Inflammation balance in skeletal muscle damage and repair

Ho T., Tang C., Chang S.L., Tsai C., Chen H., Su C.

Skeletal muscle atrophy occurs due to muscle wasting or reductions in protein associated with aging, injury, and inflammatory processes. High-mobility group box-1 (HMGB1) protein is passively released from necrotic cells and actively secreted by inflammatory cells, and is implicated in the pathogenesis of various inflammatory and immune diseases. HMGB1 is upregulated in muscle inflammation, and circulating levels of the proinflammatory cytokine interleukin-18 (IL-18) are upregulated in patients with sarcopenia, a muscle-wasting disease. We examined whether an association exists between HMGB1 and IL-18 signaling in skeletal muscle atrophy. HMGB1-induced increases of IL-18 levels enhanced the expression of muscle atrophy markers and inhibited myogenic marker expression in C2C12 and G7 myoblast cell lines. HMGB1-induced increases of IL-18 production in C2C12 cells involved the RAGE/p85/Akt/mTOR/c-Jun signaling pathway. HMGB1 short hairpin RNA (shRNA) treatment rescued the expression of muscle-specific differentiation markers in murine C2C12 myotubes and in mice with glycerol-induced muscle atrophy. HMGB1 and IL-18 signaling was suppressed in the mice after HMGB1 shRNA treatment. These findings suggest that the HMGB1/IL-18 axis is worth targeting for the treatment of skeletal muscle atrophy.

Solimando A.G., Desantis V., Ribatti D.

Mast cells play a critical role in inflammatory diseases and tumor growth. The versatility of mast cells is reflected in their ability to secrete a wide range of biologically active cytokines, including interleukins, chemokines, lipid mediators, proteases, and biogenic amines. The aim of this review article is to analyze the complex involvement of mast cells in the secretion of interleukins and the role of interleukins in the regulation of biological activities of mast cells.

Krasniewski L.K., Chakraborty P., Cui C., Mazan-Mamczarz K., Dunn C., Piao Y., Fan J., Shi C., Wallace T., Nguyen C., Rathbun I.A., Munk R., Tsitsipatis D., De S., Sen P., et. al.

Tissue-resident macrophages represent a group of highly responsive innate immune cells that acquire diverse functions by polarizing toward distinct subpopulations. The subpopulations of macrophages that reside in skeletal muscle (SKM) and their changes during aging are poorly characterized. By single-cell transcriptomic analysis with unsupervised clustering, we found 11 distinct macrophage clusters in male mouse SKM with enriched gene expression programs linked to reparative, proinflammatory, phagocytic, proliferative, and senescence-associated functions. Using a complementary classification, membrane markers LYVE1 and MHCII identified four macrophage subgroups: LYVE1−/MHCIIhi (M1-like, classically activated), LYVE1+/MHCIIlo (M2-like, alternatively activated), and two new subgroups, LYVE1+/MHCIIhi and LYVE1−/MHCIIlo. Notably, one new subgroup, LYVE1+/MHCIIhi, had traits of both M2 and M1 macrophages, while the other new subgroup, LYVE1−/MHCIIlo, displayed strong phagocytic capacity. Flow cytometric analysis validated the presence of the four macrophage subgroups in SKM and found that LYVE1− macrophages were more abundant than LYVE1+ macrophages in old SKM. A striking increase in proinflammatory markers (S100a8 and S100a9 mRNAs) and senescence-related markers (Gpnmb and Spp1 mRNAs) was evident in macrophage clusters from older mice. In sum, we have identified dynamically polarized SKM macrophages and propose that specific macrophage subpopulations contribute to the proinflammatory and senescent traits of old SKM.

Stratos I., Behrendt A., Anselm C., Gonzalez A., Mittlmeier T., Vollmar B.

Background: Muscle injuries are common in humans and are often associated with irrecoverable damage and disability. Upon muscle injury, TNF-α signaling pathways modulate the healing process and are predominantly associated with tissue degradation. In this study we assumed that TNF-α inhibition could reduce the TNF-α-associated tissue degradation after muscle injury. Materials and methods: Therefore, the left soleus muscle of 42 male Wistar rats was injured using a standardized open muscle injury model. All rats were treated immediately after injury either with infliximab (single i.p. injection; 10 mg/kg b.w.) or saline solution i.p. Final measurements were conducted at day one, four, and 14 post injury. The muscle force, the muscle cell proliferation, the muscle cell coverage as well as the myofiber diameter served as read out parameters of our experiment. Results: Systemic application of infliximab could significantly reduce the TNF-α levels in the injured muscle at day four upon trauma compared to saline treated animals. The ratio of muscle weight to body weight was increased and the twitch muscle force showed a significant rise 14 days after trauma and TNF-α inhibition. Quantification of myofiber diameter in the penumbra zone showed a significant difference between both groups at day one and four after injury, indicated by muscle hypertrophy in the infliximab group. Planimetric analysis of the injured muscle at day 14 revealed increased muscle tissue fraction in the infliximab group compared to the control animals. Muscle cell proliferation did not differ between both groups. Conclusions: These data provide evidence that the TNF-α blockade positively regulates the restauration of skeletal muscles upon injury.

Juban G., Chazaud B.

Efferocytosis, i.e., engulfment of dead cells by macrophages, is a crucial step during tissue repair after an injury. Efferocytosis delineates the transition from the pro-inflammatory phase of the inflammatory response to the recovery phase that ensures tissue reconstruction. We present here the role of efferocytosis during skeletal muscle regeneration, which is a paradigm of sterile tissue injury followed by a complete regeneration. We present the molecular mechanisms that have been described to control this process, and particularly the metabolic control of efferocytosis during skeletal muscle regeneration.

Mas-Celis F., Olea-López J., Parroquin-Maldonado J.A.

Sepsis is a major cause of death following a traumatic injury. As a life-threatening medical emergency, it is defined as the body's extreme response to an infection. Without timely treatment, sepsis can rapidly lead to tissue damage, and organ failure The capacity to limit tissue damage through metabolic adaptation and repair processes is associated with an excessive immune response of the host. It is important to make an early prediction of sepsis, based on the quick Sepsis associated Organ Failure Assessment Score (qSOFA), so an accurate treatment can be initiated reducing the morbidity and mortality at the emergency and UCI services. Many factors increase the rate of complications and the development of sepsis in a trauma patient, representing a challenge to orthopedic surgeons. Several early biomarkers that help to identify and predict the inflammatory and immune responses of the host going through polytrauma and sepsis have been studied; procalcitonin (PCT), C-reactive protein (CRP), glycosylated hemoglobin (HbA1c), the Neutrophil/lymphocyte ratio (NLR), Interleukin-17 (IL-17), Caspase-1, Vanin-1, High-density lipoproteins (HDL), and the Thrombin-activable fibrinolysis inhibitor (TAFI). Once sepsis is diagnosed, treatment must be immediately initiated with an appropriate empiric antimicrobial, an all-purpose supporting treatment, and metabolic control, followed by the specific antibiotic therapy based on blood culture. Since the participation of sepsis in polytrauma has been recognized as a key event in the outcome of patients at the ICU, the ability of the specialist to early recognize a septic process has become a key feature to reduce mortality and improve clinical prognosis.

Panci G., Chazaud B.

The adult skeletal muscle fully regenerates after injury thanks to the properties of muscle stem cells that follow the adult myogenic program to replace damaged myofibers. Muscle regeneration also relies upon the coordinated actions of several other cell types, among which immune cells. Leukocytes infiltrate the damaged muscle soon after injury and support the regeneration process in a variety of ways, from the activation of muscle stem cells to the maturation of newly formed myofibers. Leukocytes also interact with other cell types such as fibroadipogenic precursors and endothelial cells. This review presents the interactions that leukocytes develop with the cells present in their vicinity and the impact they have on skeletal muscle regeneration.

Hansen L., Joseph G., Valdivia A., Taylor W.R.

Background The growth and remodeling of vascular networks is an important component of the prognosis for patients with peripheral artery disease. One protein that has been previously implicated to play a role in this process is RAGE (receptor for advanced glycation end products). This study sought to determine the cellular source of RAGE in the ischemic hind limb and the role of RAGE signaling in this cell type. Methods and Results Using a hind limb ischemia model of vascular growth, this study found skeletal muscle satellite cells to be a novel major cellular source of RAGE in ischemic tissue by both staining and cellular sorting. Although wild‐type satellite cells increased tumor necrosis factor‐α and monocyte chemoattractant protein‐1 production in response to ischemia in vivo and a RAGE ligand in vitro, satellite cells from RAGE knockout mice lacked the increase in cytokine production both in vivo in response to ischemia and in vitro after stimuli with the RAGE ligand high‐mobility group box 1. Furthermore, encapsulated wild‐type satellite cells improved perfusion after hind limb ischemia surgery by both perfusion staining and vessel quantification, but RAGE knockout satellite cells provided no improvement over empty capsules. Conclusions Thus, RAGE expression and signaling in satellite cells is crucial for their response to stimuli and angiogenic and arteriogenic functions.

Canton M., Sánchez-Rodríguez R., Spera I., Venegas F.C., Favia M., Viola A., Castegna A.

Reactive oxygen species (ROS) are fundamental for macrophages to eliminate invasive microorganisms. However, as observed in nonphagocytic cells, ROS play essential roles in processes that are different from pathogen killing, as signal transduction, differentiation, and gene expression. The different outcomes of these events are likely to depend on the specific subcellular site of ROS formation, as well as the duration and extent of ROS production. While excessive accumulation of ROS has long been appreciated for its detrimental effects, there is now a deeper understanding of their roles as signaling molecules. This could explain the failure of the “all or none” pharmacologic approach with global antioxidants to treat several diseases. NADPH oxidase is the first source of ROS that has been identified in macrophages. However, growing evidence highlights mitochondria as a crucial site of ROS formation in these cells, mainly due to electron leakage of the respiratory chain or to enzymes, such as monoamine oxidases. Their role in redox signaling, together with their exact site of formation is only partially elucidated. Hence, it is essential to identify the specific intracellular sources of ROS and how they influence cellular processes in both physiological and pathological conditions to develop therapies targeting oxidative signaling networks. In this review, we will focus on the different sites of ROS formation in macrophages and how they impact on metabolic processes and inflammatory signaling, highlighting the role of mitochondrial as compared to non-mitochondrial ROS sources.

Cassim F., Soni A.J., Murphy S.

We present the case of a 12-year-old African girl infected with SARS-CoV-2 who was admitted to a tertiary academic hospital in Johannesburg with severe acute inflammatory myositis complicated by rhabdomyolysis and acute kidney injury requiring renal replacement therapy and intensive care. She also fulfilled the diagnostic criteria for multisystem inflammatory syndrome in children.

Furubeppu H., Ito T., Kakuuchi M., Yasuda T., Kamikokuryo C., Yamada S., Maruyama I., Kakihana Y.

BackgroundSkeletal muscle ischemia/reperfusion (I/R) injury is an important clinical issue that can cause remote organ injury. Although its pathogenesis has not been fully elucidated, recent studies have suggested that damage-associated molecular patterns (DAMPs) are mediators of remote organ injury in sterile inflammation. The purpose of this study was to investigate the possible involvement of DAMPs, including the nuclear proteins high-mobility group box 1 (HMGB1) and histone H3, in the pathogenesis of skeletal muscle I/R injury in mice.MethodsHindlimb ischemia was induced in mice through bilateral ligation of inguinal regions using rubber grommets. Reperfusion was induced by cutting the rubber grommets after 2–12 h of ischemic period. Survival rates, localization of HMGB1 and histone H3 in the gastrocnemius muscle, and circulating HMGB1 and histone H3 levels were analyzed. The effect of anti-HMGB1 and anti-histone H3 antibodies on survival was analyzed in mice with I/R injury.ResultsAll mice with hindlimb ischemia survived for at least 36 h, while all mice died within 24 h if the hindlimbs were reperfused after ischemia for 4–12 h. Immunohistochemical analysis revealed that HMGB1 translocated from the nucleus to the cytoplasm in the ischemic gastrocnemius muscle, while histone H3 was confined to the nucleus. Accordingly, serum HMGB1 levels were significantly elevated in mice with hindlimb I/R compared with normal mice or mice with hindlimb ischemia (P < 0.05). Serum histone H3 levels were not elevated after I/R. Treatment with anti-HMGB1 antibodies significantly improved survival of mice with hindlimb I/R injury compared with control antibodies (P < 0.05).ConclusionsHMGB1, but not histone H3, translocated to the cytoplasm during skeletal muscle ischemia, and was released into the systemic circulation after reperfusion in mice with I/R injury. Treatment with anti-HMGB1 antibodies partially improved survival.

Al-Zaeed N., Budai Z., Szondy Z., Sarang Z.

Skeletal muscle regeneration following injury results from the proliferation and differentiation of myogenic stem cells, called satellite cells, located beneath the basal lamina of the muscle fibers. Infiltrating macrophages play an essential role in the process partly by clearing the necrotic cell debris, partly by producing cytokines that guide myogenesis. Infiltrating macrophages are at the beginning pro-inflammatory, but phagocytosis of dead cells induces a phenotypic change to become healing macrophages that regulate inflammation, myoblast fusion and growth, fibrosis, vascularization and return to homeostasis. The TAM receptor kinases Mer and Axl are known efferocytosis receptors in macrophages functioning in tolerogenic or inflammatory conditions, respectively. Here we investigated their involvement in the muscle regeneration process by studying the muscle repair following cardiotoxin-induced injury in Mer−/− mice. We found that Axl was the only TAM kinase receptor expressed on the protein level by skeletal muscle and C2C12 myoblast cells, while Mer was the dominant TAM kinase receptor in the CD45+ cells, and its expression significantly increased during repair. Mer ablation did not affect the skeletal muscle weight or structure, but following injury it resulted in a delay in the clearance of necrotic muscle cell debris, in the healing phenotype conversion of macrophages and consequently in a significant delay in the full muscle regeneration. Administration of the TAM kinase inhibitor BMS-777607 to wild type mice mimicked the effect of Mer ablation on the muscle regeneration process, but in addition, it resulted in a long-persisting necrotic area. Finally, in vitro inhibition of TAM kinase signaling in C2C12 myoblasts resulted in decreased viability and in impaired myotube growth. Our work identifies Axl as a survival and growth receptor in the mouse myoblasts, and reveals the contribution of TAM kinase-mediated signaling to the skeletal muscle regeneration both in macrophages and in myoblasts.

Careccia G., Saclier M., Tirone M., Ruggieri E., Principi E., Raffaghello L., Torchio S., Recchia D., Canepari M., Gorzanelli A., Ferrara M., Castellani P., Rubartelli A., Rovere-Querini P., Casalgrandi M., et. al.

The redox-sensitive HMGB1 protein is a functional link between oxidative stress and persistent inflammation in muscular dystrophies.

Salo H., Qu H., Mitsiou D., Aucott H., Han J., Zhang X., Aulin C., Erlandsson Harris H.

Macrophage plasticity enables cells to obtain different functions over a broad proinflammatory and repairing spectrum. In different conditions, macrophages can be induced by high-mobility group box 1 (HMGB1), a nuclear DNA-binding protein that activates innate immunity, to polarize towards a pro- (M1) or anti-inflammatory (M2) phenotype. In this study, we investigated the phenotypes of murine bone-marrow-derived macrophages (BMDMs) induced by different HMGB1 redox isoforms in depth. Our results demonstrate that disulfide HMGB1 (dsHMGB1) induces a unique macrophage phenotype that secretes pro-inflammatory cytokines, rather than inducing metabolic changes leading to nitric oxide production. Fully reduced HMGB1 (frHMGB1) did not induce macrophage polarization. The migrating function of BMDMs was measured by scratch assay after the stimulation with dsHMGB1 and frHMGB1. Both dsHMGB1 and frHMGB1 induced cell migration. We found that dsHMGB1 mediates cytokine secretion and cellular motility, mainly through toll-like receptor 4 (TLR4). Importantly, our data shows that dsHMGB1 and frHMGB1 induce distinct BMDM polarization phenotypes, and that dsHMGB1 induces a unique phenotype differing from the classical proinflammatory macrophage phenotype.

Qualls A.E., Southern W.M., Call J.A.

Skeletal muscle mitochondria are highly adaptable, highly dynamic organelles that maintain the functional integrity of the muscle fiber by providing ATP for contraction and cellular homeostasis (e.g., Na+/K+ ATPase). Emerging as early modulators of inflammation, mitochondria sense and respond to cellular stress. Mitochondria communicate with the environment, in part, by release of physical signals called mitochondrial-derived damage-associated molecular patterns (mito-DAMPs) and deviation from routine function (e.g., reduced ATP production, Ca2+ overload). When skeletal muscle is compromised, mitochondria contribute to an acute inflammatory response necessary for myofibril regeneration; however, exhaustive signaling associated with altered or reduced mitochondrial function can be detrimental to muscle outcomes. Here, we describe changes in mitochondrial content, structure, and function following skeletal muscle injury and disuse and highlight the influence of mitochondria-cytokine crosstalk on muscle regeneration and recovery. Although the appropriate therapeutic modulation following muscle stressors remains unknown, retrospective gene expression analysis reveals that interleukin-6 (IL-6), interleukin-1β (IL-1β), chemokine C-X-C motif ligand 1 (CXCL1), and monocyte chemoattractant protein 1 (MCP-1) are significantly upregulated following three unique muscle injuries. These cytokines modulate mitochondrial function and execute bona fide pleiotropic roles that can aid functional recovery of muscle, however, when aberrant, chronically disrupt healing partly by exacerbating mitochondrial dysfunction. Multidisciplinary efforts to delineate the opposing regulatory roles of inflammatory cytokines in the muscle mitochondrial environment are required to modulate regenerative behavior following skeletal muscle injury or disuse. Future therapeutic directions to consider include quenching or limited release of mito-DAMPs and cytokines present in cytosol or circulation.

Huang C., Liang Y., Jiang A., Chen L., Sun C., Luo D., Xia Z., Li L., Jiang Y.

Pacilio S., Lombardi S., Costa R., Paris F., Petrocelli G., Marrazzo P., Cenacchi G., Alviano F.

Inflammation mechanisms play a critical role in muscle homeostasis, and in Muscular Dystrophies (MDs), the myofiber damage triggers chronic inflammation which significantly controls the disease progression. Immunomodulatory strategies able to target inflammatory pathways and mitigate the immune-mediated damage in MDs may provide new therapeutic options. Owing to its capacity of influencing the immune response and enhancing tissue repair, stem cells’ secretome has been proposed as an adjunct or standalone treatment for MDs. In this review study, we discuss the challenging points related to the inflammation condition characterizing MD pathology and provide a concise summary of the literature supporting the potential of perinatal stem cells in targeting and modulating the MD inflammation.

de Araújo Alves C.C., de Melo P.F., Vieira L., Mathur S., Burtin C., Maldaner V.Z., Durigan J.L., de Araujo C.N., de Souza V.C., Cipriano G.F., Chiappa G.R., Rodrigues G.L., Silva P.E., Cipriano Junior G.

The present study aims to describe initial changes in muscle thickness and composition, muscle growth signaling mediators, and systemic inflammation in critically ill patients after major trauma. This observational study was carried out in a Level-I nonprofit trauma center. Thirty adults requiring mechanical ventilation were assessed within 24 h post-admission. Skeletal muscle wasting was evaluated using ultrasound for muscle thickness and echogenicity along with circulating insulin-like growth factor 1 (IGF-1) and inflammatory cytokines over five consecutive days. Changes over time were assessed using ANOVA repeated-measures analysis with a Bonferroni post-hoc test. Bivariate correlations were evaluated using Pearson or Spearman coefficients. Over five days, a significant decrease (11%) in rectus femoris thickness (3.91 ± 0.86 to 3.47 ± 0.64, cm, p = 0.01) and an increase (29%) in echogenicity (62.1 ± 13.1 to 80.4 ± 17.3, AU, p < 0.01) were observed among the 30 patients included in this study. Circulating levels of IGF-1 exhibited a 38% reduction (68.8 ± 43.6 to 42.4 ± 29.4, ng/mL, p = 0.01). Furthermore, pro-inflammatory cytokine (IFN-y) increased by 17% (4.83 ± 1.39 to 5.66 ± 1.61, pg./mL, p = 0.02) from day 1 to day 5. These findings reveal substantial thickness and muscle composition alterations within 48 h post-admission, worsening over five days. Despite standard rehabilitation care, changes in IGF-1 and IFN-y levels suggest early declines in muscle growth stimulus and increased inflammation.

Zhou C., Zou Y., Huang H., Zhao F., Fan X., Bai L., Zhang X., Ye K.

Wang S., Guo W., Dong R.

Leucine has gained recognition as an athletic dietary supplement in recent years due to its various benefits; however, the underlying molecular mechanisms remain unclear. In this study, 20 basketball players were recruited and randomly assigned to two groups. Baseline exercise performance—assessed through a 282-foot sprint, free throws, three-point field goals, and self-rated practice assessments—was measured prior to leucine supplementation. Participants were then given a functional drink containing either leucine (50 mg/kg body weight) or a placebo for 28 days. After supplementation, the same exercise performance metrics were reassessed. Following leucine supplementation, biceps brachii muscle tissue from both groups was collected for transcriptome sequencing and qPCR verification. Our results suggested that leucine supplementation significantly improved 282-foot sprint performance, reducing times from 17.4 ± 0.9 to 16.2 ± 0.9 seconds in the leucine group, compared to minimal changes in the control group (from 17.3 ± 0.9 to 17.1 ± 0.8 seconds; P = 0.034). For other exercise performance metrics, no significant differences were observed (P > 0.05); however, trends toward improvement were noted. Transcriptomic analysis revealed 3,658 differentially expressed genes (DEGs) between the two groups. These DEGs were enriched in pathways related to immune response (P < 0.0001), positive regulation of cytokine production (P < 0.0001), and neutrophil extracellular trap formation (P < 0.0001), among others. Weighted Gene Co-expression Network Analysis (WGCNA) identified a module (turquoise) strongly associated with muscle growth, with DEGs in this module enriched in cytoskeletal pathways in muscle cells. Gene expression changes (α-tubulin, β-tubulin, CK18, CK8, vimentin, cofilin, gelsolin, profilin, MAP1, MAP2, MAP4, E-cadherin, and N-cadherin) were verified by qPCR. In summary, leucine supplementation improved exercise performance, particularly by significantly reducing sprint times and showing trends of improvement in other performance metrics, including three-point field goals, free throws, and self-rated well-being. Identified DEGs enriched in pathways related to immune response, cytokine production, and cell adhesion. WGCNA highlighted a key module associated with muscle growth, enriched in cytoskeletal pathways. qPCR validation confirmed the upregulation of cytoskeleton-related genes, supporting the transcriptomic findings. These results suggest that leucine enhances muscle adaptation by regulating cytoskeletal dynamics, providing molecular insights into its role in improving athletic performance.

Wang X., Tang X., Wang Y., Zhao S., Xu N., Wang H., Kuang M., Han S., Jiang Z., Zhang W.

ABSTRACTWith the development of medicine and chemistry, an increasing number of plant‐derived medicines have been shown to exert beneficial therapeutic on the treatment of various physical and psychological diseases. In particular, by using physical chemistry methods, we are able to examine the chemical components of plants and the effects of these substances on the human body. Muscle atrophy (MA) is characterized by decreased muscle mass and function, is caused by multiple factors and severely affects the quality of life of patients. The multifactorial and complex pathogenesis of MA hinders drug research and disease treatment. However, phytotherapy has achieved significant results in the treatment of MA. We searched PubMed and the Web of Science for articles related to plant‐derived substances and muscle atrophy. After applying exclusion and inclusion criteria, 166 and 79 articles met the inclusion criteria, respectively. A total of 173 articles were included in the study after excluding duplicates. The important role of phytoactives such as curcumin, resveratrol, and ginsenosides in the treatment of MA (e.g., maintaining a positive nitrogen balance in muscles and exerting anti‐inflammatory and antioxidant effects) has been extensively studied. Unfortunately, MA dose not have to a single cause, and each cause has its own unique mechanism of injury. This review focuses on the therapeutic mechanisms of active plant components in MA and provides insights into the personalized treatment of MA.

Correia M.R., Han S.W., Escalante T., Moreira V.

Wang S., Wang M., Jiang L.

The trend of muscle wasting in patients with acute severe and moderately severe pancreatitis (AP) remains unclear. This retrospective study aimed to investigate the trend of skeletal muscle area (SMA) changes and its impact on patients with severe and moderately severe AP. Patients diagnosed with AP who had repeated CT scans after intensive care unit (ICU) admission were included. The patients were categorized into moderately severe AP or severe AP groups. The generalized additive mixed model (GAMM) was used to analyze the SMA trajectories. A total of 126 patients were included. The patients in the severe AP group had more rapid muscle wasting during the first 3 weeks following ICU admission. The SMA decreased by 1.1 cm2 (95% CI: 1.3 to 0.8) per day in the severe AP group, while the SMA decreased by 0.5 cm2 (95% CI: 0.6 to 0.4) in the moderately severe AP group in the GAMM model. A larger change in the SMA during the first 10 days after admission was significantly associated with prolonged length of hospital stay (LOS) (β = − 0.205, P = 0.036). Patients with severe AP experienced more muscle wasting during the first 3 weeks after ICU admission. A larger reduction in the SMA was associated with prolonged LOS. Different patterns of muscle wasting were present during the first 3 weeks after ICU admission in moderately severe and severe AP patients. Accordingly, different nutrition and rehabilitation strategies might be employed depending upon the severity of AP.

Huang B., Gao Y., Wu L.

AimThe current study aims to delineate subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), the sacrospinalis muscle, and all abdominal musculature at the L3–L5 vertebral level from non-contrast computed tomography (CT) imagery using deep learning algorithms. Subsequently, radiomic features are collected from these segmented images and subjected to medical interpretation.Materials and methodsThis retrospective analysis includes a cohort of 315 patients diagnosed with acute necrotizing pancreatitis (ANP) who had undergone comprehensive whole-abdomen CT scans. The no new net (nnU-Net) architecture was adopted for the imagery segmentation, while Python scripts were employed to derive radiomic features from the segmented non-contrast CT images. In light of the intrinsic medical relevance of specific features, two categories were selected for analysis: first-order statistics and morphological characteristics. A correlation analysis was conducted, and statistically significant features were subjected to medical scrutiny.ResultsWith respect to VAT, skewness (p = 0.004) and uniformity (p = 0.036) emerged as statistically significant; for SAT, significant features included skewness (p = 0.023), maximum two-dimensional (2D) diameter slice (p = 0.020), and maximum three-dimensional (3D) diameter (p = 0.044); for the abdominal muscles, statistically significant metrics were the interquartile range (IQR; p = 0.023), mean absolute deviation (p = 0.039), robust mean absolute deviation (p = 0.015), elongation (p = 0.025), sphericity (p = 0.010), and surface volume ratio (p = 0.014); and for the sacrospinalis muscle, significant indices comprised the IQR (p = 0.018), mean absolute deviation (p = 0.049), robust mean absolute deviation (p = 0.025), skewness (p = 0.008), maximum 2D diameter slice (p = 0.008), maximum 3D diameter (p = 0.005), sphericity (p = 0.011), and surface volume ratio (p = 0.005).ConclusionDiminished localized deposition of VAT and SAT, homogeneity in the VAT and SAT density, augmented SAT volume, and a dispersed and heterogeneous distribution of abdominal muscle density are identified as risk factors for infectious pancreatic necrosis (IPN).

Zhang Z., Hu X., Du Q., Liu J., Chen X., Mo P., Luo M., Jiang Q., Deng L., Xiong Y.

ABSTRACTSevere fever with thrombocytopenia syndrome (SFTS) is an emerging zoonosis caused by a novel bunyavirus. Until recently, rhabdomyolysis in SFTS was not elucidated. The objective of this study was to investigate the prevalence and clinical characteristics of rhabdomyolysis and its association with AKI and prognosis in patients with SFTS. A total of 231 consecutive patients diagnosed with SFTS were enrolled, including 144 (62.3%) patients in the no rhabdomyolysis group and 87 (37.7%) patients in the rhabdomyolysis group. Clinical characteristics and laboratory parameters of SFTS patients were compared between the no rhabdomyolysis and rhabdomyolysis groups. Patients with rhabdomyolysis had more frequency of confusion, cough, sputum, chest distress, abdominal pain, petechia and ecchymosis, headache, myalgia, and myasthenia than those without rhabdomyolysis. Compared with patients in the no rhabdomyolysis group, patients in the rhabdomyolysis group had higher serum levels of laboratory parameters referring to liver, kidney, pancreas, heart, coagulation system injury, and higher viral load. The cumulative survival rate of patients with rhabdomyolysis was significantly lower than that of patients without rhabdomyolysis. Furthermore, univariate and multivariate binary logistic regression analyses demonstrated that rhabdomyolysis was an independent predictor for acute kidney injury and mortality in patients with SFTS. Rhabdomyolysis may be an important contributing factor to adverse outcomes and its effects on mortality may be mediated by acute kidney injury in SFTS. The early detection and effective intervention of rhabdomyolysis may decrease the mortality of patients with SFTS.

Ruggieri E., Domenico E.D., Locatelli A.G., Isopo F., Damanti S., Lorenzo R.D., Milan E., Musco G., Rovere-Querini P., Cenci S., Vénéreau E.

Zhuang P., Yang W., Chen Y., Zhang Y., Leboucher C., Rosenholm J.M., Zhang H.

Wu J., Tang J., Huang D., Wang Y., Zhou E., Ru Q., Xu G., Chen L., Wu Y.

Sarcopenia and AD are both classic degenerative diseases, and there is growing epidemiological evidence of their comorbidity with aging; however, the mechanisms underlying the biology of their commonality have not yet been thoroughly investigated. APP is a membrane protein that is expressed in tissues and is expressed not only in the nervous system but also in the NMJ and muscle. Deposition of its proteolytic cleavage product, Aβ, has been described as a central component of AD pathogenesis. Recent studies have shown that excessive accumulation and aberrant expression of APP in muscle lead to pathological muscle lesions, but the pathogenic mechanism by which APP and its proteolytic cleavage products act in skeletal muscle is less well understood. By summarizing and analyzing the literature concerning the role, pathogenicity and pathological mechanisms of APP and its cleavage products in the nervous system and muscles, we aimed to explore the intrinsic pathological mechanisms of myocerebral comorbidities and to provide new perspectives and theoretical foundations for the prevention and treatment of AD and sarcopenia comorbidities.

Xu M., Zhang Q., Liu X., Lu L., Li Z.

AKG, a central metabolite in the Krebs cycle, plays a vital role in cellular energy production and nitrogen metabolism. This review explores AKG’s potential therapeutic applications in skeletal muscle health and exercise performance, focusing on its mechanisms for promoting muscle regeneration and counteracting muscle atrophy. A literature search was conducted using the PubMed, Web of Science, and Scopus databases, yielding 945 articles published up to 31 October 2024. Of these, 112 peer-reviewed articles met the inclusion criteria and formed the basis of this review. AKG supports muscle recovery by stimulating muscle satellite cells (MuSCs) and macrophage polarization, aiding muscle repair and reducing fibrosis. Additionally, AKG shows promise in preventing muscle atrophy by enhancing protein synthesis, inhibiting degradation pathways, and modulating inflammatory responses, making it relevant in conditions like sarcopenia, cachexia, and injury recovery. For athletes and active individuals, AKG supplementation has enhanced endurance, reduced fatigue, and supported faster post-exercise recovery. Despite promising preliminary findings, research gaps remain in understanding AKG’s long-term effects, optimal dosage, and specific pathways, particularly across diverse populations. Further research, including large-scale clinical trials, is essential to clarify AKG’s role in muscle health and to optimize its application as a therapeutic agent for skeletal muscle diseases and an enhancer of physical performance. This review aims to provide a comprehensive overview of AKG’s benefits and identify future directions for research in both clinical and sports settings.

Elimam H., Gauvin J., Huynh D.N., Ménard L., Al‐Hawat M., Harb D., Lubell W.D., Carpentier A.C., Ong H., Marleau S.

ABSTRACTReperfusion of ischemic skeletal muscle triggers oxidative stress and an immediate inflammatory reaction, leading to damage of distant organs such as the lungs. The inflammatory process implicates numerous mediators, including cytokines, chemokines, and arachidonic acid metabolites. In the orchestration of the inflammatory cascade, a critical role is played by the cluster of differentiation‐36 receptor (CD36), a scavenger receptor class B protein (SR‐B2) which is expressed on macrophages and functions as a Toll‐like receptor coreceptor. A mouse model of hind limb ischemia‐reperfusion has been used to investigate the interplay between CD36 signaling and remote inflammation: leukocyte recruitment, regulation of the nucleotide‐binding domain leucin‐rich repeat and pyrin‐containing receptor 3 (NLRP3) inflammasome, and release of nuclear factor‐kappa B (NF‐ĸB) and arachidonic acid metabolites. Levels of reactive oxygen species, inflammatory mediators, and gene expression were measured in blood and lung tissue samples collected from anesthetized mice on which unilateral hind limb ischemia was induced by rubber band constriction for 30 min followed by reperfusion for 3 h. The CD36 modulator EP 80317, a member of the growth hormone releasing peptide 6 family, was employed as a pharmacological agent to mitigate distant lung injury following skeletal limb ischemia‐reperfusion. Targeting CD36 on monocytes/macrophages, EP 80317 abated pro‐inflammatory signaling and transcriptional activity encompassing lipid and cytokine mediators. Targeting CD36 was shown to offer promise for curtailing tissue injury following hind limb ischemia‐reperfusion.