Immunoproteasomes regulate the degradation of ubiquitin-coupled proteins and cell differentiation. However, its precise role in skeletal muscle regeneration remains unclear. In this study, we found that expression of the immunoproteasome subunit, PSMB8, increased significantly in young muscles after cardiotoxin-induced injury, whereas its expression was downregulated in injured aged mice. Genetic knockout or pharmacological inhibition of the immunoproteasome subunit, PSMB8, resulted in impaired muscle regeneration and increased interstitial fibrosis. PSMB8 inhibition by short interfering RNA (siRNA) or inhibitor decreased the differentiation ability of myoblasts. There was increased infiltration of inflammatory cells, especially Ly6Chi proinflammatory macrophages, in Psmb8 deficient muscles. In vitro, Psmb8-deficient macrophages expressed higher levels of proinflammatory cytokines and lower levels of anti-inflammatory cytokines after phagocytosis of myoblast debris, which was associated with increased activation of the NF-κB signaling pathway. Inhibition of the NF-κB pathway improves the regeneration ability and attenuates interstitial fibrosis in Psmb8-deficient muscles after injury. The overexpression of Psmb8 by adenovirus could also improve the regenerative ability of aged muscles.NEW & NOTEWORTHY The immunoproteasome subunit, PSMB8, is essential for efficient muscle regeneration and may be a new therapeutic target for age-related muscle atrophy.

Inflammation is a fundamental component of the body's response to injury or infection and is responsible for restoring tissue homeostasis and starting the wound healing process. To avoid excessive tissue damage, it is important to efficiently resolve inflammation once it is no longer necessary. In recent years, the discovery of pro-resolving lipid mediators derived from polyunsaturated fatty acids, such as Resolvin D1 (RvD1), has shed light on the resolution of inflammation. However, the impact of RvD1 on Spinal Cord Injury (SCI) remains unexplored. In this study, we provide direct evidence that the administration of RvD1 for one week after SCI fails to enhance resolution of inflammation and does not improve functional and histological outcomes. Our transcriptomic analysis reveals that RvD1 does not modulate inflammatory response pathways in the injured spinal cord but leads to significant changes in the expression of genes related to ribosomal function and extracellular matrix pathways. Unlike SCI, RvD1 treatment ameliorated neurological deficits in experimental autoimmune encephalomyelitis. Our findings represent the first report demonstrating that RvD1 treatment does not exert therapeutic actions in the context of SCI and suggest that this pro-resolving agonist may exert therapeutic actions in certain but not in all conditions involving an inflammatory component.

Macrophages are a promising target for therapeutics in various applications such as regenerative medicine and immunotherapy for cancer. Due to their plastic nature, macrophages can switch from a non-activated state to activated with the smallest environmental change. For macrophages to be effective in their respective applications, screening for phenotypic changes is necessary to elucidate the cell response to different delivery vehicles, vaccines, small molecules, and other stimuli.

We created a sensitive and dynamic high-throughput screening method for macrophages based on the activation of NF-κB. For this reporter, we placed an mRFP1 fluorescence gene under the control of an inflammatory promoter, which recruits NF-κB response elements to promote expression during the inflammatory response in macrophages. We characterized the inflammatory reporter based on key markers of an inflammatory response in macrophages including TNF-α cytokine release and immunostaining for inflammatory and non-inflammatory cell surface markers. We compared gene delivery and inflammation of several clinically relevant viral vehicles and commercially available non-viral vehicles. Statistical analysis between groups was performed with a one-way ANOVA with post-hoc Tukey's test.

The reporter macrophages demonstrated a dynamic range after LPS stimulation with an EC50 of 0.61 ng/mL that was highly predictive of TNF-α release. Flow cytometry revealed heterogeneity between groups but confirmed population level shifts in pro-inflammatory markers. Finally, we demonstrated utility of the reporter by showing divergent effects with various leading gene delivery vehicles.

This screening technique developed here provides a dynamic, high-throughput screening technique for determining inflammatory response by mouse macrophages to specific stimuli. The method presented here provides insight into the inflammatory response in mouse macrophages to different viral and non-viral gene delivery methods and provides a tool for high-throughput screening of novel vehicles.

The online version contains supplementary material available at 10.1186/s44330-025-00030-x.

Duchenne Muscular Dystrophy (DMD) is a progressive neuromuscular disorder characterized by impaired muscle repair. Forskolin (FSK), an adenylyl cyclase activator, has shown potential in enhancing muscle regeneration and limiting muscle stem cell senescence. This study aimed to evaluate the effects of FSK on muscle repair, fibrosis, inflammation, and long-term muscle function in DMD using a preclinical rat model.

BaCl2-induced muscle injury was performed on 6-month-old DMD (R-DMDdel52) and wild-type (WT) rats. FSK was supplied via short-term and long-term administration. Muscle tissues were harvested 14 days post-injury for histological analysis, including hematoxylin and eosin and Sirius red staining. Immunofluorescence was used to assess fibroadipogenic progenitors (FAPs), regeneration, muscle stem cells, and macrophage phenotypes. Moreover, we performed a study by chronically administering FSK to DMD rats from 1 to 7 months of age, either intraperitoneally (IP) or subcutaneously (SC). Functional assessments included grip strength test, in vivo muscle force measurements, plethysmography and electrocardiograms. Post-sacrifice, Tibialis anterior, diaphragm and heart tissues were histologically analyzed, to evaluate muscle architecture, fibrosis, and histopathological indices.

FSK treatment significantly improved muscle histology and reduced fibrosis in both uninjured and injured DMD muscles by decreasing the number of FAPs. Long-term FSK treatment in the acute injury model enhanced muscle regeneration, increased MuSC proliferation, and reduced senescence. FSK also modulated inflammation by reducing pro-inflammatory macrophages and promoting a shift to a restorative phenotype. However, despite these histological improvements, FSK treatment from 1 to 7 months resulted in limited functional benefits and worsened ventricular histology in the heart.

FSK shows promising results in improving muscle regeneration and reducing fibrosis in DMD, but concerns remain regarding its limited chronic functional benefits and potential adverse effects on cardiac tissue. Our results highlight the need for optimized adenylyl cyclase activators for therapeutic use in DMD patients.

The activation of histone deacetylase 2 (HDAC2) is the main pathogenesis of acute kidney injury (AKI), one of the leading causes of end-stage kidney disease. However, the regulatory role of HDAC2 upregulation on inflammation in AKI is still unclear.

In this study, we found that treatment with HDAC2 inhibitor BRD6688 could mitigate the degree of mesangial sclerosis, interstitial infiltration and tubular atrophy, reduce the concentration of blood urea nitrogen (BUN) and serum creatinine (Scr), improve the proliferation, anti-apoptotic, anti-oxidative stress and angiogenesis effects of renal cells. Our results mainly indicated that renal HDAC2 activity was increased by casein kinase 2 (CK2) in renal ischemia reperfusion (I/R) models, and HDAC2 genetic ablation in HREpiC cells suppressed the leukotriene B4 (LTB4) production. Renal leukotriene A4 hydrolase (LTA4H) activity was increased in AKI mice in a HDAC2-dependent manner. LTB4 could induce monocytes to differentiate into M1 macrophages, while BRD6688 could suppress this effect and force the M1 macrophages polarize to M2 macrophages.

Inhibition of HDAC2 activities by BRD6688 could suppress the progression of renal I/R injury through the regulation of LTA4H and macrophage polarization.

Some plasma molecules may have an effect on sarcopenia, but it is not fully understood. We aimed to comprehensively explore the causal effects of plasma proteins and metabolites on sarcopenia traits, and to unravel their network.

A two-sample Mendelian randomization design was adopted. The levels of 4,907 plasma proteins from 35,559 Icelanders, and 1,400 plasma metabolites from 8,299 Europeans, were set as exposures. Low handgrip strength, appendicular lean mass, and usual walking pace from Europeans were set as outcomes. Inverse-variance weighted (IVW) and four other methods, along with sensitivity analyzes, were performed to estimate the causal effects. Enrichment and pathway analyzes were conducted to present their characteristics. IVW was used to estimate the bidirectional relationships between sarcopenia-related proteins and metabolites, and to visualize them within a network.

We identified 76 relationships between proteins and sarcopenia traits. The absolute values of causal effects (βIVW) ranging from 0.01 to 0.35. IL2, AIF1, GDNF, CXCL13, LRRTM3, and SLPI were the top six proteins ranked by causal effects. Additionally, 22 relationships between metabolites and sarcopenia traits were identified, with absolute values of βIVW ranging from 0.02 to 0.22. Sulfate and serine/pyruvate ratio had the highest values. The network diagram showed some key nodes, such as ISOC1, GSTA1, tryptophan and 5α-androstan-3α,17β-diol monosulfate.

This work unraveled a molecular network of sarcopenia in plasma for the first time and identified some key proteins and metabolites. It may help to understand the mechanisms of sarcopenia, providing new insights for predicting, diagnosing and treating sarcopenia.

Atheroma formation is initiated by the activation of endothelial and smooth muscle cells, as well as immune cells, including neutrophils, lymphocytes, monocytes, macrophages, and dendritic cells. Monocytes, macrophages, and neutrophils are the innate immune cells that provide a rapid initial line of defence against vascular disease. These cells have a short lifespan and cannot retain memories, making them potential therapeutic targets for the inflammatory process associated with atherosclerosis. In addition, macrophages comprise the majority of vessel wall infiltrates and are, therefore, implicated in all stages of atherosclerosis progression. Neutrophils are the most common type of leukocyte found in circulation, and their high levels of matrix-degrading protease explain their significance in fibrous cap destabilization. However, the activation of immune cells becomes more complex by various microenvironmental stimuli and cytokines, which ultimately transform immune cells into their pro-inflammatory state. Different types of macrophage subsets with distinct functions in inflammation, such as M1 macrophages, cause an increase in pro-inflammatory cytokines and produce reactive oxygen species and nitric oxide, further worsening the disease. This review aims to shed light on immune-mediated inflammation in cardiovascular disease by focusing on the role of macrophage subsets in vascular inflammation and plaque stability, as well as the interaction between neutrophils and monocyte-macrophages.

Peripheral arterial disease is a common vascular disease in the elderly. Therapeutic revascularization, including angiogenic and arteriogenic therapy, is a promising treatment approach for peripheral arterial disease. However, the progress of clinical trials is not ideal, possibly due to insufficiency of preclinical models, such as not taking into account the effect of aging on vascular regeneration. Macrophages are crucial in angiogenesis and arteriogenesis. The aging microenvironment typically makes recruited monocytes and macrophages more susceptible to senescence. However, the feature of macrophages in ischemic hindlimb muscle of old individuals and their underlying role remains unclear. In this study, we reveal that macrophages of ischemic skeletal muscle in old mice are more senescent and proinflammatory. By transplanting macrophages into mice following hindlimb ischemia, we find senescent macrophages inhibit revascularization. Mechanistically, these senescent macrophages induce endothelial dysfunction via increasing vascular endothelial growth factor A-165B (VEGF-A165B) expression and secretion, and eventually impair revascularization. Notably, plasma VEGF-A165B levels are elevated in old patients with PAD and positively associated with a lower ankle brachial index (ABI). Our study suggests that targeting the senescent macrophages presents an avenue to improve age-related revascularization damage.

Platelet-rich plasma (PRP) therapy is increasingly recognized as a promising treatment for musculoskeletal disorders, including osteoarthritis (OA), tendinopathy, and muscle injuries. This narrative review synthesizes the current literature to evaluate the efficacy of PRP, with a focus on platelet dosing strategies, leukocyte composition, and preparation protocols. Evidence suggests that optimal therapeutic outcomes are achieved when platelet doses exceed 3.5 billion per injection, with cumulative doses of 10-12 billion across multiple treatments. In intra-articular applications, leukocyte-poor PRP (LP-PRP), characterized by reduced neutrophil content, demonstrates superior efficacy compared to leukocyte-rich PRP (LR-PRP). However, its effectiveness in tendon and muscle regeneration remains a subject of debate. Preliminary data suggest that the inclusion of peripheral blood mononuclear cells (PBMNCs) may enhance PRP efficacy, though robust clinical trials are required to confirm these findings. Furthermore, red blood cell contamination and pre-activation have been identified as detrimental to PRP effectiveness, highlighting the need for standardized preparation protocols. This review emphasizes the importance of tailoring PRP formulations to patient-specific factors and musculoskeletal conditions. Future research should focus on refining PRP preparation techniques, identifying optimal leukocyte compositions, and establishing standardized guidelines to enhance clinical outcomes.

Transposons and their derivatives make up a major proportion of the human genome, but they are not just relics of ancient genomes. They can still be expressed, potentially affecting the transcription of adjacent genes, and can sometimes even contribute to their coding sequence. Active transposons can integrate into new sites in the genome, potentially modifying the expression of nearby loci and leading to genetic disorders. In this review, we highlight work exploring the expression of transposons in skeletal muscles and transcriptional regulation by the KRAB-ZFP/KAP1/SETDB1 complex. We next focus on specific cases of transposon insertion causing phenotypic variation and distinct muscular dystrophies, as well as the implication of transposon expression in immune myopathies. Finally, we discuss the dysregulation of transposons in facioscapulohumeral dystrophy and aging.

Bacterial septic arthritis, an inflammatory disease caused by bacterial infections, is often accompanied by the emergence of multidrug-resistant bacteria, making therapeutic treatment a formidable challenge. With the emergence of antibiotic resistance, research on antimicrobial photodynamic therapy (aPDT) has regained attention. However, insufficient singlet oxygen production due to the hypoxia in the infection microenvironment is recognized as a key limiting the efficacy of aPDT. Hence, in this study, we designed a bacteria-targeted liposomal nanoplatform (MCPL) to alleviate hypoxia in the infectious microenvironment and enhance aPDT for bacterial septic arthritis. The nanoplatform was developed by integrating the phototherapeutic agent CyI and small-sized Pt NPs into thermosensitive liposomes, with modification of maltohexose on the liposome surface. In vitro and in vivo studies showed that MCPL could specifically target bacterial cell membranes and be thermally activated to catalytically convert endogenous hydrogen peroxide (H2O2) in the septic joint, supplementing local O2 reservoirs. This, in turn, supplies additional substrate pools for photodynamic conversion into reactive oxygen species (ROS) with bacterial toxicity. Furthermore, the antibacterial mechanism revealed that MCPL can regulate the HIF-1α and NF-κB signaling pathways in immune cells, acting as an effective modulator of antioxidant and anti-inflammatory pathways in both macrophages and neutrophils. This study demonstrates that MCPL could not induce bacterial multidrug resistance and provide as an innovative approach for treating bacterial septic arthritis.

Recent research highlights the significant role of polyphenols in alleviating post-exercise muscle damage, thus positioning them as a valuable nutritional strategy for athletes and fitness enthusiasts. Polyphenols, naturally occurring bioactive compounds abundant in fruits, vegetables, tea, wine, and other plant-based foods, are recognized for their potent antioxidant and anti-inflammatory properties. This dual mechanism is critical for combating oxidative stress and inflammation-two factors that intensify during vigorous physical activity and contribute to muscle soreness and damage. Among various polyphenols, compounds like quercetin have particularly emerged as effective agents for promoting muscle recovery and enhancing exercise performance. These protective effects are facilitated through several mechanisms, including the modulation of inflammatory pathways, acceleration of muscle repair processes, and enhancement of mitochondrial function, all of which bolster overall muscle health. As ongoing studies yield deeper insights, the potential of polyphenols to enhance athletic performance and overall health will become increasingly substantiated, leading towards their strategic incorporation into exercise nutrition protocols. Therefore, we reviewed relevant studies in order to show how efficient polyphenols can be in reducing muscle fatigue and damage and what are the exact mechanisms.

Exercise is known to acutely affect T-lymphocyte populations in the peripheral blood, which is intensity- and duration-dependent. However, effects of longer duration endurance exercise (>5 h) on T-cells in the days following are unknown. The aim of this study was to investigate the circulating T-cell changes that occur in response to an ultra-endurance event, which may provide insight into the inflammatory response to ultra-endurance exercise.

Ten individuals (m = 7, f = 3) completing an Ironman 70.3 event volunteered for the study. Peripheral blood samples were taken 1-2 days pre-race (PRE-RACE), and 1 day (RACE + 1) and 2 days (RACE + 2) post-race, with circulating T-cells enumerated by flow cytometry (total CD3+, CD4+ and CD8+ T-cells, regulatory T-cells [CD4+CD25+CD127-; TREG], naïve [CD27+CD45RA+; NA], central memory [CD27+CD45RA-; CM], effector memory [CD27-CD45RA-; EM], and effector memory CD45RA+ [CD27-CD45RA+; EMRA]).

There were no changes in total CD3+, CD4+ and CD8+ T-cells. TREG RACE + 1 was significantly higher compared to PRE-RACE, as were the proportion of CD4+ NA cells and CD8+ CM cells at RACE + 2; CD8+ EM cells fell at RACE + 2 (absolute counts and proportion).

In conclusion, the ultra-endurance event evoked T-cell changes over the 48 h recovery period, with an increase in T-cells that regulate the immune response, and a reduction in circulating EM T-cells, most likely trafficked to sites of tissue damage and inflammation.

To investigate the anti-inflammatory effect of electroacupuncture in rats with bupivacaine-induced lumbar multifidus injury and its underlying regulatory mechanism on macrophage polarization.

A total of seventy-two Sprague-Dawley male rats were randomly divided into control, model, and electroacupuncture groups. Forty-eight rats categorized in model groups were injected 0.5% bupivacaine (BPVC) into the lumbar multifidus at the L4-L5 segment. Rats in the electroacupuncture groups received the intervention for 1, 2, 3 and 5 d, respectively. The degree of macrophage infiltration and change of M1/M2 polarization were observed based on hematoxylin and eosin staining, immunohistochemistry and immunofluorescence to evaluate the anti-inflammatory effect of electroacupuncture. Meanwhile, exosomal miRNA-sequencing and bioinformatics analysis predicted the pathways and biological processes related to inflammatory response and macrophage polarization regulated by electroacupuncture intervention.

BPVC injection induced the infiltration of local macrophages at the L4-L5 segment of lumbar multifidus. Comparison of mean IOD values with 2 d and 5 d post injury revealed the highest expression of CD68+ macrophages on day 3 post injury by immunohistochemistry. (P < 0.001, P < 0.001, respectively). Compared with the model group, the cell counts of iNOs+ CD68+ M1-macrophages were lower in the electroacupuncture group, while the positive percent of CD163+ CD206+ M2-macrophages was higher in the electroacupuncture group, on day 3 after BPVC injection (P < 0.001, P < 0.001, respectively). Moreover, the results of sequencing and bioinformatic analysis suggested that exosomal miRNAs were involved in the EA regulating macrophage polarization.

Electroacupuncture can promote macrophage polarization to reduce inflammation following lumbar multifidus muscular injury.

Muscle recovery after damage is mediated by circulating factors and intracellular signaling pathways. Our previous studies have demonstrated that resistance exercise (RE)-induced circulating factors elicited sex-differential responses in damaged muscle. However, the global effects of these circulating factors on damaged muscle are largely understudied. We examined the differential effects of RE-induced circulating factors and sex on the damaged muscle proteome. Damaged vastus lateralis muscle from 3 men and 3 women from a parent study were analyzed. Participants completed 2 identical bouts of unilateral eccentric knee extensions immediately followed by either upper body RE to induce circulating factors (EXE) or 20-min seated rest (CON). Muscle biopsies collected from the damaged leg at 24 h were used. 900 proteins were identified by LC-MS/MS analysis. Ingenuity Pathway Analysis was used to detect activation prediction using z-scores for functional and pathway analyses. In men, 79 proteins were downregulated and 15 were upregulated in EXE versus CON. These differentially expressed proteins were associated with immunological and inflammatory signaling pathways. Biological functions of the differentially expressed proteins in EXE vs. CON in men include inactivating acute inflammatory signaling, neutrophil extracellular trap signaling, ROS production, and activating IL-12 signaling. These results underline that RE-induced circulating factors have a sex-specific effect on the damaged muscle proteome, where immune signaling is altered in men but not women. Given that the immune response is critical for recovery from muscle damage, these results highlight the potential role of RE-induced circulating factors that could be essential in mediating muscle recovery.

Infiltrating macrophages contribute to muscle dystrophic changes in Duchenne muscular dystrophy (DMD). In a DMD mouse model, mdx5cv mice, CC chemokine receptor type 2 (CCR2) deficiency diminishes Ly6Chi macrophage infiltration by blocking blood Ly6Chi inflammatory monocyte recruitment. This is accompanied by transient improvement of muscle damage, fibrosis, and regeneration. The benefit, however, is lost after the expansion of intramuscular Ly6Clo macrophages. To address the mechanisms underlying the Ly6Clo macrophage expansion, we compared mdx5cv/Nur77-/- and mdx5cv/Ccr2-/-/Nur7-/- mice with mdx5cv and mdx5cv/Ccr2-/- mice, respectively, and found no evidence to suggest Ly6Clo monocyte recruitment by dystrophic muscles. Single-cell RNA sequencing analysis and Flt3cre/Rosa26LSL-YFP-based lineage tracing of macrophage origins demonstrated the expansion and pathogenic activation of muscle resident macrophages in CCR2-deficient mdx5cv mice. The expansion was associated with increased cell proliferation, which appeared induced by colony-stimulating factor-1 (CSF-1) derived from fibro/adipogenic progenitors (FAPs). Our study establishes a pathogenic role for skeletal muscle resident macrophages and supports a regulatory role of FAPs in stimulating the expansion of resident macrophages in the DMD mouse model when the inflammatory macrophage infiltration is inhibited.

Volumetric muscle loss (VML) injuries are characterized by the traumatic loss of skeletal muscle, resulting in permanent damage to both tissue architecture and electrical excitability. To address this challenge, we previously developed a three-dimensional (3D) aligned collagen-glycosaminoglycan (CG) scaffold platform that supported in vitro myotube alignment and maturation. In this work, we assessed the ability of CG scaffolds to facilitate functional muscle recovery in a rat tibialis anterior (TA) model of VML. Functional muscle recovery was assessed following implantation of either nonconductive CG or electrically conductive CG-polypyrrole (PPy) scaffolds at 4, 8, and 12 weeks postinjury by in vivo electrical stimulation of the peroneal nerve. After 12 weeks, scaffold-treated muscles produced maximum isometric torque that was significantly greater than nontreated tissues. Histological analysis further supported these reparative outcomes with evidence of regenerating muscle fibers at the material-tissue interface in scaffold-treated tissues that were not observed in nonrepaired muscles. Scaffold-treated muscles possessed higher numbers of M1 and M2 macrophages at the injury, while conductive CG-PPy scaffold-treated muscles showed significantly higher levels of neovascularization as indicated by the presence of pericytes and endothelial cells, suggesting a persistent wound repair response not observed in nontreated tissues. Finally, only tissues treated with nonconductive CG scaffolds displayed neurofilament staining similar to native muscle, further corroborating isometric contraction data. Together, these findings show that both conductive and nonconductive CG scaffolds can facilitate improved skeletal muscle function and endogenous cellular repair, highlighting their potential use as therapeutics for VML injuries.

The deleterious consequences of chronic synovitis on cartilage, tendon, and bone in rheumatoid arthritis (RA) are well described. In contrast, its effects on periarticular skeletal muscle are under-studied. Furthermore, while TNF inhibition is an effective therapy for RA synovitis, it exacerbates fibrosis in muscle injury models. We aimed to investigate whether myositis and muscle fibrosis are features of inflammatory arthritis and evaluate whether targeted RA therapies influence these disease features. Periarticular muscle was analyzed in murine models of poly- and monoarticular inflammatory arthritis: serum transfer-induced arthritis, collagen-induced arthritis, K/BxN, and antigen-induced arthritis (AIA). Periarticular myositis and an increase in muscle fibroadipocyte progenitors (FAPs) were observed in all models, despite diverse arthritogenic mechanisms. Periarticular muscle fibrosis was observed from day 15 in AIA. Neither etanercept nor baricitinib suppressed periarticular myositis or subsequent fibrosis compared to vehicle, despite reducing arthritis. Notably, etanercept failed to prevent muscle fibrosis even when initiated early, but this was not linked to increased FAP survival or collagen production. Corroborating these data, radiographic and histological analyses revealed periarticular myositis in patients with RA. We conclude that periarticular myositis and fibrosis are under-recognized features of inflammatory arthritis. Targeted RA therapies may not prevent periarticular muscle sequelae, despite controlling arthritis.

Immune responses play an integral role in skeletal muscle regeneration. In the genetically inherited muscle disease Duchenne muscular dystrophy (DMD), muscle regeneration is disrupted, leading to chronic inflammation, fibrosis, and early mortality. Previously, it has been suggested that type-2 innate immune cells, particularly eosinophils and their production of IL-4, play an essential role in effective muscle regeneration after acute injury. We here re-investigate the role of eosinophils in skeletal muscle repair using mice deficient in eosinophils (ΔdblGATA), or deficient in IL-4R/IL-13R signaling through STAT6 (Stat6-/-). We show that neither deficiency has an impact on skeletal muscle regeneration in response to acute injury as quantified by fiber size, immune cell infiltration, or muscle-resident stem cell proliferation. We also investigate the role of STAT6 signaling in mdx:Stat6-/- mice, a model of DMD and, again, find that ablation of STAT6 signaling has no effect on the rate or severity of fibrotic scar formation or disease progression. In contrast to previous models, our data suggest a negligible role for eosinophils and STAT6 signaling in skeletal muscle regeneration after acute or chronic injury.

Significance: Volumetric muscle loss (VML) is caused by the loss of significant amounts of skeletal muscle tissue. VML cannot be repaired by intrinsic regenerative processes, resulting in permanent loss of muscle function and disability. Current rehabilitative-focused treatment strategies lack efficacy and do not restore muscle function, indicating the need for the development of effective regenerative strategies. Recent Advances: Recent developments implicate biomaterial-based approaches for promoting muscle repair and functional restoration post-VML. Specifically, bioscaffolds transplanted in the injury site have been utilized to mimic endogenous cues of the ablated tissue to promote myogenic pathways, increase neo-myofiber synthesis, and ultimately restore contractile function to the injured unit. Critical Issues: Despite the development and preclinical testing of various biomaterial-based regenerative strategies, effective therapies for patients are not available. The unique challenges posed for biomaterial-based treatments of VML injuries, including its scalability and clinical applicability beyond small-animal models, impede progress. Furthermore, production of tissue-engineered constructs is technically demanding, with reproducibility issues at scale and complexities in achieving vascularization and innervation of large constructs. Future Directions: Biomaterial-based regenerative strategies designed to comprehensively address the pathophysiology of VML are needed. Considerations for clinical translation, including scalability and regulatory compliance, should also be considered when developing such strategies. In addition, an integrated approach that combines regenerative and rehabilitative strategies is essential for ensuring functional improvement.

Skeletal muscle atrophy (sarcopenia) is a serious complication of liver cirrhosis, and chronic muscle inflammation plays a pivotal role in its pathologenesis. However, the detailed mechanism through which injured liver tissues mediate skeletal muscle inflammatory injury remains elusive. Here, it is reported that injured hepatocytes might secrete mtDNA-enriched extracellular vesicles (EVs) to trigger skeletal muscle inflammation by activating the cGAS-STING pathway. Briefly, injured liver secreted increased amounts of EVs into circulation, which are then engulfed primarily by macrophages in skeletal muscle and subsequently induce cGAS-STING signaling and its-mediated inflammatory response in muscles. In contrast, suppression of hepatic EV secretion or STING signaling significantly alleviated cirrhosis-induced skeletal muscle inflammation and muscle atrophy in vivo. Circulating EVs from cirrhotic patients showed higher levels of mtDNA, and the levels of EV-mtDNA positively correlated with the severity of liver injury. In injured hepatocytes, mitochondrial damage promoted the release of cytosolic mtDNA and the subsequent secretion of mtDNA-enriched EVs. This study reveals that injured hepatocyte-derived EVs induce skeletal muscle inflammation via the mtDNA‒STING axis, while targeted blockade of liver EV secretion or STING signaling represents a potential therapeutic approach for preventing cirrhosis-associated skeletal muscle atrophy.

We took a systems approach to the analysis of macrophage phenotype in regenerative and fibrotic volumetric muscle loss outcomes in mice together with analysis of systemic inflammation and of other leukocytes in the muscle, spleen, and bone marrow. Differences in expression of macrophage phenotype markers occurred as early as day 1, persisted to at least day 28, and were associated with increased numbers of leukocytes in the muscle and bone marrow, increased pro-inflammatory marker expression in splenic macrophages, and changes in the levels of pro-inflammatory cytokines in the blood. The most prominent differences were in muscle neutrophils, which were much more abundant in fibrotic outcomes compared to regenerative outcomes at day 1 after injury. However, neutrophil depletion had little to no effect on macrophage phenotype or on muscle repair outcomes. Together, these results suggest that the entire system of immune cell interactions must be considered to improve muscle repair outcomes.

Myocardial infarction (MI), a severe cardiovascular condition, is typically triggered by coronary artery disease, resulting in ischemic damage and the subsequent necrosis of the myocardium. Macrophages, known for their remarkable plasticity, are capable of exhibiting a range of phenotypes and functions as they react to diverse stimuli within their local microenvironment. In recent years, there has been an increasing number of studies on the regulation of macrophage behavior based on tissue engineering strategies, and its regulatory mechanisms deserve further investigation. This review first summarizes the effects of key regulatory factors of engineered biomaterials (including bioactive molecules, conductivity, and some microenvironmental factors) on macrophage behavior, then explores specific methods for inducing macrophage behavior through tissue engineering materials to promote myocardial repair, and summarizes the role of macrophage-host cell crosstalk in regulating inflammation, vascularization, and tissue remodeling. Finally, we propose some future challenges in regulating macrophage-material interactions and tailoring personalized biomaterials to guide macrophage phenotypes.

Infection by Mycobacterium tuberculosis (Mtb) continues to cause more than 1 million deaths annually, due to pathogen persistence in lung macrophages and dendritic cells derived from blood monocytes. While accumulation of monocyte-derived cells in the Mtb-infected lung partially depends on the chemokine receptor CCR2, the other chemoattractant receptors regulating trafficking remain undefined. We used mice expressing knock-in/knockout reporter alleles of Ccr2 and Cx3cr1 to interrogate their expression and function in monocyte-derived populations of the lungs and draining mediastinal lymph nodes during Mtb infection. CCR2 and CX3CR1 expression varied across monocyte-derived subsets stratified by cell surface Ly6C expression in both organs. We found that expression of CCR2 predicted dependence of monocyte-derived cells on the receptor for lung and lymph node accumulation. CCR2-deficient mice were also observed to have worsened lung and lymph node Mtb burden. While CX3CR1 deficiency, alone or in combination with CCR2 deficiency, did not affect cell frequencies or lung Mtb control, its absence was associated with altered positioning of monocyte-derived dendritic cells in mediastinal lymph nodes. We found that combined loss of Ccr2 and Cx3cr1 also worsened Mtb control in the mediastinal lymph node, suggesting a rationale for the persistent expression of CX3CR1 among monocyte-derived cells in pulmonary tuberculosis.

Mycobacterium tuberculosis is the respiratory pathogen responsible for the deadliest infectious disease worldwide. Susceptible humans exhibit ineffective immune responses, in which infected phagocytes are not able to eliminate the pathogen. Since recruited monocyte-derived cells serve as reservoirs for persistent infection, understanding how these phagocytes accumulate in the lung and why they are unable to eliminate Mtb can inform development of therapies that can synergize with antimicrobials to achieve faster and more durable Mtb elimination. Monocyte-derived cells express the chemokine receptors CCR2 and CX3CR1, but the role of the latter in Mtb infection remains poorly defined. The significance of our study is in elucidating the roles of these receptors in the trafficking of monocyte-derived cells in the infected lung and mediastinal lymph node. These data shed light on the host response in tuberculosis and in other pulmonary infections.

The recovery from muscle atrophy is impaired with aging as characterized by improper muscle remodeling and sustained functional deficits. Age-related deficits in muscle regrowth are tightly linked with the loss of early pro-inflammatory macrophage responses and subsequent cellular dysregulation within the skeletal muscle niche. Macrophage inflammatory phenotype is regulated at the metabolic level, highlighting immunometabolism as an emerging strategy to enhance macrophage responses and restore functional muscle regrowth. Accordingly, metabolic targets with an emphasis on glycolytic, hypoxia, and redox-related pathways stand out for their role in promoting macrophage inflammation and enhancing muscle regrowth in aging. Here we highlight promising immuno-metabolic targets that could be leveraged to restore optimal pro-inflammatory macrophage function in aging and enhance muscle regrowth following muscular atrophy.

The mechanisms behind the pro-healing effects of multicellular, bioengineered allogeneic cellularized constructs (BACC) are not known. Macrophages are key regulators of every phase of the wound healing process and the primary cells that mediate the response to biomaterials. It is hypothesized that cells within the BACC modulate macrophage behavior, which may contribute to the mechanism by which BACC promotes healing. To probe the influence of cells within the BACC compared to effects of the underlying collagen substrate, primary human macrophages are cultured in direct or indirect contact with BACC or with the same collagen substrate used in the BACC manufacturing. Macrophage phenotype is characterized over time via multiplex gene expression, protein secretion, multidimensional flow cytometry, and functional assays with fibroblasts and endothelial cells. The BACC causes macrophages to exhibit a predominately reparative phenotype over time compared to relevant collagen substrate controls, with multiple subpopulations expressing both pro-inflammatory and reparative markers. Conditioned media from macrophage-BACC co-cultures causes distinct effects on fibroblast and endothelial cell proliferation, migration, and network formation. Given the critical role of the reparative macrophage phenotype in wound healing, these results suggest that modulation of macrophage phenotype may be a critical part of the mechanisms behind BACC's pro-healing effects.

The skeletal muscle interstitial space is the extracellular region around myofibers and mediates cross-talk between resident cell types. We applied a proteomic workflow to characterize the human skeletal muscle interstitial fluid proteome at rest and in response to exercise. Following exhaustive exercise, markers of skeletal muscle damage accumulate in the interstitial space followed by the appearance of immune cell-derived proteins. Among the proteins up-regulated after exercise, we identified cathelicidin-related antimicrobial peptide (CAMP) as a bioactive molecule regulating muscle fiber development. Treatment with the bioactive peptide derivative of CAMP (LL-37) resulted in the growth of larger C2C12 skeletal muscle myotubes. Phosphoproteomics revealed that LL-37 activated pathways central to muscle growth and proliferation, including phosphatidylinositol 3-kinase, AKT serine/threonine kinase 1, mitogen-activated protein kinases, and mammalian target of rapamycin. Our findings provide a proof of concept that the interstitial fluid proteome is quantifiable via microdialysis sampling in vivo. These data highlight the importance of cellular communication in the adaptive response to exercise.

Skeletal muscle is a highly plastic tissue that can adapt relatively rapidly to a range of stimuli. In response to novel mechanical loading, e.g. unaccustomed resistance exercise, myofibers are disrupted and undergo a period of ultrastructural remodeling to regain full physiological function, normally within 7 days. The mechanisms that underpin this remodeling are believed to be a combination of cellular processes including ubiquitin-proteasome/calpain-mediated degradation, immune cell infiltration, and satellite cell proliferation/differentiation. A relatively understudied system that has the potential to be a significant contributing mechanism to repair and recovery is the autophagolysosomal system, an intracellular process that degrades damaged and redundant cellular components to provide constituent metabolites for the resynthesis of new organelles and cellular structures. This review summarizes our current understanding of the autophagolysosomal system in the context of skeletal muscle repair and recovery. In addition, we also provide hypothetical models of how this system may interact with other processes involved in skeletal muscle remodeling and provide avenues for future research to improve our understanding of autophagy in human skeletal muscle.

Sepsis, the most common cause of acute kidney injury, remains a major socioeconomic burden. A dysregulated immune response leads to progressive organ dysfunction. Although numerous inflammatory pathways were described, most are still vague and need to be studied in terms of the mechanisms to improve the therapeutic intervention. We tackled the relationship between intracellular iron overload and macrophage polarization within 6, 24, and 72 h of sepsis induction. In our study, sepsis-induced kidney injury was caused by using the cecal ligation and puncture (CLP) model. Our results indicated severe renal tissue damage with a progressive increase in serum BUN and creatinine with architectural tissue damage and positive PAS staining. There was increased expression of CD8+ CD68+ M1 macrophage markers with upregulation of iNOS and co-expression of CD163+. Alternatively, Arg1+ Fizz1+ M2 macrophage markers were downregulated with increased iNOS/Arg1 ratio. TFR1, cubilin, and DMT1, as iron transport systems, were increased compared to sham but were significant after 72 h, while ZIP8 showed no significant change. There was a correlation between iron overload and M1 macrophage polarization with CD163+ phenotype, together with fibrotic changes. The intracellular iron overload with downregulation of ferritin was strongly related to macrophage polarization that was exaggerated at 72 h. Finally, early introduced therapy to target free iron during sepsis is a proposed novel solution for protecting the renal tissue from acute injury due to macrophage activation that may end up with chronic kidney injury, if not mortality.

Metabolites and metabolic co-factors can shape the innate immune response, though the pathways by which these molecules adjust inflammation remain incompletely understood. Here we show that the metabolic cofactor Coenzyme A (CoA) enhances IL-4 driven alternative macrophage activation [m(IL-4)] in vitro and in vivo. Unexpectedly, we found that perturbations in intracellular CoA metabolism did not influence m(IL-4) differentiation. Rather, we discovered that exogenous CoA provides a weak TLR4 signal which primes macrophages for increased receptivity to IL-4 signals and resolution of inflammation via MyD88. Mechanistic studies revealed MyD88-linked signals prime for IL-4 responsiveness, in part, by reshaping chromatin accessibility to enhance transcription of IL-4-linked genes. The results identify CoA as a host metabolic co-factor that influences macrophage function through an extrinsic TLR4-dependent mechanism, and suggests that damage-associated molecular patterns (DAMPs) can prime macrophages for alternative activation and resolution of inflammation.

Aging is accompanied by a decline in neovascularization potential and increased susceptibility to ischemic injury. Here, we confirm the age-related impaired neovascularization following ischemic leg injury and impaired angiogenesis. The age-related deficits in angiogenesis arose primarily from diminished EC proliferation capacity, but not migration or VEGF sensitivity. Aged EC harvested from the mouse skeletal muscle displayed a pro-angiogenic gene expression phenotype, along with considerable changes in metabolic genes. Metabolomics analysis and 13C glucose tracing revealed impaired ATP production and blockade in glycolysis and TCA cycle in late passage HUVECs, which occurred at nicotinamide adenine dinucleotide (NAD⁺)-dependent steps, along with NAD+ depletion. Supplementation with nicotinamide mononucleotide (NMN), a precursor of NAD⁺, enhances late-passage EC proliferation and sprouting angiogenesis from aged mice aortas. Taken together, our study illustrates the importance of NAD+-dependent metabolism in the maintenance of EC proliferation capacity with age, and the therapeutic potential of NAD precursors.

Sarcopenia, which diminishes lifespan and healthspan in the elderly, is commonly exacerbated by viral pneumonia, including influenza and COVID-19. In a study of influenza A pneumonia in mice, young mice fully recovered from sarcopenia, while older mice did not. We identified a population of tissue-resident skeletal muscle macrophages that form a spatial niche with satellite cells and myofibers in young mice but are lost with age. Mice with a gain-of-function mutation in the Mertk receptor maintained this macrophage-myofiber interaction during aging and fully recovered from influenza-induced sarcopenia. In contrast, deletion of Mertk in macrophages or loss of Cx3cr1 disrupted this niche, preventing muscle regeneration. Heterochronic parabiosis did not restore the niche in old mice. These findings suggest that age-related loss of Mertk in muscle tissue-resident macrophages disrupts the cellular signaling necessary for muscle regeneration after viral pneumonia, offering a potential target to mitigate sarcopenia in aging.

Acute skeletal muscle injury initiates a process of necrosis, debris clearance, and ultimately tissue regeneration via myogenesis. While skeletal muscle stem cells (MuSCs) are responsible for populating the proliferative myogenic progenitor pool to fuel muscle repair, recruited and resident immune cells have a central role in the regulation of muscle regeneration via the execution of phagocytosis and release of soluble factors that act directly on MuSCs to regulate myogenic differentiation. Therefore, the timing of MuSC proliferation and differentiation is closely linked to the populations and behaviors of immune cells present within skeletal muscle. This has important implications for aging and muscle repair, as systemic changes in immune system function contribute to a decline in muscle regenerative capacity. Here, we present adapted protocols for the isolation of mononuclear cells from skeletal muscles for the quantification of immune cell populations using flow cytometry. We also describe a cardiotoxin skeletal muscle injury protocol and detail the expected outcomes including immune cell infiltration to the injured sites and formation of new myocytes. As immune cell function is substantially influenced by aging, we extend these approaches and outcomes to aged mice.

Skeletal muscle relies on its inherent self-repair ability to withstand continuous mechanical damage. Myofiber-intrinsic processes facilitate the repair of damage to sarcolemma and sarcomeres, but it is the coordinated interaction between muscle-resident satellite and stromal cells that are crucial in the regeneration of muscles to replace the lost muscle fibers. Fibroadipogenic progenitors (FAPs), are muscle-resident mesenchymal cells that are notable for their role in creating the dynamic stromal niche required to support long-term muscle homeostasis and regeneration. While FAP-mediated extracellular matrix formation and the establishment of a homeostatic muscle niche are essential for maintaining muscle health, excessive accumulation of FAPs and their aberrant differentiation leads to the fibrofatty degeneration that is a hallmark of myopathies and muscular dystrophies. Recent advancements, including single-cell RNA sequencing and in vivo analysis of FAPs, are providing deeper insights into the functions and specialization of FAPs, shedding light on their roles in both health and disease. This review will explore the above insights, discussing how FAP dysregulation contributes to muscle diseases. It will offer a concise overview of potential therapeutic interventions targeting FAPs to restore disrupted interactions among FAPs and muscle-resident cells, ultimately addressing degenerative muscle loss in neuromuscular diseases.

Background: Age-related changes to the orbicularis oculi muscle include impaired eyelid function, such as lagophthalmos, alterations in tear film dynamics, and aesthetic changes like wrinkles, festoons, and the descent of soft tissue. To date, the structural and functional changes that would comprehensively increase our understanding of orbicularis aging have not been analyzed. This study aims to investigate functional outcomes using surface electromyography and correlate them with ultrastructural changes in orbicularis during aging. Methods: This study enrolled 26 patients aged 37 to 78 years with a clinical diagnosis of dermatochalasis. Patients were divided into two age groups (<60 years; ≥60 years). Ultrastructural and electromyographical examinations were performed, and the electromyographical signals were correlated with the ultrastructural damage in the orbicularis. Results: This study revealed significantly lower values of average voluntary contraction and RMS of the surface electromyography signals in the older age group compared to the younger age group (p = 0.029 and p = 0.045, respectively). There was no statistically significant association between age and muscle damage (χ2(2) = 2.86, p > 0.05). There was no correlation between average voluntary contraction and the degree of ultrastructural damage in both groups (Spearman's coefficient equaled 0.06923 and 0.64366, respectively). Conclusions: sEMG measurements are valuable for monitoring age-related functional changes in the orbicularis. Aging diminishes the functional capacity of the orbicularis, as evidenced by reduced contraction strength. This study, the first to compare ultrastructural and electromyographical changes in the orbicularis among dermatochalasis patients of different ages, finds that ultrastructural damage to muscle fibers is not directly responsible for the contraction strength decline.

As a common clinical manifestation, muscle weakness is prevalent in people with mobility disorders. Further studies of muscle weakness have found that patients with muscle weakness present with persistent muscle inflammation, loss of muscle fibers, fat infiltration, and interstitial fibrosis. Therefore, we propose the concept of muscle microenvironment homeostasis, which explains the abnormal pathological changes in muscles through the imbalance of muscle microenvironment homeostasis. And we identified an interstitial progenitor cell FAP during the transition from normal muscle microenvironment homeostasis to muscle microenvironment imbalance caused by muscle damage diseases. As a kind of pluripotent stem cell, FAPs do not participate in myogenic differentiation, but can differentiate into fibroblasts, adipocytes, osteoblasts, and chondrocytes. As a kind of mesenchymal progenitor cell, it is involved in the generation of extracellular matrix, regulate muscle regeneration, and maintain neuromuscular junction. However, the muscle microenvironment is disrupted by the causative factors, and the abnormal activities of FAPs eventually contribute to the complex pathological changes in muscles. Targeting the mechanisms of these muscle pathological changes, we have identified appropriate signaling targets for FAPs to improve and even treat muscle damage diseases. In this review, we propose the construction of muscle microenvironmental homeostasis and find the key cells that cause pathological changes in muscle after homeostasis is broken. By studying the mechanism of abnormal differentiation and apoptosis of FAPs, we found a strategy to inhibit the abnormal pathological changes in muscle damage diseases and improve muscle regeneration.

Skeletal muscles are essential for locomotion and body metabolism regulation. As muscles age, they lose strength, elasticity, and metabolic capability, leading to ineffective motion and metabolic derangement. Both cellular and extracellular alterations significantly influence muscle aging. Satellite cells (SCs), the primary muscle stem cells responsible for muscle regeneration, become exhausted, resulting in diminished population and functionality during aging. This decline in SC function impairs intercellular interactions as well as extracellular matrix production, further hindering muscle regeneration. Other muscle-resident cells, such as fibro-adipogenic progenitors (FAPs), pericytes, and immune cells, also deteriorate with age, reducing local growth factor activities and responsiveness to stress or injury. Systemic signaling, including hormonal changes, contributes to muscle cellular catabolism and disrupts muscle homeostasis. Collectively, these cellular and environmental components interact, disrupting muscle homeostasis and regeneration in advancing age. Understanding these complex interactions offers insights into potential regenerative strategies to mitigate age-related muscle degeneration.

Many organs of the body are susceptible to cancer development. However, striated muscles-which include skeletal and cardiac muscles-are rarely the sites of primary cancers. Most deaths from cancer arise due to complications associated with the development of secondary metastatic tumours, for which there are few effective therapies. However, as with primary cancers, the establishment of metastatic tumours in striated muscle accounts for a disproportionately small fraction of secondary tumours, relative to the proportion of body composition. Examining why primary and metastatic cancers are comparatively rare in striated muscle presents an opportunity to better understand mechanisms that can influence cancer cell biology. To gain insights into the incidence and distribution of muscle metastases, this review presents a definitive summary of the 210 case studies of metastasis in muscle published since 2010. To examine why metastases rarely form in muscles, this review considers the mechanisms currently proposed to render muscle an inhospitable environment for cancers. The "seed and soil" hypothesis proposes that tissues' differences in susceptibility to metastatic colonization are due to differing host microenvironments that promote or suppress metastatic growth to varying degrees. As such, the "soil" within muscle may not be conducive to cancer growth. Gaining a greater understanding of the mechanisms that underpin the resistance of muscles to cancer may provide new insights into mechanisms of tumour growth and progression, and offer opportunities to leverage insights into the development of interventions with the potential to inhibit metastasis in susceptible tissues.

Muscle damage resulting from physical activities such as exercise triggers an immune response crucial for tissue repair and recovery. This study investigates the immune cell profiles in muscle biopsies of individuals engaged in resistance exercise (RE) and explores the impact of age and sex on the immune response following exercise-induced muscle damage. Microarray datasets from muscle biopsies of young and old subjects were analyzed, focusing on the gene expression patterns associated with immune cell activation. Genes were compared with immune cell signatures to reveal the cellular landscape during exercise. Results show that the most significant modulated gene after RE was Folliculin Interacting Protein 2 (FNIP2) a crucial regulator in cellular homeostasis. Moreover, the transcriptome was stratified based on the expression of FNIP2 and the 203 genes common to the groups obtained based on sex and age. Gene ontology analysis highlighted the FLCN-FNIP1-FNIP2 complex, which exerts as a negative feedback loop to Pi3k-Akt-mTORC1 pathway. Furthermore, we highlighted that the young females exhibit a distinct innate immune cell activation signature compared to males after a RE session. Specifically, young females demonstrate a notable overlap with dendritic cells (DCs), M1 macrophages, M2 macrophages, and neutrophils, while young males overlap with M1 macrophages, M2 macrophages, and motor neurons. Interestingly, in elderly subjects, both sexes display M1 macrophage activation signatures. Comparison of young and elderly signatures reveals an increased M1 macrophage percentage in young subjects. Additionally, common genes were identified in both sexes across different age groups, elucidating biological functions related to cell remodeling and immune activation. This study underscores the intricate interplay between sex, age, and the immune response in muscle tissue following RE, offering potential directions for future research. Nevertheless, there is a need for further studies to delve deeper and confirm the dynamics of immune cells in response to exercise-induced muscle damage.

A disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1) plays crucial roles in various biological processes, including myogenesis, by modulating the neurogenic locus notch homolog protein 1 (NOTCH1) signaling pathway. However, the mechanisms through which ADAMTS1 regulates myogenesis remain unclear. In this study, we generated recombinant ADAMTS1 mutants and determined their effects on muscle cell differentiation, focusing on the regulation of NOTCH1 signaling. Treatment of C2C12 cells with recombinant ADAMTS1 protein enhanced muscle cell differentiation. Meanwhile, ADAM10 treatment inhibited muscle differentiation through the activation of NOTCH1 cleavage. Recombinant ADAMTS1 reversed ADAM10-induced muscle cell atrophy by suppressing NOTCH1 activation and downregulating its target gene. Recombinant ADAMTS1 also alleviated dexamethasoneinduced muscle atrophy in a mouse model. In summary, our findings suggest that recombinant ADAMTS1 promotes muscle regeneration by suppressing NOTCH1 and highlight the potential of recombinant ADAMTS1 proteins in the treatment of muscle wasting disease. [BMB Reports 2024; 57(12): 539-545].