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Multiple processes control quiescence of muscle stem cells (MuSCs), which is instrumental to guarantee long-term replenishment of the stem cell pool. Here, we describe that the G-proteins G 12 -G 13 integrate signals from different G-protein-coupled receptors (GPCRs) to control MuSC quiescence via activation of RhoA. Comprehensive screening of GPCR ligands identified two MuSC-niche-derived factors, endothelin-3 (ET-3) and neurotensin (NT), which activate G 12 -G 13 signaling in MuSCs. Stimulation with ET-3 or NT prevented MuSC activation, whereas pharmacological inhibition of ET-3 or NT attenuated MuSC quiescence. Inactivation of Gna12-Gna13 or Rhoa but not of Gnaq-Gna11 completely abrogated MuSC quiescence, which depleted the MuSC pool and was associated with accelerated sarcopenia during aging. Expression of constitutively active RhoA prevented exit from quiescence in Gna12-Gna13 mutant MuSCs, inhibiting cell cycle entry and differentiation via Rock and formins without affecting Rac1-dependent MuSC projections, a hallmark of quiescent MuSCs. The study uncovers a critical role of G 12 -G 13 and RhoA signaling for active regulation of MuSC quiescence., (© 2024. The Author(s).)

Background: The ergogenic effects of caffeine intake on exercise performance are well-established, even if differences exist among individuals in response to caffeine intake. The genetic variation of a specific gene, human cytochrome P450 enzyme 1A2 (CYP1A2) (rs762551), may be one reason for this difference. This systematic review and meta-analysis aimed to comprehensively evaluate the influence of CYP1A2 gene types on athletes' exercise performance after caffeine intake., Methods: A literature search through 4 databases (Web of Science, PubMed, Scopus, and China National Knowledge Infrastructure) was conducted until March 2023. The effect size was expressed as the weighted mean difference (WMD) by calculating fixed effects meta-analysis if heterogeneity was not significant (I 2 ≤ 50% and p ≥ 0.1). Subgroup analyses were performed based on AA and AC/CC genotype of CYP1A2., Results: The final number of studies meeting the inclusion criteria was 12 (n = 666 participants). The overall analysis showed that the cycling time trial significantly improved after caffeine intake (WMD = -0.48, 95% confidence interval (95%CI): -0.83 to -0.13, p = 0.007). In subgroup analyses, acute caffeine intake improved cycling time trial only in individuals with the A allele (WMD = -0.90, 95%CI: -1.48 to -0.33, p = 0.002), but not the C allele (WMD = -0.08, 95%CI: -0.32 to 0.17, p = 0.53). Caffeine supplementation did not influence the Wingate (WMD = 8.07, 95%CI: -22.04 to 38.18, p = 0.60) or countermovement jump test (CMJ) performance (WMD = 1.17, 95%CI: -0.02 to 2.36, p = 0.05), and these outcomes were not influenced by CYP1A2 genotype., Conclusion: Participants with the CYP1A2 genotype with A allele improved their cycling time trials after caffeine supplementation. However, compared to placebo, acute caffeine supplementation failed to increase the Wingate or CMJ performance, regardless of CYP1A2 genotype., Competing Interests: Competing interests The authors declare that they have no competing interests., (Copyright © 2024. Production and hosting by Elsevier B.V.)

Background: Platelet-rich plasma (PRP) has demonstrated beneficial effects on healing of the bone-tendon interface (BTI)., Purpose: To determine the optimal initiation time for PRP application after rotator cuff repair in an animal model., Study Design: Controlled laboratory study., Methods: A total of 136 C57BL/6 mice were included; 40 mice were used to prepare PRP, while 96 mice underwent acute supraspinatus tendon (SST) repair. The animals were randomly divided into 4 groups: a control group and 3 groups in which PRP was injected into the injury interface immediately after surgery, on the 7th postoperative day (PRP-7d), and on the 14th postoperative day. At 4 and 8 weeks postoperatively, the animals were sacrificed, blood was collected by eyeball removal, and samples of the SST-humerus complex were collected. Histological, imaging, immunological, and biomechanical data were compared among the groups using 1-way analysis of variance with the Bonferroni post hoc test., Results: Histological analysis revealed that the fibrocartilage layer at the BTI was larger in the PRP-7d group compared to the other groups at both 4 and 8 weeks postoperatively. Moreover, the PRP-7d group exhibited improved proteoglycan content and distribution compared to the other groups. Enzyme-linked immunosorbent assay results demonstrated that at 4 weeks postoperatively, higher concentrations of transforming growth factor-β1 and platelet-derived growth factor-BB (PDGF-BB) were seen in the PRP-7d group versus the PRP-14d and control gruops ( P < .05), and at 8 weeks postoperatively, the concentration of PDGF-BB was higher in the PRP-7d group versus the control group ( P < .05). Biomechanical testing at 4 weeks postoperatively revealed that the failure load and ultimate strength of the SST-humerus complex were superior in the PRP-7d group compared to the other groups ( P < .05), at 8 weeks, PRP-7d group was superior to the control group ( P < .05). Additionally, at 8 weeks postoperatively, the PRP-7d group exhibited a greater trabecular number and trabecular thickness at the BTI compared to the PRP-14d and control gruops ( P < .05)., Conclusion: PRP promoted healing of the BTI after a rotator cuff injury at an early stage., Clinical Relevance: A PRP injection on the 7th postoperative day demonstrated superior therapeutic effects compared with injections at other time points., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: Research support was received from the Hubei Provincial Natural Science Foundation (2019CFB397), Research Fund for Young Teachers of Wuhan Sports University and Donghu Scholar Program of Wuhan Sports University (2019), and Young and Middle-Aged Scientific Research Team Project of Wuhan Sports University (21KT14). AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2024.)

Background: The probiological healing effect of platelet-rich plasma (PRP) during tissue repair has recently gathered much attention. This study aimed to conduct a systematic review and meta-analysis of patients with diabetic foot ulcer (DFU) receiving PRP or conventional treatment to evaluate their efficacy., Methods: PubMed, Excerpta Medica Database (EMBASE), Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases were comprehensively searched by 2 independent reviewers following PRISMA guidelines for the inclusion of randomized controlled trials (RCTs) comparing PRP with conventional treatments for DFUs. The primary measurements of healing rate and healing time, the methodological quality and extracted data were assessed using Review Manager 5.3. Statistical significance was set at P < 0.05., Results: A total of 10 RCTs involving 550 patients were included in this study, PRP was observed to significantly improve the healing rate (risk ratio [RR] = 1.38, 95% confidence interval [CI] 1.05-1.82, P = 0.02) and shorten the healing time (mean difference [MD] = -23.23, 95% CI -45.97 to -0.49, P = 0.05) of patients with DFU when compared to the conventional treatment., Conclusions: Compared to conventional treatment, PRP effectively promoted the healing of patients with DFU by evidently improving the healing rate and healing time., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Basic scientific studies have demonstrated positive effects of platelet-rich therapies, such as platelet-rich plasma (PRP) and platelet-rich fibrin (PRF), on tendon repair. However, clinical evidence indicating improved prognosis is controversial. In this study, we aimed to determine whether augmentation of arthroscopic rotator cuff repair with PRP and PRF improves outcomes compared to arthroscopic repair alone., Literature Survey: PubMed, Embase, and Cochrane library databases were comprehensively searched for randomized controlled trials (RCTs) published until June 2022 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. No language restriction was applied., Methodology: The primary outcomes were the rate of repeat tears after arthroscopic rotator cuff repair (retear rate) and clinical function scores (Constant-Murley Score, University of California, Los Angeles Score), and the extracted data were assessed for quality. Statistical analyses were performed using Review manager 5.3, and p < .05 was considered statistically significant., Synthesis: Ten RCTs with 628 patients were included. The results showed that augmenting surgery with PRP reduces retear rates compared to surgery alone (risk ratio [RR] = 0.40, 95% confidence interval [CI] 0.23-0.69, p = .001), whereas PRF has no effect on retear rates (p = .92). Regarding clinical function, PRP improves Constant-Murley scores (mean difference [MD] = 2.03, 95% CI 0.13-3.93, p = .04) and University of California, Los Angeles scores (MD = 1.30, 95% CI 0.36-2.24, p = .007), whereas PRF improves only Constant-Murley scores (MD = 3.93, 95% CI 1.50-6.36, p = .002). However, these differences were small and below the minimum clinically important difference threshold., Conclusions: This study showed that compared to arthroscopic rotator cuff repair alone, the application of PRP in arthroscopic rotator cuff repair reduces retear rate and improves clinical function scores, whereas the application of PRF has no clinically meaningful benefit. The small number and heterogeneity of studies as well as methodological limitations and risk of bias limit confidence in the true effect., (© 2023 American Academy of Physical Medicine and Rehabilitation.)

Background: Various muscle contraction modalities have differing effects on the musculoskeletal system. To understand the magnitude of these effects, the authors investigated the effects of eccentric and concentric contractions on the bone-tendon interface after rotator cuff repair in mice., Hypothesis: Eccentric contraction promotes healing of the bone-tendon interface after rotator cuff repair in mice better than other muscle contraction patterns., Study Design: Controlled laboratory study., Methods: The authors performed acute supraspinatus tendon repair of the right shoulder in 104 C57BL/6 mice. Animals were randomized into 4 groups postoperatively: control group (Con group), horizontal running group (Horz group), +15° uphill running group (Up group), and -15° downhill running group (Down group), with 26 animals in each group. At 4 and 8 weeks postoperatively, the authors removed the eyeball, collected blood samples, and extracted the supraspinatus tendon-humerus complex for histological, immunological, bone morphological, and biomechanical tests., Results: At 4 and 8 weeks postoperatively, the Down group exhibited a better collagen cell arrangement and fibrocartilage layer than the other 3 groups. At 4 weeks postoperatively, anti-inflammatory macrophages (M2 macrophages) were observed at the repair site in all groups except for the Con group. At 8 weeks postoperatively, M2 macrophages were withdrawn from the tendon site in all groups. The transforming growth factor β1 concentration in the Down group was greater than that in the other 3 groups at 4 weeks postoperatively, and it was higher than that in the Con group at 8 weeks postoperatively. The bone volume fraction, number of trabeculae, and thickness of trabeculae at the repair site in the Down group, as well as the ultimate strength and failure load in the biomechanical tests, were greater than those in the other 3 groups at 8 weeks postoperatively., Conclusion: Eccentric contraction promotes healing of the bone-tendon interface after rotator cuff repair in mice better than other muscle contraction patterns., Clinical Relevance: After clinical rotator cuff repair, patients can be rehabilitated by eccentric training to speed up the functional recovery of the shoulder joint., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: This work was supported by the Hubei Provincial Natural Science Foundation of China (No. 2019CFB397), Research Fund for Young Teachers of Wuhan Sports University and Donghu Scholar Program of Wuhan Sports University (2019), and Young and Middle-Aged Scientific Research Team Project of Wuhan Sports University (No. 21KT14). AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Hypothesis: Platelet-rich plasma (PRP) and corticosteroids are used to treat rotator cuff diseases. However, few reviews have compared the effects of these 2 treatments. In this study, we compared the effects of PRP and corticosteroid injection on the prognosis of rotator cuff diseases., Materials and Methods: According to the Cochrane Manual of Systematic Review of Interventions, the PubMed, Embase, and Cochrane databases were searched comprehensively. Two independent authors screened suitable studies and performed data extraction and risk of bias assessment. Only randomized controlled trials comparing the effects of PRP and corticosteroid in the treatment of rotator cuff injuries were included, as measured by clinical function and pain during different follow-up periods., Results: Nine studies with 469 patients were included in this review. In short-term treatment, corticosteroids were superior to PRP in the improvement of Constant, Simple Shoulder Test, and American Shoulder and Elbow Surgeons scores (mean difference [MD] -5.08, 95% confidence interval [CI] -10.26, 0.06; P = .05 and MD -0.97, 95% CI -1.68, -0.07; P = .03 and MD -6.67, 95% CI -12.85, -0.49; P = .03, respectively). No statistically significant difference was observed between the 2 groups at midterm (P > .05), and the recovery of the Simple Shoulder Test and American Shoulder and Elbow Surgeons scores in PRP treatment was significantly better than that in corticosteroid treatment in the long term (MD: 1.21, 95% CI: 0.68, 1.74; P < .00001 and MD: 6.96, 95% CI: 3.90, 9.61; P < .00001, respectively). In pain reduction based on visual analog scale score, corticosteroids led to better pain reduction (MD: 0.84, 95% CI: 0.03, 1.64; P = .04), but no significant difference was observed in pain reduction between the 2 groups in the any term (P > .05). However, these differences did not reach the minimum clinically important difference., Conclusions: Current analysis showed that corticosteroids have better efficacy in short term, whereas PRP is more beneficial for long-term recovery. However, no difference was observed in the mid-term efficacy between the 2 groups. Randomized controlled trials with longer follow-up periods and larger sample sizes are also needed to determine the optimal treatment., (Copyright © 2023 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Platelet-rich plasma (PRP) is widely used clinically to treat tendon injuries, and often contains leukocytes. However, the debate regarding the concentration of leukocytes in PRP is still ongoing. This study aimed to evaluate the therapeutic effects of leukocyte-rich platelet-rich plasma (LR-PRP) and leukocyte-poor platelet-rich plasma (LP-PRP) on the healing of the bone-tendon interface (BTI) of the rotator cuff. A total of 102 C57BL/6 mice were used. Thirty mice were used to prepare the PRP, while 72 underwent acute supraspinatus tendon injury repair. The animals were then randomly assigned to three groups: LR-PRP, LP-PRP and control groups. The mice were euthanized at 4 and 8 weeks postoperatively, and histological, immunological and biomechanical analyses were performed. The histological results showed that the fusion effect at the bone-tendon interface at 4 and 8 weeks after surgery was greater in the PRP groups and significantly increased at 4 weeks; however, at 8 weeks, the area of the fibrocartilage layer in the LP-PRP group increased significantly. M2 macrophages were observed at the repaired insertion for all the groups at 4 weeks. At 8 weeks, M2 macrophages withdrew back to the tendon in the control group, but some M2 macrophages were retained at the repaired site in the LR-PRP and LP-PRP groups. Enzyme-linked immunoassay results showed that the concentrations of IL-1β and TNF-α in the LR-PRP group were significantly higher than those in the other groups at 4 and 8 weeks, while the concentrations of IL-1β and TNF-α in the LP-PRP group were significantly lower than those in the control group. The biomechanical properties of the BTI were significantly improved in the PRP group. Significantly higher failure load and ultimate strength were seen in the LR-PRP and LP-PRP groups than in the control group at 4 and 8 weeks postoperatively. Thus, LR-RPR can effectively enhance the early stage of bone-tendon interface healing after rotator cuff repair, and LP-PRP could enhance the later stages of healing after rotator cuff injury.

To systematically review of randomized controlled trials (RCTs) to compared the effects of leukocyte-rich and leukocyte-poor platelet-rich plasma in arthroscopic rotator cuff repair. Two independent reviewers comprehensively searched PubMed, Embase, and Cochrane library databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Comparison of leukocyte-rich platelet-rich plasma or leukocyte-poor platelet-rich plasma in rotator cuff repair in a level I RCTs. Methodological quality assessment was carried out using Cochrane Review Manager 5.3 software. P<0.05 was considered statistically significant. Nine RCTs with 540 patients were included in this review. Meta-analysis showed that leukocyte-poor platelet-rich plasma in significantly reduced retear rate in rotator cuff repair [RR=0.56 95% CI (0.42, 0.75); P<0.05), and in clinical results, the constant score [MD=3.67, 95% CI (1.62, 5.73); P=0.0005], UCLA score [MD=1.60, 95% CI (0.79, 2.42); P=0.0001], ASES score [MD=2.16, 95% CI (0.12, 4.20); P=0.04] were significantly improved. There was a significant result in favor of PRP for the Constant score [MD=-1.24, 95% CI (-1.50, -0.99); P<0.00001], while SST scores were not significantly different among all groups [MD=0.21, 95% CI (-0.21, 0.64); P=0.32]. In conclusion, leukocyte-poor platelet-rich plasma can improved the clinical function and reduced retear rate in arthroscopic rotator cuff repair. In contrast, the efficacy of leukocyte-rich platelet-rich plasma was not significantly improved with the exception of VAS score., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Skeletal muscle stem cells (MuSCs), also called satellite cells, are instrumental for postnatal muscle growth and skeletal muscle regeneration. Numerous signaling cascades regulate the fate of MuSCs during muscle regeneration but the molecular mechanism by which MuSCs sense mechanical stimuli remain unclear. Here, we describe that Piezo1, a mechanosensitive ion channel, keeps MuSCs in a quiescent state and prevents senescence. Absence of Piezo1 induces precocious activation of MuSCs, attenuates proliferation, and impairs differentiation, essentially abolishing efficient skeletal muscle regeneration and replenishment of the MuSC pool. Furthermore, we discovered that inactivation of Piezo1 results in compensatory up-regulation of T-type voltage-gated Ca2+ channels, leading to increased Ca 2+ influx, which strongly induces NOX4 expression via cPKC. Elevated NOX4 expression in Piezo1-deficient MuSCs increases ROS levels and DNA damage, causing P53-dependent cellular senescence and cell death. The importance of the P53/P21-axis for mediating Piezo1-dependent cellular defects was confirmed by pharmacological inhibition of P53 in Piezo1-deficient mice, which abrogates increased senescence of muscle cells and normalizes muscle regeneration. Our findings uncover an essential role of Piezo1-mediated mechano-signaling in MuSCs for maintaining quiescence and preventing senescence. Reduced mechano-signaling due to decreased physical activity during aging may contribute to the increase of senescent cells and the decline of MuSC numbers in geriatric mice and humans., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Mechanical stimulation and platelet-rich plasma (PRP) have been shown to be beneficial for healing of the bone-tendon interface (BTI), but few studies have explored the efficacy of a combination of these applications. We investigated the effect of mechanical stimulation combined with PRP on rotator cuff repair in mice., Hypothesis: Mechanical stimulation combined with PRP can enhance BTI healing in a murine model of rotator cuff repair., Study Design: Controlled laboratory study., Methods: A total of 160 C57BL/6 mice were used. Overall, 40 mice were used to prepare PRP, while 120 mice underwent acute supraspinatus tendon (SST) repair. The animals were randomly assigned to 4 groups: control group, mechanical stimulation group, PRP group, and mechanical stimulation combined with PRP group (combination group). At 4 and 8 weeks postoperatively, animals were sacrificed, the eyeballs were removed to collect blood, and the SST-humeral complexes were collected. Histological, biomechanical, immunological, and bone morphometric tests were performed., Results: Histologically, at 4 and 8 weeks after surgery, the area of the fibrocartilage layer at the BTI in the combination group was larger than in the other groups. The content and distribution of proteoglycans in this layer in the combination group were significantly greater than in the other groups. At 8 weeks postoperatively, trabecular number, and trabecular bone thickness of the subchondral bone area of interest at the BTI of the combination group were greater than those of the other groups, bone volume fraction of the combination group was greater than the control group. On biomechanical testing at 4 and 8 weeks after surgery, the failure load and ultimate strength of the SST-humeral complex in the combination group were higher than in the other groups. Enzyme-linked immunosorbent assay results showed that, at 4 weeks postoperatively, the serum concentrations of transforming growth factor beta 1 and platelet-derived growth factor (PDGF) in the combination group were significantly higher than in the other groups; at 8 weeks, the PDGF-AB concentration in the combination group was higher than in the control and mechanical stimulation groups., Conclusion: Mechanical stimulation combined with PRP can effectively promote the early stage of healing after a rotator cuff injury., Clinical Relevance: These findings imply that mechanical stimulation combined with PRP can serve as a potential therapeutic strategy for rotator cuff healing.