Short-term physical inactivity induces diacylglycerol accumulation and insulin resistance in muscle via lipin1 activation

Physical inactivity impairs muscle insulin sensitivity. However, its mechanism is unclear. To model physical inactivity, we applied 24-h hind-limb cast immobilization (HCI) to mice with normal or high fat diet (HFD), and evaluated intramyocellular lipids and the insulin signaling pathway in the soleus muscle. While 2-wk HFD alone did not alter intramyocellular diacylglycerol (IMDG) accumulation, HCI alone increased it by 1.9-fold and HCI after HFD further increased it by 3.3-fold. Parallel to this, we found increased PKCε activity, reduced insulin-induced 2-deoxy-glucose (2-DOG) uptake, and reduced phosphorylation of IRβ and Akt, key molecules for insulin signaling pathway. Lipin1, which converts phosphatidic acid to diacylglycerol, showed increase of its activity by HCI, and dominant-negative lipin1 expression in muscle prevented HCI-induced IMDG accumulation and impaired insulin-induced 2-DOG uptake. Further, 24-h leg cast immobilization in human increased lipin1 expression. Thus, even short-term immobilization increases IMDG and impairs insulin sensitivity in muscle via enhanced lipin1 activity.

Contribution of Intramyocellular Lipids to Decreased Computed Tomography Muscle Density With Age

Skeletal muscle density, as determined by computed tomography (CT), has been shown to decline with age, resulting in increased frailty and morbidity. However, the mechanism underlying this decrease in muscle density remains elusive. We sought to investigate the role of intramyocellular lipid (IMCL) accumulation in the age-related decline in muscle density. Muscle density was measured using computerized tomography (CT), and IMCL content was quantified using in vivo proton magnetic resonance spectroscopy (1H-MRS). The study population consisted of 314 healthy participants (142 men, 32–98 years) of the Baltimore Longitudinal Study of Aging (BLSA). In addition to IMCL quantification, obesity-related covariates were measured, including body mass index (BMI), waist circumference, and circulating triglyceride concentration. Higher IMCL concentrations were significantly correlated with lower muscle density in older individuals, independent of age, sex, race, and the obesity-associated covariates (p < 0.01). Lower muscle density was also significantly associated with greater age-adjusted IMCL, a variable we constructed using LOESS regression (p < 0.05). Our results suggest that the accumulation of IMCL may be associated with a decrease in muscle density. This may serve to define a potential therapeutic target for treatment of age-associated decreased muscle function.

Sex-based differences in hepatic and skeletal muscle triglyceride storage and metabolism

Women and men store lipid differently within the body with men storing more fat in the android region and women storing more fat in the gynoid region. Fat is predominately stored in adipose tissue as triacylglycerides (TG); however, TG are also stored in other tissues including the liver and skeletal muscle. Excess hepatic TG storage, defined as a TG concentration >5% of liver weight and known as nonalcoholic fatty liver disease (NAFLD), is related to the metabolic syndrome. Similarly, elevated skeletal muscle TG, termed intramyocellular lipids (IMCL), are related to insulin resistance in obesity and type II diabetes. Men store more hepatic TG than women and, unsurprisingly, NAFLD is more prevalent in men than women. Women store more IMCL than men, yet type II diabetes risk is not greater, which is likely due to the manner in which women store TG within muscle. Sex-based differences in TG storage between men and women are underpinned by differences in messenger RNA expression, protein content, and enzyme activities of skeletal muscle and hepatic lipid metabolic pathways. Furthermore, women have a greater reliance on lipid during exercise because of upregulation of lipid oxidative pathways. The purpose of this review is to discuss the role of sex in mediating lipid storage and metabolism within skeletal muscle and the liver at rest and during exercise and its relationship with metabolic disease.

Accumulation of intramuscular toxic lipids, a link between fat mass accumulation and sarcopenia

Aging is characterized by a loss in muscle mass and function, which is defined as sarcopenia. It weakens individuals by increasing the risk of falls and altering their quality of life. The loss of muscle mass results from the age-related impairment of the anabolic effect of nutrients and insulin, which normally increase and decrease muscle protein synthesis and degradation rates respectively. Alterations in muscle protein metabolism have been related to the accumulation of body fat and intramyocellular lipids. In particular, some lipid species such as ceramides or diacylglycerols have been described as inhibitors of the insulin signaling pathway in different models. Accumulation of these molecules in skeletal muscle could result from a lowered buffering capacity of circulating fatty acids by adipose tissue in response to the meal, a reduction of mitochondrial oxidative capacities or chronic inflammation. However, some nutritional strategies have been identified to limit or prevent the accumulation of lipotoxic metabolites and to improve the sensitivity of muscle to nutrients or insulin.