ adultacquired flatfoot. They were treated by triple arthrodesis with osteotomy of subtalar joint (STJ),talonavicular joint (TNJ) and calcaneocuboid joint (CCJ). The combined medial and lateral incisions were used to obtain adequate exposure for CCJ, STJ and TNJ. Then the cartilages of CCJ, STJ and TNJ were completely denuded and osteotomied to restore their proper alignments. The optimal positioning of hindfoot could be gchieved and fixed by Kirschner wires. Two cannulated screws of 7.3 mm were delivered through the plantar aspect of heel to fix STJ. And then two 4.5 mm cannulated screws individually fixed TNJ and CCJ distal to proximal. Clinical evaluations were based on the AOFAS ankle-hindfoot scale and subjective assessments of pains, function, cosmesis and overall satisfaction. Radiographic evaluations included measurements of anterior-posterior talo-first metatarsal angle, lateral talocalcaneal angle, lateral talo-first metatarsal angle and an assessment of time to union for all arthrodeses. Results All patients were followedup with a mean time of 13.2 (6-21) months. The average AOFAS ankle-hindfoot scale improved from 39.4 ± 4.4 preoperatively to 83.7 ± 2. 6 postoperatively ( P ＜ 0.01 ). And the patients experienced subjective improvements in pain, function and cosmesis. Overall, all patients were satisfied.Radiographically, the rate of bone healing was 100%. The anterior-posterior talo-first metatarsal angle,lateral talocalcaneal angle and lateral talo-first metatarsal angle statistically improved. No complication, such as infection and un-union, was reported. Conclusion Triple arthrodesis with osteotomy is an effective procedure for the treatment of stage ⅡB and Ⅲ adult-acquired flatfoot deformity. It may relieve pains,correct structural deformities and obtain excellent clinical outcomes.

Key words: 
Flatfoot;  Osteotomy, Le fort;  Therapy;  Adult;  Triple Arthrodesis

[Triple arthrodesis with osteotomy for the treatment of stage IIB and stage III adult-acquired flatfoot deformity].

Screw fixation is a typical technique for the isolated subtalar joint. However, no consensus has been reached on how to select the most suitable insertion position and direction. This study aims to find the ideal screw insertion and then explore its influence on the clinical efficacy of subtalar fusion by analyzing the effects of different cannulated screw insertions on the stress distribution, anti-rotary strength, and anti-inversion/eversion strength of the subtalar joint. In this study, we investigated three cannulated screw insertions for subtalar fusion: screw insertion with the most uniform stress distribution (group A), lateral-medial parallel screw insertion (group B), and traditional longitudinally parallel screw insertion (group C). The effects of these three insertions on the loading stress of the subtalar joint (including stress distribution, anti-inversion/eversion strength, and anti-rotary strength) were comparatively analyzed with the three-dimensional finite element method to screen the ideal screw insertion. Moreover, a prospective study was conducted to analyze the influence of the ideal screw insertion on subtalar fusion, including the fusion rate, fusion time, and clinical efficacy (VAS score, AOFAS score, and complications). Group B was worse than group A with respect to the stress distribution uniformity, but slightly better than group C, and better than both groups A and C in terms of the anti-rotary strength and anti-inversion/eversion strength. The screw insertion based on the most uniform stress distribution is not feasible in surgery. Therefore, the lateral-medial antiparallel screw insertion is the ideal insertion. From January 2012 to June 2016, 48 cases were treated by subtalar fusion with the ideal screw insertion, and then followed up for 30.6 months (12–48 months). The fusion was proved in all 48 cases with a fusion rate of 100% by X-ray or CT scan. The mean time of fusion was 12.8 weeks (12–16 weeks). The VAS score decreased from 6.00 before operation to 1.03 on the last visit (P < 0.05), and the AOFAS score increased from 57.0 to 85.6 (P < 0.05), with a good and excellent rate of 95.8%. The lateral-medial parallel screw insertion not only demonstrates a good stress distribution profile of the subtalar joint but also has advantages such as easy localization and operation during surgery, as well as a high fusion rate and few complications after surgery. Therefore, it is a safe, accurate, and effective fixation mode that is worthy of being popularized clinically.

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Analysis of the stress distribution of the subtalar joint and fusion efficacy after double-screw insertion

The invention discloses a detachable talus prosthesis which comprises a talonavicular subtalar joint assembly and a tibiotalar joint assembly. On one hand, the detachable talus prosthesis is formed by combining the talonavicular subtalar joint assembly and the tibiotalar joint assembly and is easy to manufacture; on the other hand, the subtalar joint surface and talonavicular joint surface are of porous structures, and the detachable talus prosthesis has a biological function and facilitate rapid fusion and growth of prosthesis and calcaneus and scaphoid bone.

Mei-ming Xie

Papers

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

Individual headless compression screws fixed with three-dimensional image processing technology improves fusion rates of isolated talonavicular arthrodesis

[Triple arthrodesis with osteotomy for the treatment of stage IIB and stage III adult-acquired flatfoot deformity].

Analysis of the stress distribution of the subtalar joint and fusion efficacy after double-screw insertion

Detachable talus prosthesis