Arginase 1 expression is increased during hepatic stellate cell activation and facilitates collagen synthesis.

Activation of hepatic stellate cells (HSC) is a key event in the initiation of liver fibrosis. Activated HSCs proliferate and secrete excessive amounts of extracellular matrix (ECM), disturbing liver architecture and function, leading to fibrosis and eventually cirrhosis. Collagen is the most abundant constituent of ECM and proline is the most abundant amino acid of collagen. Arginine is the precursor in the biosynthetic pathway of proline. Arginine is the exclusive substrate of both nitric oxide synthase (NOS) and arginase. NOS is an M1 (proinflammatory) marker of macrophage polarization whereas arginase-1 (Arg1) is an M2 (profibrogenic) marker of macrophage polarization. Differential expression of NOS and Arg1 has not been studied in HSCs yet. To identify the expression profile of arginine catabolic enzymes during HSC activation and to investigate their role in HSC activation, primary rat HSCs were cultured-activated for 7 days and expression of iNOS and Arg1 were investigated. Nor-NOHA was used as a specific and reversible arginase inhibitor. During HSC activation, iNOS expression decreased whereas Arg1 expression increased. Inhibition of Arg1 in activated HSCs efficiently inhibited collagen production but not cell proliferation. HSC activation is accompanied by a switch of arginine catabolism from iNOS to Arg1. Inhibition of Arg1 decreases collagen synthesis. Therefore, we conclude that Arg1 can be a therapeutic target for the inhibition of liver fibrogenesis.

Efficacy of high-intensity interval- or continuous aerobic-training on insulin resistance and muscle function in adults with metabolic syndrome: a clinical trial.

PURPOSE: We carried out a randomized, clinical trial in adults of both sexes with metabolic syndrome (MS) to assess the efficacy of high-intensity, low-volume interval training (HIIT) compared to moderate-intensity continuous training (MICT) on insulin resistance (IR), muscle mass, muscle activation, and serum musclin. METHODS: Fasting glycemia, insulinemia, and glycated haemoglobin were determined by conventional methods, IR by Homeostatic model assessment (HOMA), lean mass by Dual-Energy X-ray Absorptiometry, muscle activation through carnosine by Proton Magnetic Resonance Spectroscopy, and musclin by Enzyme-Linked ImmunoSorbent Assay before and after a supervised, three-times/week, 12-week treadmill programme. HIIT (n = 29) consisted of six intervals with one-minute, high-intensity phases at 90% of peak oxygen consumption (VO2peak). MICT (n = 31) trained at 60% of VO2peak for 30 min. RESULTS: Patients had a mean age of 50.8 ± 6.0 years, body mass index of 30.6 ± 4.0 kg/m2, and VO2peak of 29.0 ± 6.3 mL.kg-1.min-1. Compared to MICT, HIIT was not superior at reducing Ln HOMA-IR (adjusted mean difference: 0.083 [95%CI - 0.092 to 0.257]), carnosine or musclin or at increasing thigh lean mass. HIIT increased carnosine by 0.66 mmol/kg.ww (95% CI 0.08-1.24) after intervention. Both interventions reduced IR, body fat percentage and increased total lean mass/height2 and VO2peak. Musclin showed a non-significant reduction with a small effect size after both interventions. CONCLUSION: Compared to MICT, HIIT is not superior at reducing IR, carnosine or musclin or at increasing skeletal muscle mass in adults with MS. Both training types improved IR, muscle mass and body composition. NCT03087721, March 22nd, 2017. TRIAL REGISTRATION NUMBER: NCT03087721. Registered March 22nd, 2017.

Musclin Is Related to Insulin Resistance and Body Composition, but Not to Body Mass Index or Cardiorespiratory Capacity in Adults.

BACKGROUND: We studied whether musclin function in humans is related to glycemic control, body composition, and cardiorespiratory capacity. METHODS: A cross-sectional study was performed in sedentary adults with or without metabolic syndrome (MS). Serum musclin was measured by enzyme-linked immunosorbent assay. Insulin resistance (IR) was evaluated by the homeostatic model assessment (HOMA-IR). Body composition was determined by dual-energy X-ray absorptiometry and muscle composition by measuring carnosine in the thigh, a surrogate of fiber types, through proton magnetic resonance spectroscopy. Cardiorespiratory capacity was assessed through direct ergospirometry. RESULTS: The control (n=29) and MS (n=61) groups were comparable in age (51.5±6.5 years old vs. 50.7±6.1 years old), sex (72.4% vs. 70.5% women), total lean mass (58.5%±7.4% vs. 57.3%±6.8%), and peak oxygen consumption (VO2peak) (31.0±5.8 mL O2./kg.min vs. 29.2±6.3 mL O2/kg.min). Individuals with MS had higher body mass index (BMI) (30.6±4.0 kg/m2 vs. 27.4± 3.6 kg/m2), HOMA-IR (3.5 [95% confidence interval, CI, 2.9 to 4.6] vs. 1.7 [95% CI, 1.1 to 2.0]), and musclin (206.7 pg/mL [95% CI, 122.7 to 387.8] vs. 111.1 pg/mL [95% CI, 63.2 to 218.5]) values than controls (P˂0.05). Musclin showed a significant relationship with HOMA-IR (ß=0.23; 95% CI, 0.12 to 0.33; P˂0.01), but not with VO2peak, in multiple linear regression models adjusted for age, sex, fat mass, lean mass, and physical activity. Musclin was significantly associated with insulin, glycemia, visceral fat, and regional muscle mass, but not with BMI, VCO2peak, maximum heart rate, maximum time of work, or carnosine. CONCLUSION: In humans, musclin positively correlates with insulinemia, IR, and a body composition profile with high visceral adiposity and lean mass, but low body fat percentage. Musclin is not related to BMI or cardiorespiratory capacity.