Ammonia Scavenger Restores Liver and Muscle Injury in a Mouse Model of Non-alcoholic Steatohepatitis With Sarcopenic Obesity

Abstract

Recent studies have revealed that sarcopenia is closely associated with obesity and non-alcoholic steatohepatitis (NASH). However, few attempted to explore the cause-and-effect relationship between sarcopenic obesity and NASH. In this study, we investigated muscular alterations in a rodent NASH model to elucidate their intrinsic relations and explore the potential therapeutic target. Forty-six 8-week-old and twenty 42-week-old male C57BL/6 mice (defined as young and middle-aged mice, respectively) were fed with a high-fat diet (HFD) for 12 or 20 weeks. A subset of young mice was subjected to ammonia lowering treatment by L-ornithine L-aspartate (LOLA). We examined body composition and muscle strength by nuclear magnetic resonance and grip strength meter, respectively. At the end of the 12th week, all HFD-fed mice developed typical steatohepatitis. Meanwhile, sarcopenia occurred in HFD-fed middle-aged mice, whereas young mice only demonstrated decreased grip strength. Until the end of week 20, young mice in the HFD group exhibited significant sarcopenia and obesity phenotypes, including decreased lean body mass and grip strength, and increased body fat mass and percentage body fat. Additionally, plasma ammonia level was markedly increased in HFD-fed mice of both ages at week 20. Plasma ammonia level was negatively associated with muscle strength and myofiber diameter in young mice. LOLA can significantly reduce plasma levels of ammonia, alanine aminotransaminase, aspartate aminotransaminase, and cholesterol in mice fed an HFD. Hepatic infiltration of inflammatory cells and collagen deposition area were significantly decreased in HFD group by LOLA treatment. Meanwhile, LOLA significantly increased lean body mass, grip strength, and average muscle fiber diameter of HFD-fed mice. These findings suggest that the occurrence of NASH precedes sarcopenia in HFD mice, and the steatohepatitis-related hyperammonemia might contribute to the pathogenesis of sarcopenia. LOLA might be an effective drug for both steatohepatitis and sarcopenic obesity.

Effects of Whey Peptide Supplementation on Sarcopenic Obesity in High-Fat Diet-Fed Mice

“…Although a lot of animal studies regarding sarcopenic obesity have been conducted, there are no clear criteria for the appropriate age of the sarcopenic obese animal model. According to previous studies, sarcopenic obesity was induced by a high-fat diet in different aged mice (the young [ 8 ], the middle-aged [ 9 ], and the old [ 10 ]). As the aged population has a higher chance of sarcopenic obesity that is easily initiated in middle age, the middle-aged animal model was used in this study.…”

Human milk extracellular vesicles enhance muscle growth and physical performance of immature mice associating with Akt/mTOR/p70s6k signaling pathway

“…Furthermore, L-Ornithine plays a critical role in creatine metabolism, a key molecule for muscle energy production, thereby contributing to improved muscle quality and exercise capacity [ 77 ]. Studies also demonstrate ornithine’s ability to increase lean body mass, grip strength, overall rod performance, and other physical attributes in mice [ 78 – 80 ]. These findings further confirm our results that HME contains a rich source of amino acids, particularly L-Ornithine, which significantly enhances growth and exercise capacity in mouse skeletal muscles.…”

Impact of L-ornithine L-aspartate on non-alcoholic steatohepatitis-associated hyperammonemia and muscle alterations

“…Indeed, while in the FOZ model ammonia concentrations are modest, in patients with cirrhosis and hepatic encephalopathy to whom LOLA is usually given as a treatment, ammonia levels are often two or even threefold higher than in healthy subjects. Wang et al ( 79 ) recently described a positive ammonia lowering effect in C57BL/6 mice with steatohepatitis, with plasma ammonia levels as high as 340 μg/dL, which are values typically observed in cirrhosis and acute liver failure with hepatic encephalopathy ( 80 , 81 ). A mouse strain effect or an issue in the assay may explain unexpectedly high ammonia values in Wang’s study as ammonemia in controls is already around a high 170 μg/dL (100 μmol/L).…”

“…Of note, they used mice exposed to a diet rich in fat (33% of calories from fat) and containing high levels of cholesterol (2%) known to structurally and functionally damage mitochondria, alter microcirculation and promote fibrosis ( 82 – 84 ). Hence, there is no body weight gain in the face of energy overload, the qualification of the model as “sarcopenic obesity” being, to say the least, misleading ( 79 ). Rather than ammonia removal, hepatoprotection could also be related to an antioxidant effect due to the conversion into glutathione of LOLA-derived glutamate or to improved microcirculation due to nitric oxide formation from L-arginine.…”