Search

Metabolic dysfunction-associated steatohepatitis (MASH, previously termed non-alcoholic steatohepatitis (NASH)), is a major complication of obesity that promotes fatty liver disease. MASH is characterized by progressive tissue fibrosis and sterile liver inflammation that can lead to liver cirrhosis, cancer, and death. The molecular mechanisms of fibrosis in MASH and its systemic control remain poorly understood. Here, we identified the secreted-type pro-fibrotic protein, procollagen C-endopeptidase enhancer-1 (PCPE-1), as a brown adipose tissue (BAT)-derived adipokine that promotes liver fibrosis in a murine obesity-induced MASH model. BAT-specific or systemic PCPE-1 depletion in mice ameliorated liver fibrosis, whereas, PCPE-1 gain of function in BAT enhanced hepatic fibrosis. High-calorie diet-induced ER stress increased PCPE-1 production in BAT through the activation of IRE-1/JNK/c-Fos/c-Jun signaling. Circulating PCPE-1 levels are increased in the plasma of MASH patients, suggesting a therapeutic possibility. In sum, our results uncover PCPE-1 as a novel systemic control factor of liver fibrosis. Synopsis: The systemic control of tissue fibrosis by metabolic organs remains poorly understood. This study identifies procollagen C-endopeptidase enhancer-1 (PCPE-1) as an adipokine released from brown adipose tissue (BAT) upon dietary obesity. Secreted PCPE-1 enhances liver fibrosis in a murine metabolic dysfunction-associated steatohepatitis (MASH) model, suggesting new therapeutic avenues. PCPE-1 is a BAT-derived adipokine in mice. Dietary obesity promotes PCPE-1 production in BAT, enhancing liver fibrosis in a murine MASH model. High-calorie diet-induced ER stress increases PCPE-1 production in BAT through the activation of the IRE-1/JNK/c-Fos/c-Jun pathway. PCPE-1 depletion or anti-PCPE-1 vaccine therapy ameliorate non-alcoholic fatty liver disease. Circulating PCPE-1 plasma levels are increased in MASH patients. The BAT-secreted, ER-stress-induced adipokine PCPE-1 systemically enhances liver fibrosis in metabolic dysfunction-associated steatohepatitis. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?We questioned whether an angiotensin‐converting enzyme (ACE) inhibitor prevents skeletal muscle fibrosis in diabetic mice.What is the main finding and its importance?Administration of ACE inhibitor prevents the increase in skeletal muscle fibrosis during the early phase after induction of diabetes by streptozotocin. Our findings might provide a new therapeutic target for skeletal muscle abnormalities in diabetes. Fibrosis is characterized by the excessive production and accumulation of extracellular matrix components, including collagen. Although the extracellular matrix is an essential component of skeletal muscle, fibrosis can have negative effects on muscle function. Skeletal muscle fibrosis was shown to be increased in spontaneously hypertensive rats and to be prevented by an angiotensin‐converting enzyme (ACE) inhibitor, an antihypertensive drug, in dystrophic mice or a mouse model of myocardial infarction. In this study, we therefore analysed whether (1) there is increased skeletal muscle fibrosis in streptozotocin (STZ)‐induced diabetic mice, and (2) a preventive effect on skeletal muscle fibrosis by administration of an ACE inhibitor. Skeletal muscle fibrosis was significantly increased in STZ‐induced diabetic mice compared with control mice from 2 to 14 days post‐STZ. The ACE inhibitor prevented both skeletal muscle fibrosis and the reduction in muscle function in STZ‐treated mice. Our study demonstrated that administration of an ACE inhibitor prevents the increase in skeletal muscle fibrosis during the early phase after onset of diabetes. Our findings might provide a new therapeutic target for skeletal muscle abnormalities in diabetes. Future studies are required to clarify whether skeletal muscle fibrosis is also linked directly to physical activity. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?We questioned whether the disruption of invariant natural killer T (iNKT) cells exacerbates left ventricular (LV) remodelling and heart failure after transverse aortic constriction in mice.What are the main findings and their importance?Pressure overload induced by transverse aortic constriction increased the infiltration of iNKT cells in mouse hearts. The disruption of iNKT cells exacerbated LV remodelling and hastened the transition from hypertrophy to heart failure, in association with the activation of mitogen‐activated protein kinase signalling. Activation of iNKT cells modulated the immunological balance in this process and played a protective role against LV remodelling and failure. Chronic inflammation is involved in the development of cardiac remodelling and heart failure (HF). Invariant natural killer T (iNKT) cells, a subset of T lymphocytes, have been shown to produce various cytokines and orchestrate tissue inflammation. The pathophysiological role of iNKT cells in HF caused by pressure overload has not been studied. In the present study, we investigated whether the disruption of iNKT cells affected this process in mice. Transverse aortic constriction (TAC) and a sham operation were performed in male C57BL/6J wild‐type (WT) and iNKT cell‐deficient Jα18 knockout (KO) mice. The infiltration of iNKT cells was increased after TAC. The disruption of iNKT cells exacerbated left ventricular (LV) remodelling and hastened the transition to HF after TAC. Histological examinations also revealed that the disruption of iNKT cells induced greater myocyte hypertrophy and a greater increase in interstitial fibrosis after TAC. The expressions of interleukin‐10 and tumour necrosis factor‐α mRNA and their ratio in the LV after TAC were decreased in the KO compared with WT mice, which might indicate that the disruption of iNKT cells leads to an imbalance between T‐helper type 1 and type 2 cytokines. The phosphorylation of extracellular signal‐regulated kinase was significantly increased in the KO mice. The disruption of iNKT cells exacerbated the development of cardiac remodelling and HF after TAC. The activation of iNKT cells might play a protective role against HF caused by pressure overload. Targeting the activation of iNKT cells might thus be a promising candidate as a new therapeutic strategy for HF. [ABSTRACT FROM AUTHOR]

Background: Exercise intolerance is a common clinical feature and is linked to poor prognosis in patients with heart failure (HF). Skeletal muscle dysfunction, including impaired energy metabolism in the skeletal muscle, is suspected to play a central role in this intolerance, but the underlying mechanisms remain elusive. Lysine acetylation, a recently identified post‐translational modification, has emerged as a major contributor to the derangement of mitochondrial metabolism. We thus investigated whether mitochondrial protein acetylation is associated with impaired skeletal muscle metabolism and lowered exercise capacity in both basic and clinical settings of HF. Methods: We first conducted a global metabolomic analysis to determine whether plasma acetyl‐lysine is a determinant factor for peak oxygen uptake (peak VO2) in HF patients. We then created a murine model of HF (n = 11) or sham‐operated (n = 11) mice with or without limited exercise capacity by ligating a coronary artery, and we tested the gastrocnemius tissues by using mass spectrometry‐based acetylomics. A causative relationship between acetylation and the activity of a metabolic enzyme was confirmed in in vitro studies. Results: The metabolomic analysis verified that acetyl‐lysine was the most relevant metabolite that was negatively correlated with peak VO2 (r = −0.81, P < 0.01). At 4 weeks post‐myocardial infarction HF, a treadmill test showed lowered work (distance × body weight) and peak VO2 in the HF mice compared with the sham‐operated mice (11 ± 1 vs. 23 ± 1 J, P < 0.01; 143 ± 5 vs. 159 ± 3 mL/kg/min, P = 0.01; respectively). As noted, the protein acetylation of gastrocnemius mitochondria was 48% greater in the HF mice than the sham‐operated mice (P = 0.047). Acetylproteomics identified the mitochondrial enzymes involved in fatty acid β‐oxidation (FAO), the tricarboxylic acid cycle, and the electron transport chain as targets of acetylation. In parallel, the FAO enzyme (β‐hydroxyacyl CoA dehydrogenase) activity and fatty acid‐driven mitochondrial respiration were reduced in the HF mice. This alteration was associated with a decreased expression of mitochondrial deacetylase, Sirtuin 3, because silencing of Sirtuin 3 in cultured skeletal muscle cells resulted in increased mitochondrial acetylation and reduced β‐hydroxyacyl CoA dehydrogenase activity. Conclusions: Enhanced mitochondrial protein acetylation is associated with impaired FAO in skeletal muscle and reduced exercise capacity in HF. Our results indicate that lysine acetylation is a crucial mechanism underlying deranged skeletal muscle metabolism, suggesting that its modulation is a potential approach for exercise intolerance in HF. [ABSTRACT FROM AUTHOR]

Skeletal muscle atrophy is induced by an imbalance between protein synthesis and degradation. Our previous studies reported that angiotensin II (AII) directly induced muscle atrophy in mice. This study investigated the role of NAD(P)H oxidase 2 (Nox2) activation by AII in the induction of skeletal muscle atrophy. For 4 weeks, either saline (vehicle: V) or AII (1000 ng kg−1 min−1) was infused into male wild-type (WT) and Nox2 knockout (KO) mice via osmotic minipumps. Experiments were performed in the following 4 groups: WT + V, KO + V, WT + AII, and KO + AII. Body weight, muscle weight, and myocyte cross-sectional area were significantly decreased in WT + AII compared to WT + V mice, and these changes were not observed in KO + AII mice. Akt phosphorylation of Ser473 and p70S6K of Thr389 was decreased, gene expression levels of MuRF-1 and atrogin-1 were increased in WT + AII compared to WT + V, and these changes were significantly attenuated in KO + AII mice. The deletion of Nox2 prevented AII-induced skeletal muscle atrophy via improving the balance between protein synthesis and degradation. Therefore, Nox2 may be a therapeutic target for AII-induced skeletal muscle atrophy. [ABSTRACT FROM AUTHOR]

New Findings What is the central question of this study? Our aim was to examine whether sesamin can prevent a decline in exercise capacity in high-fat diet-induced diabetic mice. Our hypothesis was that maintenance of mitochondrial function and attenuation of oxidative stress in the skeletal muscle would contribute to this result., What is the main finding and its importance? The new findings are that sesamin prevents the diabetes-induced decrease in exercise capacity and impairment of mitochondrial function through the inhibition of NAD(P)H oxidase-dependent oxidative stress in the skeletal muscle. Sesamin may be useful as a novel agent for the treatment of diabetes mellitus., Abstract We previously reported that exercise capacity and skeletal muscle mitochondrial function in diabetic mice were impaired, in association with the activation of NAD(P)H oxidase. It has been reported that sesamin inhibits NAD(P)H oxidase-induced superoxide production. Therefore, we examined whether the antioxidant sesamin could prevent a decline in exercise capacity in mice with high-fat diet (HFD)-induced diabetes. C57BL/6J mice were fed a normal diet (ND) or HFD, then treated or not with sesamin (0.2%) to yield the following four groups: ND, ND+Sesamin, HFD and HFD+Sesamin ( n = 10 each). After 8 weeks, body weight, fat weight, blood glucose, insulin, triglyceride, total cholesterol and fatty acid were significantly increased in HFD compared with ND mice. Sesamin prevented the increases in blood insulin and lipid levels in HFD-fed mice, but did not affect the plasma glucose. Exercise capacity determined by treadmill tests was significantly reduced in HFD mice, but almost completely recovered in HFD+Sesamin mice. Citrate synthase activity was significantly decreased in the skeletal muscle of HFD mice, and these decreases were also inhibited by sesamin. Superoxide anion and NAD(P)H oxidase activity were significantly increased in HFD mice compared with the ND mice and were ameliorated by sesamin. Sesamin prevented the decline in exercise capacity in HFD-induced diabetic mice via maintenance of mitochondrial function, fat oxidation and attenuation of oxidative stress in the skeletal muscle. Our data suggest that sesamin may be useful as a novel agent for the treatment of diabetes mellitus. [ABSTRACT FROM AUTHOR]

New findings What is the central question of this study? Does angiotensin II directly induce skeletal muscle abnormalities?, What is the main finding and its importance? Angiotensin II induces skeletal muscle abnormalities and reduced exercise capacity. Mitochondrial dysfunction and a decreased number of oxidative fibres are manifest early, while muscle atrophy is seen later. Thus, angiotensin II may play an important role in the skeletal muscle abnormalities observed in a wide variety of diseases., Skeletal muscle abnormalities, such as mitochondrial dysfunction, a decreased percentage of oxidative fibres and atrophy, are the main cause of reduced exercise capacity observed in ageing and various diseases, including heart failure. The renin-angiotensin system, particularly angiotensin II (Ang II), is activated in the skeletal muscle in these conditions. Here, we examined whether Ang II could directly induce these skeletal muscle abnormalities and investigated their time course. Angiotensin II (1000 ng kg−1 min−1) or vehicle was administered to male C57BL/6J mice (10-12 weeks of age) via subcutaneously implanted osmotic minipumps for 1 or 4 weeks. Angiotensin II significantly decreased body and hindlimb skeletal muscle weights compared with vehicle at 4 weeks. In parallel, muscle cross-sectional area was also decreased in the skeletal muscle at 4 weeks. Muscle RING finger-1 and atrogin-1 were significantly increased in the skeletal muscle from mice treated with Ang II. In addition, cleaved caspase-3 and terminal deoxynucleotidyl trasferase-mediated dUTP nick-positive nuclei were significantly increased in mice treated with Ang II at 1 and 4 weeks, respectively. Mitochondrial oxidative enzymes, such as citrate synthase, complex I and complex III activities were significantly decreased in the skeletal muscle from mice treated Ang II at 1 and 4 weeks. NAD(P)H oxidase-derived superoxide production was increased. NADH staining revealed that type I fibres were decreased and type IIb fibres increased in mice treated with Ang II at 1 week. The work and running distance evaluated by a treadmill test were significantly decreased in mice treated with Ang II at 4 weeks. Thus, Ang II could directly induce the abnormalities in skeletal muscle function and structure. [ABSTRACT FROM AUTHOR]