Lipid Accumulation In Muscle Research Articles

Impaired Suppression of Plasma Lipid Extraction and its Partitioning Away from Muscle by Insulin in Humans with Obesity.

Humans with obesity and insulin resistance exhibit lipid accumulation in skeletal muscle, but the underlying biological mechanisms responsible for the accumulation of lipid in the muscle of these individuals remain unknown. We investigated how plasma insulin modulates the extraction of circulating triglycerides (TGs) and non-esterified fatty acids (NEFAs) from ingested and endogenous origin in the muscle of lean, insulin-sensitive humans (Lean-IS) and contrasted these responses to those in humans with obesity and insulin resistance (Obese-IR). The studies were performed in a postprandial state associated with steady-state plasma TG concentrations. The arterio-venous blood sampling technique was employed to determine the extraction of circulating lipids across the forearm muscle before and after insulin infusion. We distinguished kinetics of TGs and NEFAs from ingested origin from those from endogenous origin across muscle by incorporating stable isotope-labeled triolein in the ingested fat. Insulin infusion rapidly suppressed the extraction of plasma TGs from endogenous, but not ingested, origin in the muscle of the Lean-IS, but this response was absent in the muscle of the Obese-IR. Furthermore, in the muscle of the Lean-IS, insulin infusion decreased the extraction of circulating NEFAs from both ingested and endogenous origin; however, this response was absent for NEFAs from ingested origin in the muscle of the Obese-IR subjects. Partitioning of circulating lipids away from the skeletal muscle when plasma insulin increases during the postprandial period is impaired in humans with obesity and insulin resistance.

Impaired Suppression of Plasma Lipid Extraction and its Partitioning Away from Muscle by Insulin in Humans with Obesity.

Humans with obesity and insulin resistance exhibit lipid accumulation in skeletal muscle, but the underlying biological mechanisms responsible for the accumulation of lipid in the muscle of these individuals remain unknown. We investigated how plasma insulin modulates the extraction of circulating triglycerides (TGs) and non-esterified fatty acids (NEFAs) from ingested and endogenous origin in the muscle of lean, insulin-sensitive humans (Lean-IS) and contrasted these responses to those in humans with obesity and insulin resistance (Obese-IR). The studies were performed in a postprandial state associated with steady-state plasma TG concentrations. The arterio-venous blood sampling technique was employed to determine the extraction of circulating lipids across the forearm muscle before and after insulin infusion. We distinguished kinetics of TGs and NEFAs from ingested origin from those from endogenous origin across muscle by incorporating stable isotope-labeled triolein in the ingested fat. Insulin infusion rapidly suppressed the extraction of plasma TGs from endogenous, but not ingested, origin in the muscle of the Lean-IS, but this response was absent in the muscle of the Obese-IR. Furthermore, in the muscle of the Lean-IS, insulin infusion decreased the extraction of circulating NEFAs from both ingested and endogenous origin; however, this response was absent for NEFAs from ingested origin in the muscle of the Obese-IR subjects. Partitioning of circulating lipids away from the skeletal muscle when plasma insulin increases during the postprandial period is impaired in humans with obesity and insulin resistance.

Cellular communication network factor 2 regulates smooth muscle cell transdifferentiation and lipid accumulation in atherosclerosis.

Accruing evidence illustrates an emerging paradigm of dynamic vascular smooth muscle cell (SMC) transdifferentiation during atherosclerosis progression. However, the molecular regulators that govern SMC phenotype diversification remain poorly defined. This study aims to elucidate the functional role and underlying mechanisms of cellular communication network factor 2 (CCN2), a matricellular protein, in regulating SMC plasticity in the context of atherosclerosis. In both human and murine atherosclerosis, an up-regulation of CCN2 is observed in transdifferentiated SMCs. Using an inducible murine SMC CCN2 deletion model, we demonstrate that SMC-specific CCN2 knockout mice are hypersusceptible to atherosclerosis development as evidenced by a profound increase in lipid-rich plaques along the entire aorta. Single-cell RNA sequencing studies reveal that SMC deficiency of CCN2 positively regulates machinery involved in endoplasmic reticulum stress, endocytosis, and lipid accumulation in transdifferentiated macrophage-like SMCs during the progression of atherosclerosis, findings recapitulated in CCN2-deficient human aortic SMCs. Our studies illuminate an unanticipated protective role of SMC-CCN2 against atherosclerosis. Disruption of vascular wall homeostasis resulting from vascular SMC CCN2 deficiency predisposes mice to atherosclerosis development and progression.

Effects of high α-linolenic acid transgenic rapeseed oil diet on growth performance, fat deposition, flesh quality, antioxidant capacity, and immunity of juvenile largemouth bass (Micropterus salmoides).

Omega-3 long-chain polyunsaturated fatty acid (n-3 LC-PUFA) increases in aquatic products contributes to improving meat quality, thereby positively impacting human health. Different from marine fish which primarily obtain n-3 LC-PUFAs directly from zooplankton and algae, freshwater fish mainly utilize dietary linolenic acid (ALA) as a substrate to synthesize n-3 LC-PUFAs. Our team has successfully created a transgenic rapeseed oil (TRO) with high ALA content. Therefore, we here assessed the impacts of four different diets (LR, low-fat rapeseed oil (RO) diet; HR, high-fat RO diet; LTR, low-fat TRO diet; HTR, high-fat TRO diet) on growth performance, lipid accumulation, fatty acid composition, antioxidant capacity, immunity and serum biochemical indexes of juvenile largemouth bass (Micropterus salmoides), an economically valuable freshwater fish. The results showed no significant difference in survival rate among the four dietary groups. No significant differences in body weight gain and final weight were found between the LR and LTR groups, as well as between HR and HTR groups. No matter if it was a high-fat or low-fat diet, compared with the RO diet, TRO diets significantly increased the content of n-3 LC-PUFA, improved meat quality, effectively alleviated lipid accumulation in livers and muscles of juvenile largemouth bass. In addition, using high-fat diets, TRO diet improved the antioxidant capacity and immune ability of juvenile largemouth bass, thereby promoting the overall health of fish. This study provides novel insights for fish feed formulation optimization from the perspective of genetically modified feed ingredients, and high-quality aquatic products for human consumption.

6-Gingerol improves lipid metabolism disorders in skeletal muscle by regulating AdipoR1/AMPK signaling pathway

BackgroundTo delve into the precise mechanisms by which 6-gingerol ameliorates lipid metabolism disorders in skeletal muscle. MethodsThe level of triglycerides (TG) was used to evaluate lipid deposition. In skeletal muscle, transmission electron microscopy (TEM) was employed to observe mitochondrial morphology. Additionally, PCR was applied to detect mitochondrial biogenesis, and levels of malondialdehyde (MDA), catalase (CAT), glutathione, r-glutamyl cysteingl+glycine (GSH) and nicotinamide adenine dinucleotide (NADH) were measured to assess mitochondrial oxidative stress levels. In vivo, flow cytometry and immunofluorescence assays were conducted to quantify reactive oxygen species (ROS) and mitochondrial membrane potential (MMP). Furthermore, the Seahorse XF assays was utilized to assess mitochondrial respiratory capacity. Fluorescence confocal microscopy and molecular docking were applied to analyze the binding of 6-gingerol and adiponectin receptor 1 (AdipoR1). The expression of AdipoR1, AMPK, PGC-1α and SIRT1 were detected by Western Blot. ResultsIn vivo, 6-gingerol could reduce body weight in mice induced by a high-fat diet, enhance metabolic profiles in plasma, decrease lipid accumulation in skeletal muscle and liver, and elevate adiponectin levels. In skeletal muscle, it could restore mitochondrial morphology, boost mitochondrial copy number and biogenesis, and mitigate oxidative stress. In vitro, 6-gingerol may directly interact with AdipoR1 to upregulate the expression of downstream proteins p-AMPK, SIRT1, and PGC-1α, leading to a reduction in lipid deposition, a decrease in ROS production, an increase in mitochondrial membrane potential, and an enhancement of mitochondrial respiratory capacity in C2C12 myotubes. Conclusion6-Gingerol ameliorated lipid metabolism in skeletal muscle by regulating the AdipoR1/AMPK signaling pathway.

Enhanced ECCD36 signaling promotes skeletal muscle insulin resistance in female mice.

Consumption of a Western diet (WD) increases CD36 expression in vascular, hepatic, and skeletal muscle tissues promoting lipid metabolic disorders and insulin resistance. We further examined the role of endothelial cell-specific CD36 (ECCD36) signaling in contributing to skeletal muscle lipid metabolic disorders, insulin resistance, and their underlying molecular mechanisms. Female ECCD36 wild-type (ECCD36+/+) and knock-out (ECCD36-/-) mice, aged 6 wk, were provided with either a WD or a standard chow diet for a duration of 16 wk. ECCD36+/+ WD mice were characterized by elevated fasting plasma glucose and insulin levels, increased homeostatic model assessment for insulin resistance, and glucose intolerance that was blunted in ECCD36-/- mice. Improved insulin sensitivity in ECCD36-/- mice was characterized by increased phosphoinositide 3-kinases/protein kinase B signaling that further augmented glucose transporter type 4 expression and glucose uptake. Meanwhile, 16 wk of WD feeding also increased skeletal muscle free fatty acid (FFA) and lipid accumulation, without any observed changes in plasma FFA levels. These lipid metabolic disorders were blunted in ECCD36-/- mice. Moreover, ECCD36 also mediated in vitro palmitic acid-induced lipid accumulation in cultured ECs, subsequently leading to the release of FFAs into the culture media. Furthermore, consumption of a WD increased FFA oxidation, mitochondrial dysfunction, impaired mitochondrial respiratory, skeletal muscle fiber type transition, and fibrosis. These WD-induced abnormalities were blunted in ECCD36-/- mice. These findings demonstrate that endothelial-specific ECCD36 signaling participates in skeletal muscle FFA uptake, ectopic lipid accumulation, mitochondrial dysfunction, insulin resistance, and associated skeletal muscle dysfunction in diet-induced obesity.NEW & NOTEWORTHY ECCD36 exerts "extra endothelial cell" actions in skeletal muscle insulin resistance. ECCD36 is a major mediator of Western diet-induced lipid metabolic disorders and insulin resistance in skeletal muscle. Mitochondrial dysfunction is associated with diet-induced CD36 activation and related skeletal muscle insulin resistance.

Dapagliflozin improves skeletal muscle insulin sensitivity through SIRT1 activation induced by nutrient deprivation state

Lipid peroxidation and mitochondrial damage impair insulin sensitivity in skeletal muscle. Sirtuin-1 (SIRT1) protects mitochondria and activates under energy restriction. Dapagliflozin (Dapa) is an antihyperglycaemic agent that belongs to the sodium-glucose cotransporter-2 (SGLT2) inhibitors. Evidence shows that Dapa can induce nutrient deprivation effects, providing additional metabolic benefits. This study investigates whether Dapa can trigger nutrient deprivation to activate SIRT1 and enhance insulin sensitivity in skeletal muscle. We treated diet-induced obese (DIO) mice with Dapa and measured metabolic parameters, lipid accumulation, oxidative stress, mitochondrial function, and glucose utilization in skeletal muscle. β-hydroxybutyric acid (β-HB) was intervened in C2C12 myotubes. The role of SIRT1 was verified by RNA interference. We found that Dapa treatment induced nutrient deprivation state and reduced lipid deposition and oxidative stress, improved mitochondrial function and glucose tolerance in skeletal muscle. The same positive effects were observed after β-HB intervening for C2C12 myotubes, and the promoting effects on glucose utilization were diminished by SIRT1 RNA interference. Thus, Dapa promotes a nutrient deprivation state and enhances skeletal muscle insulin sensitivity via SIRT1 activation. In this study, we identified a novel hypoglycemic mechanism of Dapa and the potential mechanistic targets.

Inflammation-associated intramyocellular lipid alterations in human pancreatic cancer cachexia.

Cancer cachexia is a multifactorial metabolic syndrome characterized by systemic inflammation and ongoing skeletal muscle loss resulting in weakness, poor quality of life, and decreased survival. Whereas lipid accumulation in skeletal muscle is associated with cancer cachexia as well as the prognosis of cancer patients, surprisingly little is known about the nature of the lipids that accumulate in the muscle during cachexia, and whether this is related to inflammation. We aimed to identify the types and distributions of intramyocellular lipids in patients with and without cancer cachexia. Rectus abdominis muscle biopsies were collected during surgery of patients with pancreatic ductal adenocarcinoma (n=10 without cachexia, n=20 cachectic without inflammation (CRP<10mg/L), n=10 cachectic with inflammation (CRP≥10mg/L). L3-CT scans were analysed to assess body composition based on validated thresholds in Hounsfield units (HU). Muscle sections were stained with Oil-Red O and H&E to assess general lipid accumulation and atrophy. Untargeted lipidomic analyses were performed on laser-microdissected myotubes using LC-MS/MS. The spatial distribution of intramyocellular lipids with differential abundance between groups was visualized by mass-spectrometry imaging. Genes coding for inflammation markers and enzymes involved in de novo ceramide synthesis were studied by qPCR. Muscle radiation attenuation was lower in cachectic patients with inflammation (median 24.3 [18.6-30.8] HU) as compared with those without inflammation (34.2 [29.3-38.7] HU, P=0.033) or no cachexia (37.4 [33.9-42.9] HU, P=0.012). Accordingly, intramyocellular lipid content was lower in non-cachectic patients (1.9 [1.6-2.1]%) as compared with those with cachexia with inflammation (5.5 [4.5-7.3]%, P=0.002) or without inflammation (4.8 [2.6-6.0]%, P=0.017). Intramyocellular lipid accumulation was associated with both local IL-6 mRNA levels (rs=0.57, P=0.015) and systemic CRP levels (rs=0.49, P=0.024). Compared with non-cachectic subjects, cachectic patients had a higher relative abundance of intramyocellular glycerophospholipids and a lower relative abundance of glycerolipids. Furthermore, increases in several intramyocellular lipids such as SM(d36:1), PC(34:1), and TG(48:1) were found in cachectic patients with inflammation and correlated with specific cachexia features. Altered intramyocellular lipid species such as PC(34:1), LPC(18:2), and TG(48:1) showed an uneven distribution in muscle sections of cachectic and non-cachectic patients, with areas featuring abundance of these lipids next to areas almost devoid of them. Intramyocellular lipid accumulation in patients with cachexia is associated with both local and systemic inflammation, and characterized by changes in defined lipid species such as glycerolipids and glycerophospholipids.

Insulin resistance and dyslipidemia in low-birth-weight goat kids.

Low birth weight (LBW) impairs the development and health of livestock by affecting postnatal growth performance and metabolic health in adulthood. Previous studies on indigenous goats in southwest China showed that LBW goat kids had higher mortality and morbidity rates, including hepatic dyslipidemia and liver damage. However, the mechanism of insulin resistance affecting lipid metabolism under LBW conditions remains unclear. In this study, we conducted in vivo glucose-insulin metabolic studies, measured biochemical parameters, and analyzed related regulatory pathways. Both glucose tolerance tests and insulin tolerance tests indicated insulin resistance in LBW goat kids compared to controls (p < 0.05). The marker of insulin resistance, homeostasis model assessment (HOMA), was 2.85-fold higher in LBW than in control goats (p < 0.01). Additionally, elevated levels of free fatty acids in both plasma and skeletal muscle were observed in LBW goats compared to normal birth weight (NBW) goats (p < 0.05). Transcriptome analysis revealed impairments in lipid metabolism and insulin signaling in LBW goats. The observed lipid accumulation was associated with the upregulation of genes linked to fatty acid uptake and transport (FABP3), fatty acid oxidation (PPARA), triacylglycerol synthesis (LPIN1 and DGAT1), oxidative stress (ANKRD2), and insulin resistance (PGC1α). Furthermore, the insulin receptor substrate 2 (IRS2) was lower in the liver of LBW goat kids (p < 0.05). While there was no change in insulin function in skeletal muscle, LBW may lead to lipid accumulation in skeletal muscle by interfering with insulin function in the liver. These findings collectively impact the health and growth performance of livestock.

A lipidomics approach reveals novel phospholipid changes in palmitate-treated C2C12 myotubes.

Type 2 diabetes mellitus (T2DM) is a highly prevalent metabolic disorder. Insulin resistance and oxidative stress are associated with T2DM development. The hypothesis that patients with T2DM show excess accumulation of lipids, such as ceramides (Cers) and diacylglycerols (DAGs), in their skeletal muscles has been widely supported; however, detailed lipidomic data at the molecular species level are limited. Therefore, in this study, we aimed to investigate the in vitro dynamics of total lipids, including phospholipids (PLs), sphingolipids, and neutral lipids, in palmitic acid-induced insulin-resistant C2C12 skeletal muscle cells. Our data demonstrated that the profiles of not only Cers and DAGs but also those of PLs showed considerably differences after palmitate treatment. We found that PL synthesis reduced and PL degradation increased after palmitate treatment. These findings may aid in the development of treatments to ameliorate muscle dysfunction caused by lipid accumulation in muscles.

Gromwell (Lithospermum erythrorhizon) Attenuates High-Fat-Induced Skeletal Muscle Wasting by Increasing Protein Synthesis and Mitochondrial Biogenesis.

Gromwell (Lithospermum erythrorhizon, LE) can mitigate obesity-induced skeletal muscle atrophy in C2C12 myotubes and high-fat diet (HFD)-induced obese mice. The purpose of this study was to investigate the anti-skeletal muscle atrophy effects of LE and the underlying molecular mechanism. C2C12 myotubes were pretreated with LE or shikonin, and active component of LE, for 24 h and then treated with 500 μM palmitic acid (PA) for an additional 24 h. Additionally, mice were fed a HFD for 8 weeks to induced obesity, and then fed either the same diet or a version containing 0.25% LE for 10 weeks. LE attenuated PA-induced myotubes atrophy in differentiated C2C12 myotubes. The supplementation of LE to obese mice significantly increased skeletal muscle weight, lean body mass, muscle strength, and exercise performance compared with those in the HFD group. LE supplementation not only suppressed obesity-induced skeletal muscle lipid accumulation, but also downregulated TNF-α and atrophic genes. LE increased protein synthesis in the skeletal muscle via the mTOR pathway. We observed LE induced increase of mitochondrial biogenesis and upregulation of oxidative phosphorylation related genes in the skeletal muscles. Furthermore, LE increased the expression of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha and the phosphorylation of adenosine monophosphate-activated protein kinase. Collectively, LE may be useful in ameliorating the detrimental effects of obesity-induced skeletal muscle atrophy through the increase of protein synthesis and mitochondrial biogenesis of skeletal muscle.

Tissue Lipid Profiles of Rainbow Trout, Oncorhynchus mykiss, Cultivated under Environmental Variables on a Diet Supplemented with Dihydroquercetin and Arabinogalactan.

Reared rainbow trout are vulnerable to environmental stressors, in particular seasonal water warming, which affects fish welfare and growth and induces a temperature response, which involves modifications in tissue lipid profiles. Dietary supplements of plant origin, including the studied mix of a flavonoid, dihydroquercetin and a polysaccharide, arabinogalactan (25 and 50 mg per 1 kg of feed, respectively), extracted from larch wood waste, were shown to facilitate stress tolerance in fish and also to be beneficial for the safety of natural ecosystems and the sustainability of aquaculture production. This four-month feeding trial aimed to determine the effects of the supplement on liver and muscle lipid accumulation and the composition in rainbow trout reared under environmental variables. During periods of environmental optimum for trout, a consistent increase in energy lipid stores, particularly triacylglycerols (2.18 vs. 1.49-fold over a growing season), and an overall increase in lipid saturation due to lower levels of PUFAs, such as eicosapentaenoic (20:5n-3), docosahexaenoic (22:6n-3) and arachidonic (20:4n-6) acids, were observed in both control and supplement-fed fish, respectively. However, in fish stressed by an increase in ambient temperature, dietary supplementation with dihydroquercetin and arabinogalactan reduced mortality (3.65 in control vs. 2.88% in supplement-fed fish, p < 0.05) and alleviated the high-temperature-induced inhibition of lipid accumulation. It also stabilised the membrane phospholipid ratio and moderated the fatty acid composition of fish muscle and liver, resulting in higher levels of n-3 PUFAs and their precursors. Thus, the natural compounds tested are beneficial in accelerating fish tolerance to environmental stressors, reducing mortality and thermal response, and moderately improving fillet quality attributes by increasing the protein/lipid ratio and the abundance of fatty acids essential for human nutrition.

Combination therapy of metformin and morin attenuates insulin resistance, inflammation, and oxidative stress in skeletal muscle of high-fat diet-fed mice.

Lipid accumulation, inflammation, and oxidative stress are the most important causes of muscle insulin resistance. The aim of this study was to investigate the single and combined treatment effects of metformin (MET) and morin (MOR) on lipid accumulation, inflammation, and oxidative stress in the skeletal muscle of mice fed a high-fat diet. The mice were supplemented with MET (230 mg/kg diet), MOR (100 mg/kg diet), and MET + MOR for 9 weeks. Our results revealed that single treatment with MET or MOR, and with a stronger effect of MET + MOR combined treatment, reduced body weight gain, improved glucose intolerance and enhanced Akt phosphorylation in the muscle tissue. In addition, plasma and muscle triglyceride levels were decreased after treatment with MET and MOR. The expression of genes involved in macrophage infiltration and polarization and pro-inflammatory cytokines showed that MET + MOR combined treatment, significantly reduced inflammation in the muscle. Furthermore, combined treatment of MET + MOR with greater efficacy than the single treatment improved several oxidative stress markers in the muscle. Importantly, combined treatment of MET and MOR could increase the expression of nuclear factor erythroid 2-related factor 2, the master regulator of the antioxidant response. These findings suggest that combination of MET with MOR might ameliorate insulin resistance, inflammation, and oxidative stress in the skeletal muscle of mice fed high-fat diet.

Genome-wide association studies to identify quantitative trait loci and positional candidate genes affecting meat quality-related traits in pigs.

Meat quality comprises a set of key traits such as pH, meat color, water-holding capacity, tenderness and marbling. These traits are complex because they are affected by multiple genetic and environmental factors. The aim of this study was to investigate the molecular genetic basis underlying nine meat quality-related traits in a Yorkshire pig population using a genome-wide association study (GWAS) and subsequent biological pathway analysis. In total, 45,926 single nucleotide polymorphism (SNP) markers from 543 pigs were selected for the GWAS after quality control. Data were analyzed using a genome-wide efficient mixed model association (GEMMA) method. This linear mixed model-based approach identified two quantitative trait loci (QTLs) for meat color (b*) on chromosome 2 (SSC2) and one QTL for shear force on chromosome 8 (SSC8). These QTLs acted additively on the two phenotypes and explained 3.92%-4.57% of the phenotypic variance of the traits of interest. The genes encoding HAUS8 on SSC2 and an lncRNA on SSC8 were identified as positional candidate genes for these QTLs. The results of the biological pathway analysis revealed that positional candidate genes for meat color (b*) were enriched in pathways related to muscle development, muscle growth, intramuscular adipocyte differentiation, and lipid accumulation in muscle, whereas positional candidate genes for shear force were overrepresented in pathways related to cell growth, cell differentiation, and fatty acids synthesis. Further verification of these identified SNPs and genes in other independent populations could provide valuable information for understanding the variations in pork quality-related traits.

LKB1 delays atherosclerosis by inhibiting phenotypic transformation of vascular smooth muscle cells

Background and objectiveAlthough liver kinase B1 (LKB1) is a well-known tumor suppressor gene, and its encoded protein has important biological functions, it is not clear whether LKB1 can inhibit atherosclerosis by regulating vascular smooth muscle cells (VSMCs). The purpose of this study is to explore the relationship among LKB1, VSMCs and atherosclerosis. Methods and resultsApoE−/− mice with VSMCs-specific overexpression of LKB1 were constructed by adeno-associated virus transfection technique, and then fed with high-fat diet for eight weeks. The effect of LKB1 overexpression on atherosclerosis in mice was investigated by oil red O staining, HE staining, immunofluorescence and Western Blot. The results showed that the expression of LKB1 mRNA and protein in arterial tissue of mice increased significantly after overexpression of LKB1. The degree of atherosclerosis, smooth muscle fiber proliferation and lipid accumulation were significantly alleviated in the overexpression group. The results of Western Blot showed that the expression of α-SMA was increased, while the expression of OPN and CD68 was significantly decreased in the overexpression group (P < 0.05). The Immunofluorescence results of Image Pro Plus software analysis showed that the co-localization relationship between α-SMA and CD68 was more obvious in the control group (P < 0.01). ConclusionOur results suggested that LKB1 can delay the progression of atherosclerosis by inhibiting the phenotypic transition of VSMCs.

Nutritional regulation of skeletal muscle energy metabolism, lipid accumulation and meat quality in pigs.

The quality of pork determines consumers' purchase intention, which directly affects the economic value of pork. Minimizing the proportion of inferior pork and producing high quality pork are the ultimate goals of the pig industry. Muscle energy metabolism, serving as a regulative hub in organism energy expenditure and storage as a fat deposit, is compatible with myofiber type composition, affecting meat color, intramuscular fat content, tenderness, pH values and drip loss. Increasing data illustrate that dietary nutrients and bioactive ingredients affect muscle energy metabolism, white adipose browning and fat distribution, and myofiber type composition in humans, and rodents. Recently, some studies have shown that modulating muscle energy metabolism and lipid accumulation through nutritional approaches could effectively improve meat quality. This article reviews the progress and development in this field, and specifically discusses the impacts of dietary supply of amino acids, lipids, and gut microbiota as well as maternal nutrition on skeletal muscle energy metabolism, lipid accumulation and meat quality of pigs, so as to provide comprehensive overview with respect to effective avenues for improving meat quality.

CDK4-E2F3 signals enhance oxidative skeletal muscle fiber numbers and function to affect myogenesis and metabolism.

Understanding how skeletal muscle fiber proportions are regulated is vital to understanding muscle function. Oxidative and glycolytic skeletal muscle fibers differ in their contractile ability, mitochondrial activity, and metabolic properties. Fiber-type proportions vary in normal physiology and disease states, although the underlying mechanisms are unclear. In human skeletal muscle, we observed that markers of oxidative fibers and mitochondria correlated positively with expression levels of PPARGC1A and CDK4 and negatively with expression levels of CDKN2A, a locus significantly associated with type 2 diabetes. Mice expressing a constitutively active Cdk4 that cannot bind its inhibitor p16INK4a, a product of the CDKN2A locus, were protected from obesity and diabetes. Their muscles exhibited increased oxidative fibers, improved mitochondrial properties, and enhanced glucose uptake. In contrast, loss of Cdk4 or skeletal muscle-specific deletion of Cdk4's target, E2F3, depleted oxidative myofibers, deteriorated mitochondrial function, and reduced exercise capacity, while increasing diabetes susceptibility. E2F3 activated the mitochondrial sensor PPARGC1A in a Cdk4-dependent manner. CDK4, E2F3, and PPARGC1A levels correlated positively with exercise and fitness and negatively with adiposity, insulin resistance, and lipid accumulation in human and rodent muscle. All together, these findings provide mechanistic insight into regulation of skeletal muscle fiber-specification that is of relevance to metabolic and muscular diseases.

Endothelial MRs mediate Western diet-induced lipid disorders and skeletal muscle insulin resistance in females.

Consumption of a Western diet (WD) consisting of excess fat and carbohydrates activates the renin-angiotensin-aldosterone system, which has emerged as an important risk factor for systemic and tissue insulin resistance. We recently discovered that activated mineralocorticoid receptors (MRs) in diet-induced obesity induces CD36 expression, increases ectopic lipid accumulation, and results in systemic and tissue insulin resistance. Here, we further investigated whether endothelial cell (EC) specific MR (ECMR) activation participates in WD-induced ectopic skeletal muscle lipid accumulation, insulin resistance and dysfunction. Six-week-old female ECMR knockout (ECMR-/-) and wild type (ECMR+/+) mice were fed either a WD or a chow diet for 16 weeks. ECMR-/- mice were found to have decreased WD-induced in vivo glucose intolerance and insulin resistance at 16-weeks. Improved insulin sensitivity was accompanied by increased glucose transporter type 4 (Glut4) expression in conjunction with improved soleus insulin metabolic signaling in phosphoinositide 3-kinases/protein kinase B and endothelial nitric oxide synthase activation. Additionally, ECMR-/- also blunted WD-induced increases in CD36 expression and associated elevations in soleus free fatty acid, total intramyocellular lipid content, oxidative stress, and soleus fibrosis. Moreover, in vitro and in vivo activation of ECMR increased EC derived exosomal CD36 that was further taken up by skeletal muscle cells, leading to increased skeletal muscle CD36 levels. These findings indicate that in the context of an obesogenic WD, enhanced ECMR signaling increases EC derived exosomal CD36 resulting in increased uptake and elevated concentrations of CD36 in skeletal muscle cells, contributing to increased lipid metabolic disorders and soleus insulin resistance.

Cabergoline counteracts adipose and skeletal muscle lipid accumulation through promoting oxidative pathway: an in vivo and in vitro preclinical study

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Effects of Triheptanoin on Mitochondrial Respiration and Glycolysis in Cultured Fibroblasts from Neutral Lipid Storage Disease Type M (NLSD-M) Patients

Neutral lipid storage disease type M (NLSD-M) is an ultra-rare, autosomal recessive disorder that causes severe skeletal and cardiac muscle damage and lipid accumulation in all body tissues. In this hereditary pathology, the defective action of the adipose triglyceride lipase (ATGL) enzyme induces the enlargement of cytoplasmic lipid droplets and reduction in the detachment of mono- (MG) and diglycerides (DG). Although the pathogenesis of muscle fiber necrosis is unknown, some studies have shown alterations in cellular energy production, probably because MG and DG, the substrates of Krebs cycle, are less available. No tests have been tried with medium-chain fatty acid molecules to evaluate the anaplerotic effect in NLSD cells. In this study, we evaluated the in vitro effect of triheptanoin (Dojolvi®), a highly purified chemical triglyceride with seven carbon atoms, in fibroblasts obtained from five NLSD-M patients. Glycolytic and mitochondrial functions were determined by Seahorse XF Agylent Technology, and cellular viability and triglyceride content were measured through colorimetric assays. After the addition of triheptanoin, we observed an increase in glycolysis and mitochondrial respiration in all patients compared with healthy controls. These preliminary results show that triheptanoin is able to induce an anaplerotic effect in NLSD-M fibroblasts, paving the way towards new therapeutic strategies.