Myostatin regulates the fibrogenic phenotype of hepatic stellate cells via c-jun N-terminal kinase activation

Delogu, W.; Caligiuri, Alessandra; Provenzano, A.; Rosso, Chiara; Bugianesi, Elisabetta; Coratti, Andrea; Macías-Barragán, José; Galastri, Sara; Maira, Giovanni Di; Marra, Fabio

doi:10.1016/j.dld.2019.03.002

Cited by 38 publications

(37 citation statements)

References 44 publications

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“…Whether therapeutic trials aimed at the reduction of the IL-6 activity, such as endurance exercise or anti-IL-6 antibodies, may be beneficial for cancer associated sarcopenia in humans need to be studied further. 47 In the aspect of HCC as the ultimate outcome of liver fibrosis, IL-6 has a profibrogenic role, and myostatin seems to be fibrogenic, 48 while follistatin may attenuate fibrosis, 37 which warrants further studies. There are some limitations in this study.…”

Section: Discussionmentioning

confidence: 99%

The association of the serum levels of myostatin, follistatin, and interleukin-6 with sarcopenia, and their impacts on survival in patients with hepatocellular carcinoma

et al. 2020

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Background/Aims: The role of serum myokine levels in sarcopenia and the outcome of hepatocellular carcinoma (HCC) patients are not clear. This study investigated the serum levels of myostatin, follistatin, and interleukin-6 (IL-6) in HCC patients and their association with sarcopenia and survival.Methods: Using prospectively collected pretreatment samples from 238 HCC patients in a hospital from 2012 to 2015, the serum levels of 3 myokines were determined and compared to 50 samples from age and sex-matched healthy controls. Sarcopenia was evaluated using the psoas muscle index (PMI) measured at the third lumbar level in the computed tomography, and clinical data were collected until 2017.Results: The median levels of the 3 myokines for the male and female HCC patients were as follow: myostatin (3,979.3 and 2,976.3 pg/mL), follistatin (2,118.5 and 2,174.6 pg/mL), and IL-6 (2.5 and 2.7 pg/mL), respectively. Those in the HCC patients were all significantly higher than in the healthy controls. In the HCC patient, the median PMI was 4.43 (males) and 2.17 cm<sup>2</sup>/m<sup>2</sup> (females) with a sarcopenic prevalence of 56.4%. The serum levels of myostatin, IL-6 and follistatin in the HCC patients showed a positive, negative, and no correlation with PMI, respectively. The serum follistatin level was an independent factor for poor survival in HCC patients.Conclusions: The serum levels of myostatin, follistatin, and IL-6 and their correlation with sarcopenia and survival were presented in HCC patients for the first time. The role of the serum follistatin level as a poor prognostic biomarker warrants further study.

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Section: Discussionmentioning

confidence: 99%

The association of the serum levels of myostatin, follistatin, and interleukin-6 with sarcopenia, and their impacts on survival in patients with hepatocellular carcinoma

et al. 2020

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“…reported that exercise is effective for improving liver stiffness in patients with NAFLD . Although the causal relationship between exercise and hepatic fibrosis remains unclear, myokines, including myostatin and irisin, are known to be involved in the regulation of hepatic fibrogenesis . As exercise regulates expression of these myokines, exercise might suppress progression of hepatic fibrosis through alterations in myokines.…”

Section: Discussionmentioning

confidence: 99%

“…36,37 Although the causal relationship between exercise and hepatic fibrosis remains unclear, myokines, including myostatin and irisin, are known to be involved in the regulation of hepatic fibrogenesis. 38,39 As exercise regulates expression of these myokines, 40,41 exercise might suppress progression of hepatic fibrosis through alterations in myokines. In addition, aging and physical inactivity are associated with inflammation, which causes the progression of hepatic fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Profiles of advanced hepatic fibrosis evaluated by FIB‐4 index and shear wave elastography in health checkup examinees

Yamamura

Kawaguchi

Nakano

et al. 2019

Hepatology Research

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Aim Advanced hepatic fibrosis is seen in individuals with potential hepatocellular carcinoma and cardiovascular disease. Hepatic fibrosis can be assessed using a combination of the FIB‐4 index and imaging modalities, including shear wave elastography. We aimed to investigate the prevalence of advanced fibrosis in the general population and the profiles associated with advanced fibrosis using a data‐mining analysis. Methods We enrolled 1155 health checkup examinees (median age 53 years, 685 women, 470 male). Advanced fibrosis was defined by FIB‐4 index ≥1.3 and liver stiffness ≥8.07 kPa using shear wave elastography. Participants were classified as normal‐mild fibrosis (n = 1035) or advanced fibrosis (n = 120). Factors associated with advanced fibrosis were analyzed by logistic regression and decision‐tree analyses. Results Advanced fibrosis was observed in 10.4% of participants (120/1155). In the logistic regression analysis, independent factors for advanced fibrosis were age (≥75 years; OR 2.12, 95% CI 1.021–4.415; P = 0.0419) and the presence of metabolic syndrome (OR 2.51, 95% CI 1.416–4.462; P = 0.0017). The decision‐tree analysis showed two profiles associated with advanced fibrosis: profile 1 – individuals aged ≥65 years with metabolic syndrome and mild‐to‐moderate alcohol consumption (prevalence of advanced fibrosis 73.3%); and profile 2 – individuals without metabolic syndrome, aged ≥75 years, with no exercise habit (prevalence of advanced fibrosis 56.3%). Conclusions Advanced fibrosis was observed in 10.4% of health checkup examinees. Furthermore, we showed that aging, metabolic syndrome with mild‐to‐moderate alcohol consumption, and physical inactivity were associated with advanced fibrosis. Thus, prevention of metabolic syndrome and alcohol withdrawal, as well as exercise habits, might inhibit the progression of hepatic fibrosis.

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“…The possible mechanism of high myostatin levels being significantly associated with HCC development can be explained by a direct link between myostatin and hepatic fibrogenesis. Myostatin activates a fibrotic progression via C-Jun N-terminal kinase activation or NF-κB-dependent activation: The muscle-liver axis ( Supplementary Figure S1 ) [ 11 , 32 , 33 , 34 , 35 ]. Given that ongoing hepatic fibrosis is an important factor for HCC development [ 36 ], high myostatin levels in high-risk patients activate fibrotic progression and likely play a role in HCC development.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, preclinical studies showed that myostatin expression was significantly increased in different tumor tissues and could block cancer cell death by regulating mitochondrial metabolism [ 10 ]. Myostatin aggravates hepatic fibrosis through activation of hepatic stellate cells via c-Jun n-terminal kinase activation [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Serum Myostatin Predicts the Risk of Hepatocellular Carcinoma in Patients with Alcoholic Cirrhosis: A Multicenter Study

Kim

Kang

Lee

et al. 2020

Cancers

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Background and Aim: Previous studies reported that serum myostatin is associated with sarcopenia. We aimed to elucidate the association between serum myostatin levels and hepatocellular carcinoma (HCC) development in patients with alcoholic liver cirrhosis (ALC). Methods: This retrospective, multicenter study assessed 1077 Asian ALC patients enrolled from 2007 to 2017. The primary endpoint was the development of HCC within 5 years. Cox proportional hazards model analyses were used to assess the association of serum myostatin levels and HCC development. The time-dependent areas under the receiver operating characteristic curve (AUROC) of serum myostatin for 5-year HCC development were calculated. Serum myostatin levels were measured using an enzyme-linked immunosorbent assay with samples collected on the index date. Results: During a median follow-up of 2.5 years, 5-year cumulative HCC incidence rates were 6.7% in the total population. The median level of serum myostatin was 3.3 ng/mL (interquartile, 2.1–5.2 ng/mL). The AUROC of serum myostatin for 5-year HCC development was 0.78 (95% confidence interval [CI], 0.76–0.81). In Cox proportional hazards model analyses, age, gender, platelet counts, and serum myostatin levels were independent risk factors for HCC development (adjusted hazard ratios [HRs] of age, male gender, platelet counts, and serum myostatin: 1.03, 2.79, 0.996, 1.18, respectively; all p < 0.05). Patients with high myostatin levels had a significantly higher risk of 5-year HCC development than those with low myostatin levels (HR 7.53, p < 0.001). Conclusion: Higher serum myostatin levels were significantly associated with a higher risk of developing HCC in ALC patients, which could identify high-risk patients who need stringent surveillance.

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Myostatin regulates the fibrogenic phenotype of hepatic stellate cells via c-jun N-terminal kinase activation

Cited by 38 publications

References 44 publications

The association of the serum levels of myostatin, follistatin, and interleukin-6 with sarcopenia, and their impacts on survival in patients with hepatocellular carcinoma

The association of the serum levels of myostatin, follistatin, and interleukin-6 with sarcopenia, and their impacts on survival in patients with hepatocellular carcinoma

Profiles of advanced hepatic fibrosis evaluated by FIB‐4 index and shear wave elastography in health checkup examinees

Serum Myostatin Predicts the Risk of Hepatocellular Carcinoma in Patients with Alcoholic Cirrhosis: A Multicenter Study

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