Characterization of the gut-liver-muscle axis in cirrhotic patients with sarcopenia.
Ponziani Francesca Romana,Picca Anna,Marzetti Emanuele,Calvani Riccardo,Conta Giorgia,Del Chierico Federica,Capuani Giorgio,Faccia Mariella,Fianchi Francesca,Funaro Barbara,Josè Coelho-Junior Helio,Petito Valentina,Rinninella Emanuele,Paroni Sterbini Francesco,Reddel Sofia,Vernocchi Pamela,Cristina Mele Maria,Miccheli Alfredo,Putignani Lorenza,Sanguinetti Maurizio,Pompili Maurizio,Gasbarrini Antonio,
Liver international : official journal of the International Association for the Study of the Liver
BACKGROUND & AIM:Sarcopenia is frequent in cirrhosis and is associated with unfavourable outcomes. The role of the gut-liver-muscle axis in this setting has been poorly investigated. The aim of this study was to identify gut microbiota, metabolic and inflammatory signatures associated with sarcopenia in cirrhotic patients. METHODS:Fifty cirrhotic patients assessed for the presence of sarcopenia by the quantification of muscle mass and strength were compared with age- and sex-matched controls. A multiomic analysis, including gut microbiota composition and metabolomics, serum myokines and systemic and intestinal inflammatory mediators, was performed. RESULTS:The gut microbiota of sarcopenic cirrhotic patients was poor in bacteria associated with physical function (Methanobrevibacter, Prevotella and Akkermansia), and was enriched in Eggerthella, a gut microbial marker of frailty. The abundance of potentially pathogenic bacteria, such as Klebsiella, was also increased, to the detriment of autochthonous ones. Sarcopenia was associated with elevated serum levels of pro-inflammatory mediators and of fibroblast growth factor 21 (FGF21) in cirrhotic patients. Gut microbiota metabolic pathways involved in amino acid, protein and branched-chain amino acid metabolism were up-regulated, in addition to ethanol, trimethylamine and dimethylamine production. Correlation networks and clusters of variables associated with sarcopenia were identified, including one centred on Klebsiella/ethanol/FGF21/Eggerthella/Prevotella. CONCLUSIONS:Alterations in the gut-liver-muscle axis are associated with sarcopenia in patients with cirrhosis. Detrimental but also compensatory functions are involved in this complex network.
10.1111/liv.14876
HMGB1/autophagy pathway mediates the atrophic effect of TGF-β1 in denervated skeletal muscle.
Yang Xiaofan,Xue Pingping,Liu Xin,Xu Xiang,Chen Zhenbing
Cell communication and signaling : CCS
BACKGROUND:Transforming growth factor beta 1 (TGF-β1) is a classical modulator of skeletal muscle and regulates several processes, such as myogenesis, regeneration and muscle function in skeletal muscle diseases. Skeletal muscle atrophy, characterized by the loss of muscle strength and mass, is one of the pathological conditions regulated by TGF-β1, but the underlying mechanism involved in the atrophic effects of TGF-β1 is not fully understood. METHODS:Mice sciatic nerve transection model was created and gastrocnemius were analysed by western blot, immunofluorescence staining and fibre diameter quantification after 2 weeks. Exogenous TGF-β1 was administrated and high-mobility group box-1 (HMGB1), autophagy were blocked by siRNA and chloroquine (CQ) respectively to explore the mechanism of the atrophic effect of TGF-β1 in denervated muscle. Similar methods were performed in C2C12 cells. RESULTS:We found that TGF-β1 was induced in denervated muscle and it could promote atrophy of skeletal muscle both in vivo and in vitro, up-regulated HMGB1 and increased autophagy activity were also detected in denervated muscle and were further promoted by exogenous TGF-β1. The atrophic effect of TGF-β1 could be inhibited when HMGB1/autophagy pathway was blocked. CONCLUSIONS:Thus, our data revealed that TGF-β1 is a vital regulatory factor in denervated skeletal muscle in which HMGB1/ autophagy pathway mediates the atrophic effect of TGF-β1. Our findings confirmed a new pathway in denervation-induced skeletal muscle atrophy and it may be a novel therapeutic target for patients with muscle atrophy after peripheral nerve injury.
10.1186/s12964-018-0310-6
Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member.
McPherron A C,Lawler A M,Lee S J
Nature
The transforming growth factor-beta (TGF-beta) superfamily encompasses a large group of growth and differentiation factors playing important roles in regulating embryonic development and in maintaining tissue homeostasis in adult animals. Using degenerate polymerase chain reaction, we have identified a new murine TGF-beta family member, growth/differentiation factor-8 (GDF-8), which is expressed specifically in developing and adult skeletal muscle. During early stages of embryogenesis, GDF-8 expression is restricted to the myotome compartment of developing somites. At later stages and in adult animals, GDF-8 is expressed in many different muscles throughout the body. To determine the biological function of GDF-8, we disrupted the GDF-8 gene by gene targeting in mice. GDF-8 null animals are significantly larger than wild-type animals and show a large and widespread increase in skeletal muscle mass. Individual muscles of mutant animals weigh 2-3 times more than those of wild-type animals, and the increase in mass appears to result from a combination of muscle cell hyperplasia and hypertrophy. These results suggest that GDF-8 functions specifically as a negative regulator of skeletal muscle growth.
10.1038/387083a0
The Hippo Pathway: Biology and Pathophysiology.
Ma Shenghong,Meng Zhipeng,Chen Rui,Guan Kun-Liang
Annual review of biochemistry
The Hippo pathway was initially discovered in as a key regulator of tissue growth. It is an evolutionarily conserved signaling cascade regulating numerous biological processes, including cell growth and fate decision, organ size control, and regeneration. The core of the Hippo pathway in mammals consists of a kinase cascade, MST1/2 and LATS1/2, as well as downstream effectors, transcriptional coactivators YAP and TAZ. These core components of the Hippo pathway control transcriptional programs involved in cell proliferation, survival, mobility, stemness, and differentiation. The Hippo pathway is tightly regulated by both intrinsic and extrinsic signals, such as mechanical force, cell-cell contact, polarity, energy status, stress, and many diffusible hormonal factors, the majority of which act through G protein-coupled receptors. Here, we review the current understanding of molecular mechanisms by which signals regulate the Hippo pathway with an emphasis on mechanotransduction and the effects of this pathway on basic biology and human diseases.
10.1146/annurev-biochem-013118-111829
Targeting TGF-β signal transduction for fibrosis and cancer therapy.
Molecular cancer
Transforming growth factor β (TGF-β) has long been identified with its intensive involvement in early embryonic development and organogenesis, immune supervision, tissue repair, and adult homeostasis. The role of TGF-β in fibrosis and cancer is complex and sometimes even contradictory, exhibiting either inhibitory or promoting effects depending on the stage of the disease. Under pathological conditions, overexpressed TGF-β causes epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) deposition, cancer-associated fibroblast (CAF) formation, which leads to fibrotic disease, and cancer. Given the critical role of TGF-β and its downstream molecules in the progression of fibrosis and cancers, therapeutics targeting TGF-β signaling appears to be a promising strategy. However, due to potential systemic cytotoxicity, the development of TGF-β therapeutics has lagged. In this review, we summarized the biological process of TGF-β, with its dual role in fibrosis and tumorigenesis, and the clinical application of TGF-β-targeting therapies.
10.1186/s12943-022-01569-x
Anti-fibrotic effects of branched-chain amino acids on hepatic stellate cells.
Lee Hae Lim,Lee Jungmin,Cha Jung Hoon,Cho Sungwoo,Sung Pil Soo,Hur Wonhee,Yoon Seung Kew,Bae Si Hyun
The Korean journal of internal medicine
BACKGROUND/AIMS:Patients with liver cirrhosis (LC) have low levels of branched-chain amino acids (BCAAs). There is accumulating evidence that BCAAs have anti- fibrotic effects in cirrhosis. This study is aimed to evaluate the effect of BCAAs on the function and phenotype of activated hepatic stellate cells (HSCs). METHODS:LX-2, an immortalized human stellate cell line, was used in in vitro experiments. LX-2 cells were exposed to transforming growth factor β1 (TGF-β1) and BCAAs or to valine, leucine, and isoleucine, which are components of BCAAs. Activation of the TGF-β signaling pathway in LX-2 cells was observed using real-time quantitative polymerase chain reaction and Western blotting. RESULTS:The increased expression of snail family transcriptional repressor 1 (SNAI1) was observed in LX-2 cells activated by TGF-β1. After BCAA treatment, its expression was significantly decreased at the mRNA level. The increased expression of Col1α1 and TIMP2 at the mRNA level and alpha smooth muscle actin at the protein level in activated LX-2 cells decreased after BCAA treatment. Among the BCAA components, leucine and valine significantly abrogated TGF-β-induced activation of LX-2 cells. BCAA treatment led to the decreased phosphorylation of Smad2 and p38 proteins, which are markers for Smad and Smad-independent p38 mitogen-activated protein kinase signaling pathways, respectively. CONCLUSION:BCAA treatment can improve hepatic fibrosis by directly affecting the activated state of hepatic stellate cells through inhibition of the TGF-β signaling pathway. Among BCAA components, leucine and valine mainly abrogated TGF-β-induced activation of HSCs. Our results suggest that BCAA may be used to attenuate the progression of liver fibrosis.
10.3904/kjim.2020.197
Gut microbiota-bile acid-skeletal muscle axis.
Trends in microbiology
The gut microbiota represents a 'metabolic organ' that can regulate human metabolism. Intact gut microbiota contributes to host homeostasis, whereas compositional perturbations, termed dysbiosis, are associated with a wide range of diseases. Recent evidence demonstrates that dysbiosis, and the accompanying loss of microbiota-derived metabolites, results in a substantial alteration of skeletal muscle metabolism. As an example, bile acids, produced in the liver and further metabolized by intestinal microbiota, are of considerable interest since they regulate several host metabolic pathways by activating nuclear receptors, including the farnesoid X receptor (FXR). Indeed, alteration of gut microbiota may lead to skeletal muscle atrophy via a bile acid-FXR pathway. This Review aims to suggest a new pathway that connects different mechanisms, involving the gut-muscle axis, that are often seen as unrelated, and, starting from preclinical studies, we hypothesize new strategies aimed at optimizing skeletal muscle functionality.
10.1016/j.tim.2022.10.003
EPA and DHA promote cell proliferation and enhance activity of the Akt-TOR-S6K anabolic signaling pathway in primary muscle cells of turbot (Scophthalmus maximus L.).
Fish physiology and biochemistry
Fish growth and health are predominantly governed by dietary nutrient supply. Although the beneficial effects of omega-3 polyunsaturated fatty acids supplementation have been shown in a number of fish species, the underlying mechanisms are still mostly unknown. In this study, we conducted an investigation into the effects of EPA and DHA on cell proliferation, nutrient sensing signaling, and branched-chain amino acids (BCAA) transporting in primary turbot muscle cells. The findings revealed that EPA and DHA could stimulate cell proliferation, promote protein synthesis and inhibit protein degradation through activation of target of rapamycin (TOR) signaling pathway, a pivotal nutrient-sensing signaling cascade. While downregulating the expression of myogenin and myostatin, EPA and DHA increased the level of myogenic regulatory factors, such as myoD and follistatin. Furthermore, we observed a significant increase in the concentrations of intracellular BCAAs following treatment with EPA or DHA, accompanied by an upregulation of the associated amino acid transporters. Our study providing valuable insights into the mechanisms underlying the growth-promoting effects of omega-3 fatty acids in fish.
10.1007/s10695-024-01351-4
Effects of branched-chain amino acid supplementation and resistance training in postmenopausal women.
Bagheri Reza,Forbes Scott C,Candow Darren G,Wong Alexei
Experimental gerontology
BACKGROUND:The age-related loss in muscular function is typically accelerated after menopause. Resistance training (RT) has been shown to increase muscle mass and strength in postmenopausal women. Branched-chain amino acid (BCAA) supplementation acutely increases myofibrillar protein synthesis (MPS) and decreases muscle soreness following RT. However, the combined effects of BCAA supplementation and RT on muscle mass, strength, and regulatory factors on postmenopausal cohorts are currently unknown. The purpose of this study was to explore the combined effects of BCAA supplementation and RT on muscle mass, strength, and regulatory factors in postmenopausal women. METHODS:Thirty postmenopausal women were randomly assigned to one of three conditions: RT and placebo (PLA; n = 10), RT and BCAA (BCAA; 9 g/day; n = 10), or control (CON; n = 10). Muscle mass, strength, and serum concentrations of muscle regulatory factors (myostatin, follistatin, and insulin-like growth factor-1 [IGF-1]) were assessed before and following 8 weeks of whole-body supervised RT (3×/week, 3-4 sets using 60-75% 1-repetition maximum [1-RM]). RESULTS:There were significant increases (P < 0.05) in muscle mass and strength in both the PLA and BCAA conditions. Additionally, myostatin significantly (P < 0.05) decreased, while IGF-1 (P < 0.05) increased following PLA and BCAA. However, follistatin significantly increased in the BCAA condition. There were no differences between RT conditions over time. Furthermore, there were no changes in any variable after CON. CONCLUSIONS:Short-term (8 weeks) RT is an effective intervention for improving muscle mass, strength, and muscle regulatory factors in postmenopausal women. The addition of BCAA supplementation to RT failed to augment these physiological changes.
10.1016/j.exger.2020.111185