Fat Accumulation In Skeletal Muscle Research Articles

Gracilaria chorda attenuates obesity‐related muscle wasting through activation of SIRT1/PGC1α in skeletal muscle of mice

AbstractGracilaria chorda (GC) is a red algal species that is primarily consumed in Asia. Here, we investigated the effect of GC on obesity‐related skeletal muscle wasting. Furthermore, elucidating its impact on the activation of sirtuin 1 (SIRT1)/peroxisome proliferator‐activated receptor gamma coactivator 1α (PGC1α) constituted a critical aspect in understanding the underlying mechanism of action. In this study, 6‐week‐old male C57BL/6 mice were fed a high‐fat diet (HFD) for 8 weeks to induce obesity, then continued on the HFD for another 8 weeks while orally administered GC. GC decreased ectopic fat accumulation in skeletal muscle and increased muscle weight, size, and function in obese mice. Furthermore, GC reduced skeletal muscle atrophy and increased hypertrophy in mice. We hypothesized that the activation of SIRT1/PGC1α by GC regulates skeletal muscle atrophy and hypertrophy. We observed that GC increased the expression of SIRT1 and PGC1α in skeletal muscle of mice and in C2C12 cells, which increased mitochondrial function and biogenesis. In addition, when C2C12 cells were treated with the SIRT1‐specific inhibitor EX‐527, no changes were observed in the protein levels of SIRT1 and PGC1α in the GC‐treated C2C12 cells. Therefore, GC attenuated obesity‐related muscle wasting by improving mitochondrial function and biogenesis through the activation of SIRT1/PGC1α in the skeletal muscle of mice.

Proteomic analysis shows decreased type I fibers and ectopic fat accumulation in skeletal muscle from women with PCOS.

Polycystic ovary syndrome's (PCOS) main feature is hyperandrogenism, which is linked to a higher risk of metabolic disorders. Gene expression analyses in adipose tissue and skeletal muscle reveal dysregulated metabolic pathways in women with PCOS, but these differences do not necessarily lead to changes in protein levels and biological function. To advance our understanding of the molecular alterations in PCOS, we performed global proteomic and phosphorylation site analysis using tandem mass spectrometry, and analyzed gene expression and methylation. Adipose tissue and skeletal muscle were collected at baseline from 10 women with and without PCOS, and in women with PCOS after 5 weeks of treatment with electrical stimulation. Perilipin-1, a protein that typically coats the surface of lipid droplets in adipocytes, was increased whereas proteins involved in muscle contraction and type I muscle fiber function were downregulated in PCOS muscle. Proteins in the thick and thin filaments had many altered phosphorylation sites, indicating differences in protein activity and function. A mouse model was used to corroborate that androgen exposure leads to a shift in muscle fiber type in controls but not in skeletal muscle-specific androgen receptor knockout mice. The upregulated proteins in muscle post treatment were enriched in pathways involved in extracellular matrix organization and wound healing, which may reflect a protective adaptation to repeated contractions and tissue damage due to needling. A similar, albeit less pronounced, upregulation in extracellular matrix organization pathways was also seen in adipose tissue. Our results suggest that hyperandrogenic women with PCOS have higher levels of extra-myocellular lipids and fewer oxidative insulin-sensitive type I muscle fibers. These could be key factors leading to insulin resistance in PCOS muscle while electric stimulation-induced tissue remodeling may be protective. Swedish Research Council (2020-02485, 2022-00550, 2020-01463), Novo Nordisk Foundation (NNF22OC0072904), and IngaBritt and Arne Lundberg Foundation. Clinical trial number NTC01457209.

Proteomic analysis shows decreased type I fibers and ectopic fat accumulation in skeletal muscle from women with PCOS

Background:Polycystic ovary syndrome’s (PCOS) main feature is hyperandrogenism, which is linked to a higher risk of metabolic disorders. Gene expression analyses in adipose tissue and skeletal muscle reveal dysregulated metabolic pathways in women with PCOS, but these differences do not necessarily lead to changes in protein levels and biological function.Methods:To advance our understanding of the molecular alterations in PCOS, we performed global proteomic and phosphorylation site analysis using tandem mass spectrometry, and analyzed gene expression and methylation. Adipose tissue and skeletal muscle were collected at baseline from 10 women with and without PCOS, and in women with PCOS after 5 weeks of treatment with electrical stimulation.Results:Perilipin-1, a protein that typically coats the surface of lipid droplets in adipocytes, was increased whereas proteins involved in muscle contraction and type I muscle fiber function were downregulated in PCOS muscle. Proteins in the thick and thin filaments had many altered phosphorylation sites, indicating differences in protein activity and function. A mouse model was used to corroborate that androgen exposure leads to a shift in muscle fiber type in controls but not in skeletal muscle-specific androgen receptor knockout mice. The upregulated proteins in muscle post treatment were enriched in pathways involved in extracellular matrix organization and wound healing, which may reflect a protective adaptation to repeated contractions and tissue damage due to needling. A similar, albeit less pronounced, upregulation in extracellular matrix organization pathways was also seen in adipose tissue.Conclusions:Our results suggest that hyperandrogenic women with PCOS have higher levels of extra-myocellular lipids and fewer oxidative insulin-sensitive type I muscle fibers. These could be key factors leading to insulin resistance in PCOS muscle while electric stimulation-induced tissue remodeling may be protective.Funding:Swedish Research Council (2020-02485, 2022-00550, 2020-01463), Novo Nordisk Foundation (NNF22OC0072904), and IngaBritt and Arne Lundberg Foundation. Clinical trial number NTC01457209.

Abstract 16841: Skeletal Muscle Fat Predicts Exercise Intolerance and Decreased Survival in Symptomatic Heart Failure With Preserved Ejection Fraction

Introduction: Heart failure with preserved ejection fraction (HFpEF) is characterized by marked exercise intolerance (EI) and increased mortality. HFpEF is now thought to involve multi-organ dysfunction and skeletal muscle (SkM) changes including muscle loss and muscle fatty infiltration have been reported in HFpEF patients. However, it is not known if SkM changes are associated with cardiovascular (CV) mortality. Hypothesis: Skeletal muscle fat accumulation in symptomatic HFpEF patients is associated with worse EI and decreased survival. Methods: Patients with a clinical diagnosis of HFpEF and left ventricular ejection fraction > 50% (n=64, age 65.2±11.2, BMI 38.6±8.2, mean±SD, 53% women) underwent 3T conventional magnetic resonance imaging (MRI) of the calf muscle to determine SkM mass and T2-weighted MRI for SkM fat fraction (FF) with subcutaneous fat excluded. Baseline EI was quantified by six-minute walk distance (6MW). HFpEF patients were followed prospectively for a minimum of 18 months for survival (median follow up 39.3 months). Simple linear regression was used to determine relationships with EI while Kaplan-Meier survival curves with log rank tests were created to explore CV mortality. Results: SkM FF was closely and inversely associated with 6MW (1A), but SkM mass (1B) was not, indicating that EI in HFpEF is more closely associated with SkM quality than quantity. SkM FF was not related to body mass index (BMI) (1C). When the HFpEF cohort was stratified based on median FF (median=18.79%), SkM FF predicted significantly worse survival from CV death (1D, p=0.0192). Conclusions: This is the first report to show that SkM fat content predicts cardiovascular mortality in HFpEF patients. Further, EI in HFpEF patients is closely associated with SkM fat accumulation but not sarcopenia. Thus, reducing SkM fat content may represent a new target for reducing EI and improving CV survival in HFpEF patients.

Common Regulators of Lipid Metabolism and Bone Marrow Adiposity in Postmenopausal Women.

A variety of metabolic disorders are associated with a decrease in estradiol (E2) during natural or surgical menopause. Postmenopausal women are prone to excessive fat accumulation in skeletal muscle and adipose tissue due to the loss of E2 via abnormalities in lipid metabolism and serum lipid levels. In skeletal muscle and adipose tissue, genes related to energy metabolism and fatty acid oxidation, such as those encoding peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and estrogen-related receptor alpha (ERRα), are downregulated, leading to increased fat synthesis and lipid metabolite accumulation. The same genes regulate lipid metabolism abnormalities in the bone marrow. In this review, abnormalities in lipid metabolism caused by E2 deficiency were investigated, with a focus on genes able to simultaneously regulate not only skeletal muscle and adipose tissue but also bone metabolism (e.g., genes encoding PGC-1α and ERRα). In addition, the mechanisms through which mesenchymal stem cells lead to adipocyte differentiation in the bone marrow as well as metabolic processes related to bone marrow adiposity, bone loss, and osteoporosis were evaluated, focusing on the loss of E2 and lipid metabolic alterations. The work reviewed here suggests that genes underlying lipid metabolism and bone marrow adiposity are candidate therapeutic targets for bone loss and osteoporosis in postmenopausal women.

Factors inducingtransdifferentiation of myoblasts into adipocytes.

Fat infiltration in skeletal muscle is observed in several myopathies,is associated with muscular dysfunction, and is strongly correlated with insulin resistance, diabetes, obesity, and aging. In animal production, skeletal muscle fat (also known as intermuscular and intramuscular fat) is positively related to meat quality including tenderness, flavor, and juiciness. Thus, understanding the cell origin and regulation mechanism of skeletal muscle fat infiltration is important for developing therapies against human myopathies as well as for improving meat quality. Notably, age, sarcopenia, oxidative stress, injury, and regeneration can activate adipogenic differentiation potential in myoblasts and affect fat accumulation in skeletal muscle. In addition, several transcriptional and nutritional factors can directly induce transdifferentiation of myoblasts into adipocytes. In this review, we focused on the recent progress in understanding the muscle-to-adipocyte differentiation and summarized and discussed the genetic, nutritional, and physiological factors that can induce transdifferentiation of myoblasts into adipocytes. Moreover, the regulatory roles and mechanisms of these factors during the transdifferentiation process were also discussed.

Chrysanthemi Zawadskii var. Latilobum Attenuates Obesity-Induced Skeletal Muscle Atrophy via Regulation of PRMTs in Skeletal Muscle of Mice.

As obesity promotes ectopic fat accumulation in skeletal muscle, resulting in impaired skeletal muscle and mitochondria function, it is associated with skeletal muscle loss and dysfunction. This study investigated whether Chrysanthemi zawadskii var. latilobum (CZH) protected mice against obesity-induced skeletal muscle atrophy and the underlying molecular mechanisms. High-fat diet (HFD)-induced obese mice were orally administered either distilled water, low-dose CZH (125 mg/kg), or high-dose CZH (250 mg/kg) for 8 w. CZH reduced obesity-induced increases in inflammatory cytokines levels and skeletal muscle atrophy, which is induced by expression of atrophic genes such as muscle RING-finger protein 1 and muscle atrophy F-box. CZH also improved muscle function according to treadmill running results and increased the muscle fiber size in skeletal muscle. Furthermore, CZH upregulated mRNA and protein levels of protein arginine methyltransferases (PRMT)1 and PRMT7, which subsequently attenuated mitochondrial dysfunction in the skeletal muscle of obese mice. We also observed that CZH significantly decreased PRMT6 mRNA and protein expression, which resulted in decreased muscle atrophy. These results suggest that CZH ameliorated obesity-induced skeletal muscle atrophy in mice via regulation of PRMTs in skeletal muscle.

Non-invasive Quantification of Fat Deposits in Skeletal Muscle Predicts Cardiovascular Outcome in Kidney Failure.

Fat accumulation in skeletal muscle was recently established as a major risk factor for cardiovascular disease (CVD) in the general population, but its relevance for patients with kidney failure is unknown. Here we examined the potential association between muscle radiation attenuation (MRA), a non-invasive indicator of fat deposits in muscle, and cardiovascular events in patients with kidney failure treated with peritoneal dialysis (PD) and investigated dynamic changes and determinants of MRA in this population. We retrospectively assessed MRA on computed tomography images collected yearly in 101 incident patients with kidney failure starting PD between January 2006 and December 2015. After a median of 21 months on dialysis, 34 patients had 58 non-fatal cardiovascular events, and 22 patients had died. Baseline MRA was associated with cardiovascular events during time on dialysis, and patients with higher MRA (reflecting lower amounts of fat in muscle) showed a reduced incidence of CVD, independently of traditional risk factors (adjusted HR, 0.91; 95% CI, 0.86–0.97, P = 0.006). Multivariate regression analysis identified old age, female gender, visceral fat area, and low residual urine volume as independent determinants of MRA. As compared with reference values from a healthy population, patients with kidney failure had lower MRA (i.e., increased fat accumulation), independently of age, gender, and body-mass index. The subset of patients who underwent kidney transplantation showed a significant increase in MRA after restoration of kidney function. These observations expand the association between ectopic fat accumulation and CVD to the population on dialysis, and suggest that kidney failure is reversibly associated with fatty muscle infiltration.

Inefficient ATP synthesis by inhibiting mitochondrial respiration causes lipids to decrease in MSTN-lacking muscles of loach Misgurnus anguillicaudatus.

Myostatin (MSTN) lacking could lead to enhanced muscle growth and lipid metabolism disorder in animals. Plenty of researches have been performed to warrant a better understanding of the mechanisms underlying the enhanced muscle growth; however, mechanisms for lipid metabolic changes are poorly understood. In this study, MSTN-depletion loaches Misgurnus anguillicaudatus (MU for short) were firstly generated by CRISPR/Cas9 technique. Based on histological observation, we found that skeletal muscle fat accumulation in MU sharply reduced compared with wild-type loaches (WT for short). To further investigate the fat change, muscle lipidomic analysis was performed. There were no significant differences in three membrane phospholipid contents between WT and MU. The contents of six other major lipid species in MU muscles were all significantly lower than those in WT muscles, indicating that MSTN deficiency could obviously decrease muscle lipid production in the loach. Meanwhile, it was also supported by results of three lipogenesis-related genes' expressions. And then combined with muscle ATP determination and gene expression profiles of the five mitochondrial respiration chain complexes, we speculated that MSTN lacking may cause the weak of mitochondrial respiration functions in the loach muscles, leading to ATP synthesis decreasing and finally reducing the production of lipids.

21 Increased dietary isoleucine enhances lipogenesis and fat accumulation in skeletal muscle through depressing AMPK phosphorylation in pigs.

21 Increased dietary isoleucine enhances lipogenesis and fat accumulation in skeletal muscle through depressing AMPK phosphorylation in pigs.

Surplus dietary isoleucine intake enhanced monounsaturated fatty acid synthesis and fat accumulation in skeletal muscle of finishing pigs

BackgroundIsoleucine (Ile) has been implicated in the regulation of energy homeostasis and adipogenesis. However, the impact of surplus dietary Ile intake on muscle lipogenesis remains unknown. The present study aimed to investigate the impact of dietary supplementation of extra-Ile on lipogenesis, fatty acid profile and lipid accumulation in skeletal muscle in finishing pigs.MethodsForty-eight barrows with initial body weight of 77.0 ± 0.1 kg were allotted to one of two groups and fed diets containing 0.39%, 0.53% standardized ileal digestible (SID) Ile with six replicates per treatment and four pigs per replicate for 30 d.ResultsDietary Ile intake significantly improved the intramuscular fat (IMF) content and monounsaturated fatty acid (MUFA) concentration in the skeletal muscle (P < 0.05), and decreased the drip loss and shear force (P < 0.05) without influencing the growth performance of pigs (P > 0.05). Moreover, the phosphorylation of adenosine monophosphate activated protein kinase α (AMPKα) and acetyl coenzyme A carboxylase (ACC) proteins that monitor lipid metabolism were decreased in skeletal muscle of pigs offered extra-Ile diet (P < 0.05). The mRNA expression of adipose-specific genes adipocyte determination and differentiation factor 1 (ADD1), fatty acid synthase (FAS), and stearoyl-CoA desaturase (SCD) were upregulated and the activity of SCD was increased as well (P < 0.05).ConclusionsSurplus dietary Ile intake could increase IMF accumulation and MUFA synthesis in skeletal muscle through depressing the phosphorylation of AMPKα-ACC and stimulating the expression and activity of SCD, and increasing the capability of lipogenesis in skeletal muscle.

Supplementation with branched-chain amino acids ameliorates hypoalbuminemia, prevents sarcopenia, and reduces fat accumulation in the skeletal muscles of patients with liver cirrhosis.

Liver cirrhosis induces marked metabolic disorders, protein-energy malnutrition, and sarcopenia. The objective of the study reported here was to investigate the effects of dietary branched-chain amino acids (BCAAs) on systemic glucose metabolism, skeletal muscle, and prognosis of patients with liver cirrhosis. Japanese patients with liver cirrhosis (n=21) were enrolled into a longitudinal study in which their diets were supplemented with BCAAs. We evaluated glucose metabolism and analyzed the skeletal muscle area index (SAI) and intramuscular adipose tissue content (IMAC) using computed tomography. After 48weeks of supplementation with BCAAs, there were no changes in glucose metabolism and skeletal muscle findings. In patients with ameliorated hypoalbuminemia, IMAC was significantly decreased and SAI was preserved concomitant with decreasing 90- and 120-min post-challenge plasma glucose levels (P<0.01 each). In patients without increased albumin levels, IMAC was significantly increased and the SAI was significantly decreased (P<0.01 each). Liver-related event-free survival rates for 72months were 63.6% in patients with decreased IMAC and 20.0% in patients with increased IMAC. Amelioration of hypoalbuminemia associated with BCAA supplementation correlated with decreased fat accumulation in skeletal muscle, maintenance of skeletal muscle mass, and improved glucose sensitivity, all factors which may contribute to improving the survival of patients with liver cirrhosis.

Steroidogenic Acute Regulatory Protein (StAR) Overexpression Reduces Inflammation and Insulin Resistance in Obese Mice.

Steroidogenic acute regulatory protein (StAR), a mitochondrial cholesterol delivery protein, plays a beneficial role in hyperlipidemia, NAFLD, and endothelial inflammation. Elevated circulating fatty acids and low grade inflammation are known as key risk factors of insulin resistance and type 2 diabetes. In the present study, C57BL/6J mice were fed with HFD and infected with recombinant adenovirus expressing StAR by tail-vein injection. Intraperitoneal glucose/insulin tolerance test was performed to assess the insulin sensitivity. Morphological analysis and intramuscular lipid determination were used to illustrate the adipose hypertrophy and ectopic fat accumulation in skeletal muscle. The levels of inflammatory factor and nitric oxide were determined by ELISA and classic Griess reagent methods, respectively. The fatty acids composition was analysis using gas chromatography-mass spectrometry (GC-MS). The expression of genes associated with inflammation and insulin resistance were determined by Western blotting and qPCR to elucidate the underlying mechanism. We demonstrated that StAR overexpression ameliorated insulin resistance and systemic inflammatory response with the reduction of adipose hypertrophy and intramuscular lipid in HFD-fed mice. In addition, StAR overexpression increased serum unsaturated fatty acids (UFAs) and PPARγ expression in muscle and adipose tissue of obese mice. In conclusion, StAR may activate PPARγ by increasing UFAs, which leads to a protective role in systemic inflammation and insulin resistance in obese mice. J. Cell. Biochem. 118: 3932-3942, 2017. © 2017 Wiley Periodicals, Inc.

Exploring crucial aspects of diabetes and obesity

Exploring crucial aspects of diabetes and obesity

Effect of Intramuscular Adipose Tissue Content on Prognosis in Patients Undergoing Hepatocellular Carcinoma Resection

BackgroundIt has recently been reported that myosteatosis, the infiltration of fat in skeletal muscle, is associated with insulin resistance and type 2 diabetes mellitus. The present study investigated the effect of skeletal muscle fat accumulation on short- and long-term outcomes following partial hepatectomy for hepatocellular carcinoma (HCC) and aimed to identify prognostic factors. MethodsThe records of 141 HCC patients who underwent hepatectomy were retrospectively reviewed. Clinicopathological and outcome data from 71 patients with high intramuscular adipose tissue content (IMAC) were compared with those from 70 patients with low IMAC. ResultsThe 5-year overall survival rate was 46 % among patients with high IMAC and 75 % among those with low IMAC. The 5-year disease-free survival rates in these groups were 18 and 38 %, respectively. Multivariate analysis revealed that high IMAC was predictive of an unfavorable prognosis. High IMAC was significantly correlated with liver dysfunction, higher intraoperative blood loss, the need for blood transfusion, and comorbid diabetes mellitus. ConclusionsGreater fat accumulation in skeletal muscle was predictive of worse overall survival after partial hepatectomy in patients with HCC, even with adjustment for other known predictors. The identification of patients with greater skeletal muscle fat accumulation before hepatectomy could permit early preventive strategies to maintain muscle quality and thus improve prognosis and patient selection for hepatectomy.

Skeletal muscle fat accumulation and increased fatty acid saturation are related to worsening glucose control in older adults (133.8)

Increased inter‐muscular adipose tissue (IMAT) content and intra‐myocellular lipid (IMCL) fatty acid saturation (FAS) are implicated in insulin resistance (IR), but potential relationships require further investigation because of limited data. This study examined the associations between IMAT content, IMCL FAS, and fasting plasma glucose concentrations in 10 men and women, age range 65‐76 y, plasma glucose 101±11 mg/dL (range 87‐114 mg/dL). Thigh muscle and adipose tissue volumes (magnetic resonance imaging) and the FAS of vastus lateralis IMCL (from muscle biopsies using Coherent Anti‐scattering Raman Spectroscopy and Spontaneous Raman Spectroscopy) were quantified. IMAT volume, standardized with respect to muscle tissue volume (ratio 0.10±0.02), was positively correlated with the ratio of saturated to unsaturated fatty acids in IMCL (r=0.709, p=0.02). IMAT volume and IMCL FAS were both positively associated with plasma glucose concentration (β=300.6, p=0.02, and β=105.4, p=0.02, respectively). These results suggest that inter‐muscular fat accumulation and increased myocellular fatty acid saturation are related to each other and both may contribute to worsening glucose control.Grant Funding Source: Supported by NIH UL1 TR000006, Purdue Ingest Behav Res Ctr, Amer Egg Board, Dairy Res Inst

Can resveratrol help to maintain metabolic health?

The number of people suffering from metabolic diseases is dramatically increasing worldwide. This stresses the need for new therapeutic strategies to combat this growing epidemic of metabolic diseases. A reduced mitochondrial function is one of the characteristics of metabolic diseases and therefore a target for intervention. Here we review the evidence that mitochondrial function may act as a target to treat and prevent type 2 diabetes mellitus, and, if so, whether these effects are due to reduction in skeletal muscle fat accumulation. We describe how exercise may affect these parameters and can be beneficial for type 2 diabetes. We next focus on alternative ways to improve mitochondrial function in a non-exercise manner. Thus, in 2003, resveratrol (3,5,4'-trihydroxystilbene) was discovered to be a small molecule activator of sirtuin 1, an important molecular target regulating cellular energy metabolism and mitochondrial homoeostasis. Rodent studies have clearly demonstrated the potential of resveratrol to improve various metabolic health parameters. Here we review data in human subjects that is available on the effects of resveratrol on metabolism and mitochondrial function and discuss how resveratrol may serve as a new therapeutic strategy to preserve metabolic health. We also discuss whether the effects of resveratrol are similar to the effects of exercise training and therefore if resveratrol can be considered as an exercise mimetic.

Quercetin can reduce insulin resistance without decreasing adipose tissue and skeletal muscle fat accumulation

Quercetin exhibits a wide range of biological functions. The first aim of the present work was to analyze the effects of quercetin on fat accumulation in adipose tissue and glycemic control in rats. Any potential involvement of muscle fatty acid oxidation in its effect on glycemic control was also assessed. Animals were fed a high-fat high-sucrose diet either supplemented with quercetin (30mg/kg body weight/day), or not supplemented, for 6weeks. One week before killing, a glucose tolerance test was carried out. Muscle triacylglycerol content, serum glucose, insulin, fructosamine and free fatty acids were measured, and homeostatic model assessment for insulin resistance (HOMA-IR) was calculated. The activities of lipogenic enzymes and lipoprotein lipase in adipose tissue, carnitine palmitoyl transferase-1b (CPT-1b) and citrate synthase in skeletal muscle, and the expression of several genes, ACO, CD36, CPT-1b, PPAR-α, PGC-1α, UCP3, TFAM and COX-2 in skeletal muscle were analyzed. Quercetin caused no significant reduction in body weight or adipose tissue sizes. However, fructosamine, basal glucose and insulin, and consequently HOMA-IR, were significantly reduced by quercetin. No changes were observed in the activity of lipogenic enzymes and lipoprotein lipase. Muscle triacylglycerol content was similar in both experimental groups. The expression of ACO, CD36, CPT-1b, PPAR-α, PGC-1α, UCP3, TFAM and COX-2 remained unchanged. It can be concluded that quercetin is more effective as an anti-diabetic than as an anti-obesity biomolecule. The improvement in insulin resistance induced by this flavonoid is not mediated by a delipidating effect in skeletal muscle.

Severity of non‐alcoholic steatohepatitis is associated with substitution of adipose tissue in skeletal muscle

The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is now focusing on its organ cross-talk with not only adipose tissue but also systemic skeletal muscle. Cross-sectional and longitudinal studies were conducted to determine the role of intramuscular adipose tissue content (IMAC) measured by computed tomography on the severity of NAFLD/non-alcoholic steatohepatitis (NASH). Two hundred eight Japanese patients with NAFLD/NASH diagnosed by liver biopsy were enrolled into a cross-sectional study. Twenty-one patients were enrolled in a longitudinal study and received a programmed diet and exercise intervention, in some cases the combination of pharmacotherapy. We measured IMAC in the multifidus muscle and biochemical parameters, and conducted liver histology to assess NAFLD/NASH status. Histopathological stage in terms of simple steatosis and Brunt's classification was significantly correlated with IMAC (P < 0.01). Multivariate logistic regression analysis indicated that risk factors associated with the severity of NASH were IMAC and aging (IMAC: odds ratio = 2.444, P < 0.05; Age: odds ratio = 2.355, P < 0.05). The interventions improved histopathological changes in 11 patients with NASH as well as IMAC. These results suggest that skeletal muscle fat accumulation may have been linked to the pathogenesis and severity of NASH.

High Oxidative Capacity Due to Chronic Exercise Training Attenuates Lipid-Induced Insulin Resistance

Fat accumulation in skeletal muscle combined with low mitochondrial oxidative capacity is associated with insulin resistance (IR). Endurance-trained athletes, characterized by a high oxidative capacity, have elevated intramyocellular lipids, yet are highly insulin sensitive. We tested the hypothesis that a high oxidative capacity could attenuate lipid-induced IR. Nine endurance-trained (age = 23.4 ± 0.9 years; BMI = 21.2 ± 0.6 kg/m2) and 10 untrained subjects (age = 21.9 ± 0.9 years; BMI = 22.8 ± 0.6 kg/m2) were included and underwent a clamp with either infusion of glycerol or intralipid. Muscle biopsies were taken to perform high-resolution respirometry and protein phosphorylation/expression. Trained subjects had ∼32% higher mitochondrial capacity and ∼22% higher insulin sensitivity (P < 0.05 for both). Lipid infusion reduced insulin-stimulated glucose uptake by 63% in untrained subjects (P < 0.05), whereas this effect was blunted in trained subjects (29%, P < 0.05). In untrained subjects, lipid infusion reduced oxidative and nonoxidative glucose disposal (NOGD), whereas trained subjects were completely protected against lipid-induced reduction in NOGD, supported by dephosphorylation of glycogen synthase. We conclude that chronic exercise training attenuates lipid-induced IR and specifically attenuates the lipid-induced reduction in NOGD. Signaling data support the notion that high glucose uptake in trained subjects is maintained by shuttling glucose toward storage as glycogen.