Physical activity reduces cancer-associated mortality through multiple mechanisms, including tumor immune microenvironment (TIME) reprogramming. However, whether and how physiological interventions promote anti-tumor immunity remain elusive. Here, we report that clinically relevant voluntary exercise promotes muscle-derived extracellular vesicle (EV)-associated miR-29a-3p for tumor extracellular matrix (ECM) inhibition in patients and mouse models, thereby permitting immune cell infiltration and immunotherapy. Mechanistically, an unbiased screening identifies EV-associated miR-29a-3p in response to leisure-time physical activity or voluntary exercise. MiR-29a-3p-containing EVs accumulate in tumors and downregulate collagen composition by targeting COL1A1. Gain- and loss-of-function experiments and cytometry by time of flight (CyTOF) demonstrate that myocyte-secreted miR-29a-3p promotes anti-tumor immunity. Combining immunotherapy with voluntary exercise or miR-29a-3p further enhances anti-tumor efficacy. Clinically, miR-29a-3p correlates with reduced ECM, increased T cell infiltration, and response to immunotherapy. Our work reveals the predictive value of miR-29a-3p for immunotherapy, provides mechanistic insights into exercise-induced anti-cancer immunity, and highlights the potential of voluntary exercise in sensitizing immunotherapy.

Aim: To discuss the progress of extracellular matrix (ECM) characteristics, mitochondrial homeostasis, and their potential crosstalk in the pathogenesis of sarcopenia, a geriatric syndrome characterized by a generalized and progressive reduction in muscle mass, strength, and physical performance.Methods: This review focuses on the anatomy and physiology of skeletal muscle, alterations of ECM and mitochondria during ageing, and the role of the interplay between ECM and mitochondria in the pathogenesis of sarcopenia.Results: Emerging evidence points to a clear interplay between mitochondria and ECM in various tissues and organs. Under the ageing process, the ECM undergoes changes in composition and physical properties that may mediate mitochondrial changes via the systematic metabolism, ROS, SPARC pathway, and AMPK/PGC-1α signalling, which in turn exacerbate muscle degeneration. However, the precise effects of such crosstalk on the pathobiology of ageing, particularly in skeletal muscle, have not yet been fully understood.Conclusion: The changes in skeletal muscle ECM and mitochondria are partially responsible for the worsened muscle function during the ageing process. A deeper understanding of their alterations and interactions in sarcopenic patients can help prevent sarcopenia and improve its prognoses.

Massive rotator cuff tears (MRCTs) are difficult to repair because of the retraction and poor mobility of torn tendons. In the current study, co-electrospun dual nano-scaffolds of poly(lactic-co-glycolic acid)/collagen I-polycaprolactone/nanohydroxyapatite (PLGA/Col-PCL/nHA) were fabricated and used to bridge MRCTs of infraspinatus tendons in a rabbit model. PLGA–PCL served as a control. The PLGA or the PLGA/Col sides of the dual scaffolds connected the tendon stumps. The PCL or PCL/nHA side was inserted into the bone tunnel at the insertion of the infraspinatus tendon. Fibroblasts showed higher viability and collagen secretion when seeded on a PLGA/Col scaffold compared to a PLGA scaffold. Osteoblasts seeded on a PCL/nHA scaffold grew better with higher mineralization than on a PCL scaffold. Histologically, collagen regenerated along PLGA scaffolds, but showed poor ingrowth to scaffolds compared with the PLGA/Col group. Newly formed bone was observed on the PCL scaffold, but was less than that on the PCL/nHA scaffold. At 6 weeks post repair, the regenerated tendon in both groups had similar maximum load to failure and ultimate stress but significantly lower stiffness in the PLGA–PCL group and a higher cross-sectional area in the PLGA/Col-PCL/nHA group compared with normal values. At 12 weeks, the maximum failure load, ultimate stress and cross-sectional areas of the regenerated tendon in the PLGA/Col-PCL/nHA group were significantly higher than in the PLGA–PCL and normal groups. The biomechanical properties of the PLGA–PCL group were similar to normal except for a larger cross-sectional area. Our data showed that the co-electrospun dual nano-scaffolds are promising in bridging MRCTs. Doping with Col and nHA further strengthens tissue regeneration.

The inferior biocompatibility of the polyethylene terephthalate (PET) artificial ligament may lead to poor healing in both the intra-articular part (IAP) and the intraosseous part (IOP) after anterior cruciate ligament (ACL) reconstruction. This study aimed to systematically investigate the effect of silk fibroin (SF) and hydroxyapatite (HA) segmented coating on graft ligamentization and osseointegration processes of the PET ligament. Several techniques including scanning electron microscopy (SEM) and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, X-ray diffraction (XRD) and water contact angle (WCA) measurements were carried out to validate the introduction of SF and HA. The segmented coating ligament was assessed both in vitro and in vivo. The results of SEM and cell counting kit-8 (CCK-8) assay revealed that the L929 fibroblasts and MC3T3-E1 osteoblasts exhibited better adhesion and proliferation performance on the PET–SF and PET–HA fibers, respectively, compared to those on the uncoated PET fibers. HA promoted osteogenic differentiation of MC3T3-E1 in terms of the levels of alkaline phosphatase (ALP) activity and calcium deposition. Furthermore, the in vivo study in a beagle ACL reconstruction model demonstrated that the segmented coating could enhance the graft ligamentization and osseointegration processes as indicated by the better tissue infiltration in the IAP and more bone ingrowth in the IOP of the ligament than the control group according to the results of micro-computed tomography (micro-CT), histology, real-time polymerase chain reactions (RT-PCRs) and biomechanical tests. Therefore, the SF and HA segmented coating ligaments may display a great potential application for the clinical augmentation of graft healing in ACL reconstruction surgery.

Background: Acute skeletal muscle injury is common in sports. The injured muscle cannot fully recover due to fibrosis resulting from myofibroblasts. Understanding the origin of fibroblasts is, therefore, important for the development of anti-fibrotic therapies. Accumulating evidence shows that a mechanism called macrophage-myofibroblast transition (MMT) can lead to tissue or organ fibrosis, yet it is still unclear whether MMT exists in skeletal muscle and the exact mechanisms. Methods: Single-cell transcriptome of mice skeletal muscle after acute injury was analyzed with a specific attention on the process of MMT. Cell–cell interaction network, pseudotime trajectory analysis, Gene Ontology (GO), and Kyoto Genome Encyclopedia (KEGG) were conducted. A series of experiments in vivo and in vitro were launched for verification. Results: Single cell transcriptomic analysis indicated that, following acute injury, there were much interactions between macrophages and myofibroblasts. A detailed analysis on macrophages indicated that, CD68⁺α-SMA⁺ cells, which represented the status of MMT, mainly appeared at five days post-injury. KEGG/GO analysis underlined the involvement of complement system, within which C3ar1, C1qa, C1qb, and C1qc were up-regulated. Trajectory analysis also confirmed a potential shift from macrophages to myofibroblasts. These findings were verified by histological study in mice skeletal muscle, that there were much MMT cells at five days, declined gradually, and vanished 14 days after trauma, when there was remarkable fibrosis formation within the injured muscle. Moreover, C3a stimulation could directly induce MMT in BMDMs. Conclusion: Fibrosis following acute injury is disastrous to skeletal muscle, but the origin of myofibroblasts remains unclear. We proved that, following acute injury, macrophage-myofibroblast transition happened in skeletal muscle, which may contribute to fibrosis formation. This phenomenon mainly occurred at five days post-injury. The complement system can activate MMT. More evidence is needed to directly support the pro-fibrotic role of MMT in skeletal muscle fibrosis after acute injury.