The potential of endurance exercise-derived exosomes to treat metabolic diseases

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Abstract

Endurance exercise-mediated multisystemic adaptations are known to mitigate metabolism-related disorders such as obesity and type 2 diabetes mellitus (T2DM). However, the underlying molecular mechanisms that promote crosstalk between organs and orchestrate the pro-metabolic effects of endurance exercise remain unclear. Exercise-induced release of peptides and nucleic acids from skeletal muscle and other organs (collectively termed 'exerkines') has been implicated in mediating these systemic adaptations. Given that the extracellular milieu is probably not a hospitable environment for labile exerkines, a lipid vehicle-based mode of delivery has originated over the course of evolution. Two types of extracellular vesicles, exosomes and microvesicles, have been shown to contain proteins and nucleic acids that participate in a variety of physiological and pathological processes. Exosomes, in particular, have been shown to facilitate the exchange of peptides, microRNA, mRNA and mitochondrial DNA between cells and tissues. Intriguingly, circulatory extracellular vesicle content increases in an intensity-dependant manner in response to endurance exercise. We propose that the systemic benefits of exercise are modulated by exosomes and/or microvesicles functioning in an autocrine, paracrine and/or endocrine manner. Furthermore, we posit that native or modified exosomes, and/or microvesicles enriched with exerkines will have therapeutic utility in the treatment of obesity and T2DM.

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Muscles, exercise and obesity: skeletal muscle as a secretory organ.

Bente K. Pedersen, Mark A. Febbraio (2012)

During the past decade, skeletal muscle has been identified as a secretory organ. Accordingly, we have suggested that cytokines and other peptides that are produced, expressed and released by muscle fibres and exert either autocrine, paracrine or endocrine effects should be classified as myokines. The finding that the muscle secretome consists of several hundred secreted peptides provides a conceptual basis and a whole new paradigm for understanding how muscles communicate with other organs, such as adipose tissue, liver, pancreas, bones and brain. However, some myokines exert their effects within the muscle itself. Thus, myostatin, LIF, IL-6 and IL-7 are involved in muscle hypertrophy and myogenesis, whereas BDNF and IL-6 are involved in AMPK-mediated fat oxidation. IL-6 also appears to have systemic effects on the liver, adipose tissue and the immune system, and mediates crosstalk between intestinal L cells and pancreatic islets. Other myokines include the osteogenic factors IGF-1 and FGF-2; FSTL-1, which improves the endothelial function of the vascular system; and the PGC-1α-dependent myokine irisin, which drives brown-fat-like development. Studies in the past few years suggest the existence of yet unidentified factors, secreted from muscle cells, which may influence cancer cell growth and pancreas function. Many proteins produced by skeletal muscle are dependent upon contraction; therefore, physical inactivity probably leads to an altered myokine response, which could provide a potential mechanism for the association between sedentary behaviour and many chronic diseases.

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Endurance running and the evolution of Homo.

Dennis M. Bramble, Daniel Lieberman (2004)

Striding bipedalism is a key derived behaviour of hominids that possibly originated soon after the divergence of the chimpanzee and human lineages. Although bipedal gaits include walking and running, running is generally considered to have played no major role in human evolution because humans, like apes, are poor sprinters compared to most quadrupeds. Here we assess how well humans perform at sustained long-distance running, and review the physiological and anatomical bases of endurance running capabilities in humans and other mammals. Judged by several criteria, humans perform remarkably well at endurance running, thanks to a diverse array of features, many of which leave traces in the skeleton. The fossil evidence of these features suggests that endurance running is a derived capability of the genus Homo, originating about 2 million years ago, and may have been instrumental in the evolution of the human body form.

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Fibroblast Growth Factor 21 Reverses Hepatic Steatosis, Increases Energy Expenditure, and Improves Insulin Sensitivity in Diet-Induced Obese Mice

Jing-Jing Xu, David J. B. Lloyd, Clarence Hale … (2009)

OBJECTIVE—Fibroblast growth factor 21 (FGF21) has emerged as an important metabolic regulator of glucose and lipid metabolism. The aims of the current study are to evaluate the role of FGF21 in energy metabolism and to provide mechanistic insights into its glucose and lipid-lowering effects in a high-fat diet–induced obesity (DIO) model. RESEARCH DESIGN AND METHODS—DIO or normal lean mice were treated with vehicle or recombinant murine FGF21. Metabolic parameters including body weight, glucose, and lipid levels were monitored, and hepatic gene expression was analyzed. Energy metabolism and insulin sensitivity were assessed using indirect calorimetry and hyperinsulinemic-euglycemic clamp techniques. RESULTS—FGF21 dose dependently reduced body weight and whole-body fat mass in DIO mice due to marked increases in total energy expenditure and physical activity levels. FGF21 also reduced blood glucose, insulin, and lipid levels and reversed hepatic steatosis. The profound reduction of hepatic triglyceride levels was associated with FGF21 inhibition of nuclear sterol regulatory element binding protein-1 and the expression of a wide array of genes involved in fatty acid and triglyceride synthesis. FGF21 also dramatically improved hepatic and peripheral insulin sensitivity in both lean and DIO mice independently of reduction in body weight and adiposity. CONCLUSIONS—FGF21 corrects multiple metabolic disorders in DIO mice and has the potential to become a powerful therapeutic to treat hepatic steatosis, obesity, and type 2 diabetes.