Regulation of tissue crosstalk by skeletal muscle-derived myonectin and other myokines.

The integrated control of animal physiology requires intimate tissue crosstalk, a vital task mediated by circulating humoral factors. As one type of these factors, adipose tissue-derived adipokines have recently garnered attention as important regulators of systemic insulin sensitivity and metabolic homeostasis. However, the realization that skeletal muscle also secretes a variety of biologically and metabolically active polypeptide factors (collectively called myokines) has provided a new conceptual framework to understand the critical role skeletal muscle plays in coordinating whole-body energy balance. Here, we highlight recent progress made in the myokine field and discuss possible roles of myonectin, which we have recently identified as a potential postprandial signal derived from skeletal muscle to integrate metabolic processes in other tissues, such as adipose and liver; one of its roles is to promote fatty acid uptake into cells. Myonectin is also likely an important mediator in inter-tissue crosstalk

The mechanical stimulation of myotubes counteracts the effects of tumor-derived factors through the modulation of the activin/follistatin ratio

Activin negatively affects muscle fibers and progenitor cells in aging (sarcopenia) and in chronic diseases characterized by severe muscle wasting (cachexia). High circulating activin levels predict poor survival in cancer patients. However, the relative impact of activin in mediating muscle atrophy and hampered homeostasis is still unknown. To directly assess the involvement of activin, and its physiological inhibitor follistatin, in cancer-induced muscle atrophy, we cultured C2C12 myotubes in the absence or in the presence of a mechanical stretching stimulus and in the absence or presence of C26 tumor-derived factors (CM), so as to mimic the mechanical stimulation of exercise and cancer cachexia, respectively. We found that CM induces activin release by myotubes, further exacerbating the negative effects of tumor-derived factors. In addition, mechanical stimulation is sufficient to counteract the adverse tumor-induced effects on muscle cells, in association with an increased follistatin/activin ratio in the cell culture medium, indicating that myotubes actively release follistatin upon stretching. Recombinant follistatin counteracts tumor effects on myotubes exclusively by rescuing fusion index, suggesting that it is only partially responsible for the stretch-mediated rescue. Therefore, besides activin, other tumor-derived factors may play a significant role in mediating muscle atrophy. In addition to increasing follistatin secretion mechanical stimulation induces additional beneficial responses in myotubes. We propose that in animal models of cancer cachexia and in cancer patients purely mechanical stimuli play an important role in mediating the rescue of the muscle homeostasis reported upon exercise

Skeletal muscle: a significant novel neurohypophyseal hormone-secreting organ

Vasopressin (arg8-vasopressin) and oxytocin are closely relalated hormones, synthesized as pre-hormones in the magnocellular neurons of the paraventricular Q6 and supraoptic nuclei of the hypothalamus. Vasopressin and oxytocin are secreted in response to a variety of physiological stimuli, serving such different functions as controlling water balance, milk ejection, uterine contraction, mood, and parental behavior (Lechan and Toni, 2000; Costa et al., 2014a)

PGC-1a in muscle links metabolism to inflammation

1. In higher eukaryotes, metabolism and immunity are tightly coupled. However, whereas in evolutionary terms, a compromised immune response due to undernourishment has been the predominant problem, the inflammatory response to obesity and other life style-associated diseases has increased in relevance in Western societies in the last hundred years. 2. Traditionally, fat tissue has been considered as the major source of pro-inflammatory secreted factors in these pathologies. In recent years however, the contribution of other tissues to a disease-causing chronic inflammation has been increasingly appreciated. 3. The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is one of the key regulatory factors in the active skeletal muscle. Aberrant expression of PGC-1α in inactive muscle fibres could link a sedentary life style, persistent systemic inflammation and the higher risk for many chronic diseases. Modulation of PGC-1α activity in skeletal muscle might accordingly have a broad therapeutic effect. Here, recent advances in the understanding of the role of muscle PGC-1α in health and disease are reviewed

Beneficial effect of voluntary exercise on experimental colitis in mice fed a high-fat diet : the role of irisin, adiponectin and proinflammatory biomarkers

Inflammatory bowel diseases (IBDs) are a heterogeneous group of disorders exhibited by two major phenotypic forms: Crohn‘s disease and ulcerative colitis. Although the aetiology of IBD is unknown, several factors coming from the adipose tissue and skeletal muscles, such as cytokines, adipokines and myokines, were suggested in the pathogenesis of ulcerative colitis; however, it has not been extensively studied whether voluntary exercise can ameliorate that disorder. We explored the effect of moderate exercise (i.e., voluntary wheel running) on the disease activity index (DAI), colonic blood flow (CBF), plasma irisin and adiponectin levels and real-time PCR expression of proinflammatory markers in mesenteric fat in mice with 2,4,6-trinitrobenzenesulfonic acid (TNBS) colitis fed a high-fat diet (HFD) compared to those on a standard chow diet (SD). Macroscopic and microscopic colitis in sedentary SD mice was accompanied by a significant fall in CBF, some increase in colonic tissue weight and a significant increase in the plasma levels of tumour necrosis factor-alpha (TNF-α), IL-6, monocyte chemotactic protein 1 (MCP-1) and IL-13 (p < 0.05). In sedentary HFD mice, colonic lesions were aggravated, colonic tissue weight increased and the plasma TNF-α, IL-6, MCP-1, IL-1β and leptin levels significantly increased. Simultaneously, a significant decrease in the plasma irisin and adiponectin levels was observed in comparison with SD mice (p < 0.05). Exercise significantly decreased macroscopic and microscopic colitis, substantially increased CBF and attenuated the plasma TNF-α, IL-6, MCP-1, IL-1β and leptin levels while raising the plasma irisin and the plasma and WAT concentrations of adiponectin in HFD mice (p < 0.05). We conclude that: (1) experimental colitis is exacerbated in HFD mice, possibly due to a fall in colonic microcirculation and an increase in the plasma and mesenteric fat content of proinflammatory biomarkers; and (2) voluntary physical activity can attenuate the severity of colonic damage in mice fed a HFD through the release of protective irisin and restoration of plasma adiponectin

Differential Myokine Expression in a Model for Myotonic Dystrophy Type I

Myotonic dystrophy type 1 (DM1) is a multi-systemic disease resulting in severe muscle weakening and wasting. Skeletal muscle wasting is the predominant cause of morbidity and mortality and is responsible for 60% of DM1-associated deaths. DM1 is caused by CTG repeat expansion in the 3’ untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. Myokines are proteins that are produced and released by muscle cells in response to muscular contractions. Previous studies indicated that myokine signaling is deregulated in a mouse model expressing expanded CUG repeat (CUGexp) RNA. The goal of this work was to assess muscle-specific differential expression of myokines in mice expressing CUGexp RNA, relative to non-CUGexp RNA expressing control mice. Previously published RNA-seq datasets were compared to determine which putative myokines, identified in skeletal muscle samples of healthy subjects, were differentially expressed in CUGexp expressing mice. Myokines that display significant differential expression at 6, 12, and 20 weeks of repeat expression include the Cx3cl1, Cxcl10, and Gdf5. Primers were designed customary for these genes and specified for regions with constitutive exons to allow consideration of overall expression levels. Primers were then optimized using RT-PCR. The developed primers will be used to validate differential expression levels of these myokines using quantitative RT-PCR. Validated myokines will be assessed in unaffected and DM1 human myoblast cell lines to determine the contribution of these myokines to the skeletal muscle phenotype in DM1

Physical exercise and myokines

Among the types of muscles present in the body is skeletal muscle, which is the one that allows the development of physical activity thanks to the contractile activity of its muscle cells. It is known that physical exercise involves the release of plasma, by the skeletal muscle, of molecules called myokines as a result of muscle contraction. These myokines seem to be at the base of the beneficial effect of physical exercise on health. For this reason, this article reviews the characteristics and properties of the most important myokines and how they can contribute to a healthier aging

The Role of Exercise-Induced Myokines in Muscle Homeostasis and the Defense against Chronic Diseases

Chronic inflammation is involved in the pathogenesis of insulin resistance, atherosclerosis, neurodegeneration, and tumour growth. Regular exercise offers protection against type 2 diabetes, cardiovascular diseases, colon cancer, breast cancer, and dementia. Evidence suggests that the protective effect of exercise may to some extent be ascribed to the antiinflammatory effect of regular exercise. Here we suggest that exercise may exert its anti-inflammatory effect via a reduction in visceral fat mass and/or by induction of an anti-inflammatory environment with each bout of exercise. According to our theory, such effects may in part be mediated via muscle-derived peptides, so-called “myokines”. Contracting skeletal muscles release myokines with endocrine effects, mediating direct anti-inflammatory effects, and/or specific effects on visceral fat. Other myokines work locally within the muscle and exert their effects on signalling pathways involved in fat oxidation and glucose uptake. By mediating anti-inflammatory effects in the muscle itself, myokines may also counteract TNF-driven insulin resistance. In conclusion, exercise-induced myokines appear to be involved in mediating both systemic as well as local anti-inflammatory effects

Myokines and Resistance Training : A Narrative Review

In the last few years, the muscular system has gained attention due to the discovery of the muscle-secretome and its high potency for retaining or regaining health. These cytokines, described as myokines, released by the working muscle, are involved in anti-inflammatory, metabolic and immunological processes. These are able to influence human health in a positive way and are a target of research in metabolic diseases, cancer, neurological diseases, and other non-communicable diseases. Therefore, different types of exercise training were investigated in the last few years to find associations between exercise, myokines and their effects on human health. Particularly, resistance training turned out to be a powerful stimulus to enhance myokine release. As there are different types of resistance training, different myokines are stimulated, depending on the mode of training. This narrative review gives an overview about resistance training and how it can be utilized to stimulate myokine production in order to gain a certain health effect. Finally, the question of why resistance training is an important key regulator in human health will be discussed