CISD3/MiNT is required for complex I function, mitochondrial integrity, and skeletal muscle maintenance.

Mitochondria play a central role in muscle metabolism and function. A unique family of iron-sulfur proteins, termed CDGSH Iron Sulfur Domain-containing (CISD/NEET) proteins, support mitochondrial function in skeletal muscles. The abundance of these proteins declines during aging leading to muscle degeneration. Although the function of the outer mitochondrial CISD/NEET proteins, CISD1/mitoNEET and CISD2/NAF-1, has been defined in skeletal muscle cells, the role of the inner mitochondrial CISD protein, CISD3/MiNT, is currently unknown. Here, we show that CISD3 deficiency in mice results in muscle atrophy that shares proteomic features with Duchenne muscular dystrophy. We further reveal that CISD3 deficiency impairs the function and structure of skeletal muscles, as well as their mitochondria, and that CISD3 interacts with, and donates its [2Fe-2S] clusters to, complex I respiratory chain subunit NADH Ubiquinone Oxidoreductase Core Subunit V2 (NDUFV2). Using coevolutionary and structural computational tools, we model a CISD3-NDUFV2 complex with proximal coevolving residue interactions conducive of [2Fe-2S] cluster transfer reactions, placing the clusters of the two proteins 10 to 16 Å apart. Taken together, our findings reveal that CISD3/MiNT is important for supporting the biogenesis and function of complex I, essential for muscle maintenance and function. Interventions that target CISD3 could therefore impact different muscle degeneration syndromes, aging, and related conditions.

Gouqi-derived nanovesicles (GqDNVs) inhibited dexamethasone-induced muscle atrophy associating with AMPK/SIRT1/PGC1α signaling pathway.

With the increasing trend of global aging, sarcopenia has become a significant public health issue. Goji berry, also known as "Gou qi zi" in China, is a traditional Chinese herb that can enhance the structure and function of muscles and bones. Otherwise, previous excellent publications illustrated that plant-derived exosome-like nanoparticles can exert good bioactive functions in different aging or disease models. Thus, we issued the hypothesis that Gouqi-derived nanovesicles (GqDNVs) may also have the ability to improve skeletal muscle health, though the effect and its mechanism need to be explored. Hence, we have extracted GqDNVs from fresh berries of Lycium barbarum L. (goji) and found that the contents of GqDNVs are rich in saccharides and lipids. Based on the pathway annotations and predictions in non-targeted metabolome analysis, GqDNVs are tightly associated with the pathways in metabolism. In muscle atrophy model mice, intramuscular injection of GqDNVs improves the cross-sectional area of the quadriceps muscle, grip strength and the AMPK/SIRT1/PGC1α pathway expression. After separately inhibiting AMPK or PGC1α in C2C12 cells with dexamethasone administration, we have found that the activated AMPK plays the chief role in improving cell proliferation induced by GqDNVs. Furthermore, the energy-targeted metabolome analysis in the quadriceps muscle demonstrates that the GqDNVs up-regulate the metabolism of amino sugar and nucleotide sugar, autophagy and oxidative phosphorylation process, which indicates the activation of muscle regeneration. Besides, the Spearman rank analysis shows close associations between the quality and function of skeletal muscle, metabolites and expression levels of AMPK and SIRT1. In this study, we provide a new founding that GqDNVs can improve the quality and function of skeletal muscle accompanying the activated AMPK/SIRT1/PGC1α signaling pathway. Therefore, GqDNVs have the effect of anti-aging skeletal muscle as a potential adjuvant or complementary method or idea in future therapy and research.

Disuse-Induced Muscle Fatigue: Facts and Assumptions.

Skeletal muscle unloading occurs during a wide range of conditions, from space flight to bed rest. The unloaded muscle undergoes negative functional changes, which include increased fatigue. The mechanisms of unloading-induced fatigue are far from complete understanding and cannot be explained by muscle atrophy only. In this review, we summarize the data concerning unloading-induced fatigue in different muscles and different unloading models and provide several potential mechanisms of unloading-induced fatigue based on recent experimental data. The unloading-induced changes leading to increased fatigue include both neurobiological and intramuscular processes. The development of intramuscular fatigue seems to be mainly contributed by the transformation of soleus muscle fibers from a fatigue-resistant, "oxidative" "slow" phenotype to a "fast" "glycolytic" one. This process includes slow-to-fast fiber-type shift and mitochondrial density decline, as well as the disruption of activating signaling interconnections between slow-type myosin expression and mitochondrial biogenesis. A vast pool of relevant literature suggests that these events are triggered by the inactivation of muscle fibers in the early stages of muscle unloading, leading to the accumulation of high-energy phosphates and calcium ions in the myoplasm, as well as NO decrease. Disturbance of these secondary messengers leads to structural changes in muscles that, in turn, cause increased fatigue.

Comparison of Muscle Regeneration Effects at Different Melittin Concentrations in Rabbit Atrophied Muscle.

This research aimed to explore the healing impacts of Melittin treatment on gastrocnemius muscle wasting caused by immobilization with a cast in rabbits. Twenty-four rabbits were randomly allocated to four groups. The procedures included different injections: 0.2 mL of normal saline to Group 1 (G1-NS); 4 µg/kg of Melittin to Group 2 (G2-4 µg/kg Melittin); 20 µg/kg of Melittin to Group 3 (G3-20 µg/kg Melittin); and 100 µg/kg of Melittin to Group 4 (G4-100 µg/kg Melittin). Ultrasound was used to guide the injections into the rabbits' atrophied calf muscles following two weeks of immobilization via casting. Clinical measurements, including the length of the calf, the compound muscle action potential (CMAP) of the tibial nerve, and the gastrocnemius muscle thickness, were assessed. Additionally, cross-sectional slices of gastrocnemius muscle fibers were examined, and immunohistochemistry and Western blot analyses were performed following two weeks of therapy. The mean regenerative changes, as indicated by clinical parameters, in Group 4 were significantly more pronounced than in the other groups (p < 0.05). Furthermore, the cross-sectional area of the gastrocnemius muscle fibers and immunohistochemical indicators in Group 4 exceeded those in the remaining groups (p < 0.05). Western blot analysis also showed a more significant presence of anti-inflammatory and angiogenic cytokines in Group 4 compared to the others (p < 0.05). Melittin therapy at a higher dosage can more efficiently activate regeneration in atrophied gastrocnemius muscle compared to lower doses of Melittin or normal saline.

Oleocanthal Protects C2C12 Myotubes against the Pro-Catabolic and Anti-Myogenic Action of Stimuli Able to Induce Muscle Wasting In Vivo.

Oleocanthal (OC) is a monophenol of extra-virgin olive oil (EVOO) endowed with antibiotic, cardioprotective and anticancer effects, among others, mainly in view of its antioxidant and anti-inflammatory properties. OC has been largely investigated in terms of its anticancer activity, in Alzheimer disease and in collagen-induced arthritis; however, the possibility that it can also affect muscle biology has been totally overlooked so far. This study is the first to describe that OC modulates alterations induced in C2C12 myotubes by stimuli known to induce muscle wasting in vivo, namely TNF-α, or in the medium conditioned by the C26 cachexia-inducing tumor (CM-C26). C2C12 myotubes were exposed to CM-C26 or TNF-α in the presence or absence of OC for 24 and 48 h and analyzed by immunofluorescence and Western blotting. In combination with TNF-α or CM-C26, OC was revealed to be able to restore both the myotube's original size and morphology and normal levels of both atrogin-1 and MuRF1. OC seems unable to impinge on the autophagic-lysosomal proteolytic system or protein synthesis. Modulations towards normal levels of the expression of molecules involved in myogenesis, such as Pax7, myogenin and MyHC, were also observed in the myotube cultures exposed to OC and TNF-α or CM-C26. In conclusion, the data presented here show that OC exerts a protective action in C2C12 myotubes exposed to TNF-α or CM-C26, with mechanisms likely involving the downregulation of ubiquitin-proteasome-dependent proteolysis and the partial relief of myogenic differentiation impairment.

Epigallocatechin gallate protects against fat and muscle atrophy in B16BL6 melanoma-bearing mice on a high-fat diet.

AIMS: Epidemiological evidence indicates that there is a substantial association between body mass index (BMI) and at least ten forms of cancer, including melanoma, and BMI imbalance contributes to the poor survival rate of cancer patients before and after therapy. Nevertheless, few pharmacological studies on models of obesity and cancer have been reported. In this study, we administered epigallocatechin gallate (EGCG) to B16BL6 tumor-bearing mice that received a high-fat diet (HFD) to examine its impact. METHODS: B16BL6 tumor-bearing mice were fed a HFD. Body weight and food intake were documented every week. We conducted a Western blot analysis to examine the protein levels in the tumor, gastrocnemius (GAS), and tibialis anterior (TA) muscles, as well as the inguinal and epididymal white adipose tissues (iWAT and eWAT). KEY FINDINGS: EGCG has been shown to have anti-cancer effects equivalent to those of cisplatin, a chemotherapy drug. Furthermore, EGCG protected against the loss of epidydimal white adipose tissue by regulating protein levels of lipolysis factors of adipose triglyceride lipase and hormone-sensitive lipase as well as WAT browning factors of uncoupling protein 1, as opposed to cisplatin. EGCG was shown to reduce the protein levels of muscular atrophy factors of muscle RING-finger protein-1, whereas cisplatin did not contribute to rescuing the atrophy of TA and GAS muscles. CONCLUSION: Taken together, our findings indicate that EGCG has a preventive effect against cachexia symptoms and has anti-cancer effects similar to those of cisplatin in tumor-bearing mice fed a high-fat diet.

Deciphering the Therapeutic Role of Lactate in Combating Disuse-Induced Muscle Atrophy: An NMR-Based Metabolomic Study in Mice.

Disuse muscle atrophy (DMA) is a significant healthcare challenge characterized by progressive loss of muscle mass and function resulting from prolonged inactivity. The development of effective strategies for muscle recovery is essential. In this study, we established a DMA mouse model through hindlimb suspension to evaluate the therapeutic potential of lactate in alleviating the detrimental effects on the gastrocnemius muscle. Using NMR-based metabolomic analysis, we investigated the metabolic changes in DMA-injured gastrocnemius muscles compared to controls and evaluated the beneficial effects of lactate treatment. Our results show that lactate significantly reduced muscle mass loss and improved muscle function by downregulating Murf1 expression, decreasing protein ubiquitination and hydrolysis, and increasing myosin heavy chain levels. Crucially, lactate corrected perturbations in four key metabolic pathways in the DMA gastrocnemius: the biosynthesis of phenylalanine, tyrosine, and tryptophan; phenylalanine metabolism; histidine metabolism; and arginine and proline metabolism. In addition to phenylalanine-related pathways, lactate also plays a role in regulating branched-chain amino acid metabolism and energy metabolism. Notably, lactate treatment normalized the levels of eight essential metabolites in DMA mice, underscoring its potential as a therapeutic agent against the consequences of prolonged inactivity and muscle wasting. This study not only advances our understanding of the therapeutic benefits of lactate but also provides a foundation for novel treatment approaches aimed at metabolic restoration and muscle recovery in conditions of muscle wasting.

Identifying the potential therapeutic effects of miR­6516 on muscle disuse atrophy.

Muscle atrophy is a debilitating condition with various causes; while aging is one of these causes, reduced engagement in routine muscle­strengthening activities also markedly contributes to muscle loss. Although extensive research has been conducted on microRNAs (miRNAs/miRs) and their associations with muscle atrophy, the roles played by miRNA precursors remain underexplored. The present study detected the upregulation of the miR­206 precursor in cell­free (cf)RNA from the plasma of patients at risk of sarcopenia, and in cfRNAs from the muscles of mice subjected to muscle atrophy. Additionally, a decline in the levels of the miR­6516 precursor was observed in mice with muscle atrophy. The administration of mimic­miR­6516 to mice immobilized due to injury inhibited muscle atrophy by targeting and inhibiting cyclin­dependent kinase inhibitor 1b (Cdkn1b). Based on these results, the miR­206 precursor appears to be a potential biomarker of muscle atrophy, whereas miR­6516 shows promise as a therapeutic target to alleviate muscle deterioration in patients with muscle disuse and atrophy.

Niacin supplementation attenuates the regression of three-dimensional capillary architecture in unloaded female rat skeletal muscle.

Inactivity can lead to muscle atrophy and capillary regression in skeletal muscle. Niacin (NA), known for inducing hypermetabolism, may help prevent this capillary regression. In this study involving adult female Sprague-Dawley rats, the animals were randomly assigned to one of four groups: control (CON), hindlimb unloading (HU), NA, and HU with NA supplementation (HU + NA). For a period of 2 weeks, the rats in the HU and HU + NA groups underwent HU, while those in the NA and HU + NA groups received NA (750 mg/kg) twice daily through oral administration. The results demonstrated that HU lowered capillary number, luminal diameter, and capillary volume, as well as decreased succinate dehydrogenase activity, slow fiber composition, and PGC-1α expression within the soleus muscle. However, NA supplementation prevented these alterations in capillary structure due to unloading by stimulating PGC-1α factors and inhibiting mitochondrial dysfunction. Therefore, NA supplementation could serve as a potential therapeutic approach for preserving the capillary network and mitochondrial metabolism of muscle fibers during periods of inactivity.

Differential effects of cholecalciferol and calcitriol on muscle proteolysis and oxidative stress in angiotensin II-induced C2C12 myotube atrophy.

Renin-angiotensin system activation contributes to skeletal muscle atrophy in aging individuals with chronic diseases. We aimed to explore the effects of cholecalciferol (VD3) and calcitriol (1,25VD3) on signaling of muscle proteolysis and oxidative stress in myotubes challenged with angiotensin II (AII). The mouse C2C12 myotubes were assigned to vehicle, AII, AII + VD3, AII + 1,25VD3, and AII + losartan groups. The expression levels of muscle-specific E3 ubiquitin ligase proteins, autophagy-related proteins, and oxidative stress markers were investigated. We demonstrated the diverse effects of VD3 and 1,25VD3 on AII-induced myotube atrophy. The myotube diameter was preserved by treatment with 100 nM VD3 and losartan, while 1 and 10 nM 1,25VD3 increased levels of FoxO3a, MuRF1, and atrogin-1 protein expression in myotubes exposed to AII. Treatment with AII + 10 nM 1,25VD3 resulted in the upregulation of LC3B-II, LC3B-II/LC3B-I, and mature cathepsin L, which are autophagic marker proteins. The p62/SQSTM1 protein was downregulated and vitamin D receptor was upregulated after treatment with AII + 10 nM 1,25VD3. A cellular redox imbalance was observed as AII + 10 nM 1,25VD3-induced reactive oxygen species and NADPH oxidase-2 overproduction, and these changes were associated with an inadequate response of antioxidant superoxide dismutase-1 and catalase proteins. Collectively, these findings provide a translational perspective on the role of vitamin D3 in alleviating muscle atrophy related to high levels of AII.

Exosomes in the pathogenesis and treatment of cancer-related cachexia.

Cancer-related cachexia is a metabolic syndrome characterized by weight loss, adipose tissue decomposition, and progressive skeletal muscle atrophy. It is a major complication of many advanced cancers and seriously affects the quality of life and survival of cancer patients. However, the specific molecules that mediate cancer-related cachexia remain elusive, and the fundamental cellular and molecular mechanisms associated with muscle atrophy and lipidolysis in cancer patients still need to be investigated. Exosomes, a newly discovered class of small extracellular vesicles that facilitate intercellular communication, have a significant role in the onset and development of various cancers. Studies have shown that exosomes play a role in the onset and progression of cancer-related cachexia by transporting active molecules such as nucleic acids and proteins. This review aimed to provide an overview of exosome developments in cancer-induced skeletal muscle atrophy and adipose tissue degradation. More importantly, exosomes were shown to have potential as diagnostic markers or therapeutic strategies for cachexia and were prospected, providing novel strategies for the diagnosis and treatment of cancer-related cachexia.

The crosstalk between macrophages and cancer cells potentiates pancreatic cancer cachexia.

With limited treatment options, cachexia remains a major challenge for patients with cancer. Characterizing the interplay between tumor cells and the immune microenvironment may help identify potential therapeutic targets for cancer cachexia. Herein, we investigate the critical role of macrophages in potentiating pancreatic cancer induced muscle wasting via promoting TWEAK (TNF-like weak inducer of apoptosis) secretion from the tumor. Specifically, depletion of macrophages reverses muscle degradation induced by tumor cells. Macrophages induce non-autonomous secretion of TWEAK through CCL5/TRAF6/NF-κB pathway. TWEAK promotes muscle atrophy by activating MuRF1 initiated muscle remodeling. Notably, tumor cells recruit and reprogram macrophages via the CCL2/CCR2 axis and disrupting the interplay between macrophages and tumor cells attenuates muscle wasting. Collectively, this study identifies a feedforward loop between pancreatic cancer cells and macrophages, underlying the non-autonomous activation of TWEAK secretion from tumor cells thereby providing promising therapeutic targets for pancreatic cancer cachexia.

LSD1 inhibition circumvents glucocorticoid-induced muscle wasting of male mice.

Synthetic glucocorticoids (GC), such as dexamethasone, are extensively used to treat chronic inflammation and autoimmune disorders. However, long-term treatments are limited by various side effects, including muscle atrophy. GC activities are mediated by the glucocorticoid receptor (GR), that regulates target gene expression in various tissues in association with cell-specific co-regulators. Here we show that GR and the lysine-specific demethylase 1 (LSD1) interact in myofibers of male mice, and that LSD1 connects GR-bound enhancers with NRF1-associated promoters to stimulate target gene expression. In addition, we unravel that LSD1 demethylase activity is required for triggering starvation- and dexamethasone-induced skeletal muscle proteolysis in collaboration with GR. Importantly, inhibition of LSD1 circumvents muscle wasting induced by pharmacological levels of dexamethasone, without affecting their anti-inflammatory activities. Thus, our findings provide mechanistic insights into the muscle-specific GC activities, and highlight the therapeutic potential of targeting GR co-regulators to limit corticotherapy-induced side effects.

The role of mitochondrial dynamics and mitophagy in skeletal muscle atrophy: from molecular mechanisms to therapeutic insights.

Skeletal muscle is the largest metabolic organ of the human body. Maintaining the best quality control and functional integrity of mitochondria is essential for the health of skeletal muscle. However, mitochondrial dysfunction characterized by mitochondrial dynamic imbalance and mitophagy disruption can lead to varying degrees of muscle atrophy, but the underlying mechanism of action is still unclear. Although mitochondrial dynamics and mitophagy are two different mitochondrial quality control mechanisms, a large amount of evidence has indicated that they are interrelated and mutually regulated. The former maintains the balance of the mitochondrial network, eliminates damaged or aged mitochondria, and enables cells to survive normally. The latter degrades damaged or aged mitochondria through the lysosomal pathway, ensuring cellular functional health and metabolic homeostasis. Skeletal muscle atrophy is considered an urgent global health issue. Understanding and gaining knowledge about muscle atrophy caused by mitochondrial dysfunction, particularly focusing on mitochondrial dynamics and mitochondrial autophagy, can greatly contribute to the prevention and treatment of muscle atrophy. In this review, we critically summarize the recent research progress on mitochondrial dynamics and mitophagy in skeletal muscle atrophy, and expound on the intrinsic molecular mechanism of skeletal muscle atrophy caused by mitochondrial dynamics and mitophagy. Importantly, we emphasize the potential of targeting mitochondrial dynamics and mitophagy as therapeutic strategies for the prevention and treatment of muscle atrophy, including pharmacological treatment and exercise therapy, and summarize effective methods for the treatment of skeletal muscle atrophy.

The role of TGF-ß signaling in muscle atrophy, sarcopenia and cancer cachexia.

Skeletal muscle, comprising a significant proportion (40 to 50 percent) of total body weight in humans, plays a critical role in maintaining normal physiological conditions. Muscle atrophy occurs when the rate of protein degradation exceeds protein synthesis. Sarcopenia refers to age-related muscle atrophy, while cachexia represents a more complex form of muscle wasting associated with various diseases such as cancer, heart failure, and AIDS. Recent research has highlighted the involvement of signaling pathways, including IGF1-Akt-mTOR, MuRF1-MAFbx, and FOXO, in regulating the delicate balance between muscle protein synthesis and breakdown. Myostatin, a member of the TGF-ß superfamily, negatively regulates muscle growth and promotes muscle atrophy by activating Smad2 and Smad3. It also interacts with other signaling pathways in cachexia and sarcopenia. Inhibition of myostatin has emerged as a promising therapeutic approach for sarcopenia and cachexia. Additionally, other TGF-ß family members, such as TGF-ß1, activin A, and GDF11, have been implicated in the regulation of skeletal muscle mass. Furthermore, myostatin cooperates with these family members to impair muscle differentiation and contribute to muscle loss. This review provides an overview of the significance of myostatin and other TGF-ß signaling pathway members in muscular dystrophy, sarcopenia, and cachexia. It also discusses potential novel therapeutic strategies targeting myostatin and TGF-ß signaling for the treatment of muscle atrophy.

Taurine Rescues Cancer-induced Atrophy in Human Skeletal Muscle Cells via Ameliorating the Inflammatory Tumor Microenvironment.

BACKGROUND/AIM: Cancer cachexia is a wasting syndrome that has a devastating impact on the prognosis of patients with cancer. It is well-documented that pro-inflammatory cytokines are involved in the progression of this disorder. Therefore, this study was conducted to investigate the protective effect of taurine, an essential nonprotein amino acid with great anti-inflammatory properties, in attenuating muscle atrophy induced by cancer. MATERIALS AND METHODS: Conditioned media (CM) derived from T24 human bladder carcinoma cells with or without 5 mM taurine were incubated with human skeletal muscle cells (HSkMCs) and their differentiation was examined. The intracellular reactive oxygen species (ROS), morphology, and the catabolic pathway were monitored. RESULTS: T24-derived CM with high levels of TNF-α and IL-6 caused aberrant ROS accumulation and formation of atrophic myotubes by HSkMCs. In T24 cancer cells, taurine significantly inhibited the production of TNF-α and IL-6. In HSkMCs, taurine increased ROS clearance during differentiation and preserved the myotube differentiation ability impaired by the inflammatory tumor microenvironment. In addition, taurine ameliorated myotube atrophy by regulating the Akt/FoxO1/MuRF1 and MAFbx signaling pathways. CONCLUSION: Taurine rescues cancer-induced atrophy in human skeletal muscle cells by ameliorating the inflammatory tumor microenvironment. Taurine supplementation may be a promising approach for intervening with the progression of cancer cachexia.

Photobiomodulation therapy moderates cancer cachexia-associated muscle wasting through activating PI3K/AKT/FoxO3a pathway.

Cancer cachexia-associated muscle wasting as a multifactorial wasting syndrome, is an important factor affecting the long-term survival rate of tumor patients. Photobiomodulation therapy (PBMT) has emerged as a promising tool to cure and prevent many diseases. However, the effect of PBMT on skeletal muscle atrophy during cancer progression has not been fully demonstrated yet. Here, we found PBMT alleviated the atrophy of myotube diameter induced by cancer cells in vitro, and prevented cancer-associated muscle atrophy in mice bearing tumor. Mechanistically, the alleviation of muscle wasting by PBMT was found to be involved in inhibiting E3 ubiquitin ligases MAFbx and MuRF-1. In addition, transcriptomic analysis using RNA-seq and GSEA revealed that PI3K/AKT pathway might be involved in PBMT-prevented muscle cachexia. Next, we showed the protective effect of PBMT against muscle cachexia was totally blocked by AKT inhibitor in vitro and in vivo. Moreover, PBMT-activated AKT promoted FoxO3a phosphorylation and thus inhibiting the nucleus entry of FoxO3a. Lastly, in cisplatin-treated muscle cachexia model, PBMT had also been shown to ameliorate muscle atrophy through enhancing PI3K/AKT pathway to suppress MAFbx and MuRF-1 expression. These novel findings revealed that PBMT could be a promising therapeutic approach in treating muscle cachexia induced by cancer.

Caffeic acid alleviates skeletal muscle atrophy in 5/6 nephrectomy rats through the TLR4/MYD88/NF-kB pathway.

Skeletal muscle atrophy is a common complication of chronic kidney disease (CKD) that affects the quality of life and prognosis of patients. We aimed to investigate the effects and mechanisms of caffeic acid (CA), a natural phenolic compound, on skeletal muscle atrophy in CKD rats. Male Sprague-Dawley rats underwent 5/6 nephrectomy (NPM) and were treated with CA (20, 40, or 80 mg/kg/day) for 10 weeks. The body and muscle weights, renal function, hemoglobin, and albumin were measured. The histological, molecular, and biochemical changes in skeletal muscles were evaluated using hematoxylin-eosin staining, quantitative real-time PCR, malondialdehyde/catalase/superoxide dismutase/glutathione level detection, and enzyme-linked immunosorbent assay. Western blotting and network pharmacology were applied to identify the potential targets and pathways of CA, CKD, and muscle atrophy. The results showed that CA significantly improved NPM-induced muscle-catabolic effects, reduced the expression of muscle atrophy-related proteins (muscle atrophy F-box and muscle RING finger 1) and proinflammatory cytokines (interleukin [IL]-6, tumor necrosis factor-alpha, and IL-1ß), and attenuated muscle oxidative stress. Network pharmacology revealed that CA modulated the response to oxidative stress and nuclear factor kappa B (NF-κB) signaling pathway and that Toll-like receptor 4 (TLR4) was a key target. In vivo experiment confirmed that CA inhibited the TLR4/myeloid differentiation primary response 88 (MYD88)/NF-kB signaling pathway, reduced muscle iron levels, and restored glutathione peroxidase 4 activity, thereby alleviating ferroptosis and inflammation in skeletal muscles. Thus, CA might be a promising therapeutic agent for preventing and treating skeletal muscle atrophy in CKD by modulating the TLR4/MYD88/NF-κB pathway and ferroptosis.

Oncostatin M signaling drives cancer-associated skeletal muscle wasting.

Progressive weakness and muscle loss are associated with multiple chronic conditions, including muscular dystrophy and cancer. Cancer-associated cachexia, characterized by dramatic weight loss and fatigue, leads to reduced quality of life and poor survival. Inflammatory cytokines have been implicated in muscle atrophy; however, available anticytokine therapies failed to prevent muscle wasting in cancer patients. Here, we show that oncostatin M (OSM) is a potent inducer of muscle atrophy. OSM triggers cellular atrophy in primary myotubes using the JAK/STAT3 pathway. Identification of OSM targets by RNA sequencing reveals the induction of various muscle atrophy-related genes, including Atrogin1. OSM overexpression in mice causes muscle wasting, whereas muscle-specific deletion of the OSM receptor (OSMR) and the neutralization of circulating OSM preserves muscle mass and function in tumor-bearing mice. Our results indicate that activated OSM/OSMR signaling drives muscle atrophy, and the therapeutic targeting of this pathway may be useful in preventing muscle wasting.

Dietary supplementation with Lacticaseibacillus rhamnosus IDCC3201 alleviates sarcopenia by modulating the gut microbiota and metabolites in dexamethasone-induced models.

Probiotics can exert direct or indirect influences on various aspects of health claims by altering the composition of the gut microbiome and producing bioactive metabolites. The aim of this study was to examine the effect of Lacticaseibacillus rhamnosus IDCC3201 on skeletal muscle atrophy in dexamethasone-induced C2C12 cells and a mouse animal model. Dexamethasone treatment significantly reduced C2C12 muscle cell viability, myotube diameter, and levels of muscle atrophic markers (Atrogin-1 and MuRF-1). These effects were alleviated by conditioned media (CM) and cell extract (EX) derived from L. rhamnosus IDCC3201. In addition, we assessed the in vivo therapeutic effect of L. rhamnosus IDCC3201 in a mouse model of dexamethasone (DEX)-induced muscle atrophy. Supplementation with IDCC3201 resulted in significant enhancements in body composition, particularly in lean mass, muscle strength, and myofibril size, in DEX-induced muscle atrophy mice. In comparison to the DEX-treatment group, the normal and DEX + L. rhamnosus IDCC3201 groups showed a higher transcriptional level of myosin heavy chain family genes (MHC1, MHC1b, MHC2A, 2bB, and 2X) and a reduction in atrophic muscle makers. These analyses revealed that L. rhamnosus IDCC3201 supplementation led to increased production of branched-chain amino acids (BCAAs) and improved the Allobaculum genus within the gut microbiota of muscle atrophy-induced groups. Taken together, our findings suggest that L. rhamnosus IDCC3201 represents a promising dietary supplement with the potential to alleviate sarcopenia by modulating the gut microbiome and metabolites.