The extracellular matrix (ECM) is a highly dynamic compartment that undergoes remodeling as a result of injury and repair. Over the past decade, mounting evidence in humans and rodents suggest that ECM remodeling is associated with diet-induced insulin resistance in several metabolic tissues. Additionally, integrin receptors for the ECM have also been implicated in the regulation of insulin action. This review will address what is currently known about the ECM, integrins and insulin action in the muscle, liver and adipose tissue. Understanding how ECM remodeling and integrin signaling regulates insulin action may aid in the development of new therapeutic targets for the treatment of insulin resistance and type 2 diabetes.

In summary, 1000 mg x d(-1) Q versus P for 2 wk by untrained males was associated with a small but significant improvement in 12-min treadmill time trial performance and modest but insignificant increases in the relative copy number of mitochondrial DNA and messenger RNA levels of four genes related to mitochondrial biogenesis.

Protein hyperacetylation is associated with glucose intolerance and insulin resistance, suggesting that the enzymes regulating the acetylome play a role in this pathological process. Sirtuin 3 (SIRT3), the primary mitochondrial deacetylase, has been linked to energy homeostasis. Thus, it is hypothesized that the dysregulation of the mitochondrial acetylation state, via genetic deletion of SIRT3, will amplify the deleterious effects of a high-fat diet (HFD). Hyperinsulinemic-euglycemic clamp experiments show, for the first time, that mice lacking SIRT3 exhibit increased insulin resistance due to defects in skeletal muscle glucose uptake. Permeabilized muscle fibers from HFD-fed SIRT3 knockout (KO) mice showed that tricarboxylic acid cycle substrate–based respiration is decreased while fatty acid–based respiration is increased, reflecting a fuel switch from glucose to fatty acids. Consistent with reduced muscle glucose uptake, hexokinase II (HKII) binding to the mitochondria is decreased in muscle from HFD-fed SIRT3 KO mice, suggesting decreased HKII activity. These results show that the absence of SIRT3 in HFD-fed mice causes profound impairments in insulin-stimulated muscle glucose uptake, creating an increased reliance on fatty acids. Insulin action was not impaired in the lean SIRT3 KO mice. This suggests that SIRT3 protects against dietary insulin resistance by facilitating glucose disposal and mitochondrial function.

The accelerated metabolic demands of the working muscle cannot be met without a robust response from the liver. If not for the hepatic response, sustained exercise would be impossible. The liver stores, releases, and recycles potential energy. Exercise would result in hypoglycemia if it were not for the accelerated release of energy as glucose. The energetic demands on the liver are largely met by increased oxidation of fatty acids mobilized from adipose tissue. Adaptations immediately following exercise facilitate the replenishment of glycogen stores. Pancreatic glucagon and insulin responses orchestrate the hepatic response during and immediately following exercise. Like skeletal muscle and other physiological systems, liver adapts to repeated demands of exercise by increasing its capacity to produce energy by oxidizing fat. The ability of regular physical activity to increase fat oxidation is protective and can reverse fatty liver disease. Engaging in regular physical exercise has broad ranging positive health implications including those that improve the metabolic health of the liver.

Two-week supplementation with Q-EGCG was effective in augmenting GOBA andin countering inflammation after 3 d of heavy exertion in trained cyclists.

Highlights d Mitochondria lacking CrAT and Sirt3 are susceptible to extreme protein acetylation d Hyperacetylation is accompanied by disturbances in redox balance and insulin action d Hyperacetylation does not affect mitochondrial respiration and enhances fat oxidation d Sirt3 flux and acetyl-lysine turnover promote a fuel switch from fat to glucose

Diet-induced muscle insulin resistance is associated with expansion of extracellular matrix (ECM) components, such as collagens, and the expression of collagenbinding integrin, a2b1. Integrins transduce signals from ECM via their cytoplasmic domains, which bind to intracellular integrin-binding proteins. The integrinlinked kinase (ILK)-PINCH-parvin (IPP) complex interacts with the cytoplasmic domain of b-integrin subunits and is critical for integrin signaling. In this study we defined the role of ILK, a key component of the IPP complex, in diet-induced muscle insulin resistance. Wild-type (ILK lox/lox ) and muscle-specific ILK-deficient (ILK lox/lox HSAcre) mice were fed chow or a high-fat (HF) diet for 16 weeks. Body weight was not different between ILK lox/lox and ILK lox/lox HSAcre mice. However, HF-fed ILK lox/lox HSAcre mice had improved muscle insulin sensitivity relative to HF-fed ILK lox/lox mice, as shown by increased rates of glucose infusion, glucose disappearance, and muscle glucose uptake during a hyperinsulinemic-euglycemic clamp. Improved muscle insulin action in the HF-fed ILK lox/lox HSAcre mice was associated with increased insulin-stimulated phosphorylation of Akt and increased muscle capillarization. These results suggest that ILK expression in muscle is a critical component of diet-induced insulin resistance, which possibly acts by impairing insulin signaling and insulin perfusion through capillaries.Insulin resistance is a commonly associated risk factor for many pathophysiological conditions, including diabetes, cardiovascular diseases, neurological changes, liver diseases, and sleep apnea (1,2). A defect in glucose utilization in the skeletal muscle is a major component of insulin resistance. The pathogenesis of muscle insulin resistance is not fully understood, and pharmacological interventions that reduce insulin resistance are limited and often lose efficacy over time (e.g., biguanides) or have adverse side effects (e.g., thiazolidinediones) (3). Our recent studies have suggested a novel role for extramyocellular factors in regulating muscle insulin action. Expansion of extracellular matrix (ECM) components, such as the collagens and the expression of the collagen-binding integrin a2b1, are associated with muscle insulin resistance induced by a high-fat (HF) diet (4). The ECM is in direct contact with the muscle capillaries. Defects in recruitment of muscle capillaries contribute to the development of muscle insulin resistance (5). Transduction of ECM signals through integrins requires interaction of the integrin cytoplasmic domains with cellular proteins. To investigate the link between ECM-integrin signaling and muscle insulin resistance, we studied a highly conserved central downstream component of the ECM-integrin signaling, integrin-linked kinase (ILK), and its role in muscle insulin resistance.ILK, a pseudokinase with adaptor function, is a central component of the ILK-PINCH-parvin complex (IPP) (6). This complex binds to the cytoplasmic domain of b-integrin subunits. The IPP co...

SUMMARY Acyl CoA metabolites derived from the catabolism of carbon fuels can react with lysine residues of mitochondrial proteins, giving rise to a large family of post-translational modifications (PTMs). Mass spectrometry-based detection of thousands of acyl-PTMs scattered throughout the proteome has established a strong link between mitochondrial hyperacylation and cardiometabolic diseases; however, the functional consequences of these modifications remain uncertain. Here, we use a comprehensive respiratory diagnostics platform to evaluate three disparate models of mitochondrial hyperacylation in the mouse heart caused by genetic deletion of malonyl CoA decarboxylase (MCD), SIRT5 demalonylase and desuccinylase, or SIRT3 deacetylase. In each case, elevated acylation is accompanied by marginal respiratory phenotypes. Of the >60 mitochondrial energy fluxes evaluated, the only outcome consistently observed across models is a ~15% decrease in ATP synthase activity. In sum, the findings suggest that the vast majority of mitochondrial acyl PTMs occur as stochastic events that minimally affect mitochondrial bioenergetics.