Myokines

Exercise-induced muscle damage is an important topic in exercise physiology. However several aspects of our understanding of how muscles respond to highly stressful exercise remain unclear In the first section of this review we address the evidence that exercise can cause muscle damage and inflammation in otherwise healthy human skeletal muscles. We approach this concept by comparing changes in muscle function (i.e., the force-generating capacity) with the degree of leucocyte accumulation in muscle following exercise. In the second section, we explore the cytokine response to 'muscle-damaging exercise', primarily eccentric exercise. We review the evidence for the notion that the degree of muscle damage is related to the magnitude of the cytokine response. In the third and final section, we look at the satellite cell response to a single bout of eccentric exercise, as well as the role of the cyclooxygenase enzymes (COX1 and 2). In summary, we propose that muscle damage as eva...

During the last two decadesnumerous research teams demonstratedthat skeletalmuscles
function as an exercise-dependent endocrine organ secreting dozens of myokines. Variety of
physiological and pathophysiological implications of skeletalmusclemyokines secretion has been
described; however, upstream signals and sensing mechanisms underlying this phenomenon
remain poorly understood. It is well documented that in skeletal muscles intensive exercise triggers
dissipation of transmembrane gradient of monovalent cations caused by permanent activation
of voltage-gated Naþ and Kþ channels. Recently, we demonstrated that sustained elevation
of the [Naþ]i/[Kþ]i ratio triggers expression of dozens ubiquitous genes including several canonical
myokines, such as interleukin-6 and cyclooxygenase 2, in the presence of intra- and extracellular
Ca2þ chelators. These data allowed us to suggest a novel [Naþ]i/[Kþ]i-sensitive, Ca2þ
i -independent
mechanism of excitation-transcription coupling which triggers myokine production. This pathway
exists in parallel with canonical signaling mediated by Ca2þ
i , AMP-activated protein kinase and
hypoxia-inducible factor 1a (HIF-1a). In ourmini-reviewwe briefly summarize data supporting this
hypothesis as well as unresolved issues aiming to forthcoming studies.

Exercise-induced muscle damage is an important topic in exercise physiology. However several aspects of our understanding of how muscles respond to highly stressful exercise remain unclear In the first section of this review we address the evidence that exercise can cause muscle damage and inflammation in otherwise healthy human skeletal muscles. We approach this concept by comparing changes in muscle function (i.e., the force-generating capacity) with the degree of leucocyte accumulation in muscle following exercise. In the second section, we explore the cytokine response to 'muscle-damaging exercise', primarily eccentric exercise. We review the evidence for the notion that the degree of muscle damage is related to the magnitude of the cytokine response. In the third and final section, we look at the satellite cell response to a single bout of eccentric exercise, as well as the role of the cyclooxygenase enzymes (COX1 and 2). In summary, we propose that muscle damage as eva...

Metabolic dysfunction in skeletal muscle is a major contributor to the development of type 2 diabetes. Endurance exercise training has long been established as an effective means to directly restore skeletal muscle glucose and lipid uptake and metabolism. However, in addition to the direct effects of skeletal muscle on glucose and lipids, there is renewed interest in the ability of skeletal muscle to coordinate metabolic activity of other tissues, such as adipose tissue and liver. The purpose of this study was to examine the effects of endurance exercise on the expression level of two novel muscle-derived secreted factors, or myokines, Myonectin and Fibronectin type III domain containing 5 (FNDC5), the precursor for Irisin. Methods. We performed immunoblot analysis and quantitative real-time PCR analysis of Myonectin and FNDC5 in the diaphragm muscles of obese Zucker rat (OZR) and lean Zucker rat (LZR) with 9 weeks of aerobic training on a motorized treadmill. Results. We show that myonectin gene expression is increased in the OZR model of obesity and decreases with exercise in both lean and obese Zucker rats. Conversely, myonectin protein concentration was elevated with exercise. Similarly, FNDC5 mRNA levels are significantly higher in the OZR, however exercise training had no effect on the expression level of FNDC5 in either the LZR or OZR. We did not observe any difference in muscle protein content of Irisin with obesity or exercise. Conclusion. Our data shows that exercise training does not increase either FNDC5 or myonectin gene expression, indicating that increased transcriptional regulation of these myokines is not induced by exercise. However, our data also indicates a yet to be explored disconnect between myonectin gene expression and protein content. Further, this report highlights the importance of verifying reference genes when completing gene expression analysis. We found that many commonly used reference genes varied significantly by obesity and/or exercise and would have skewed the results of this study if used to normalize gene expression data. The unstable reference genes include: beta-Actin, beta-2-microglobulin, Non-POU domain containing, octamer-binding, Peptidylprolyl isomerase H, 18S ribosomal RNA, TATA box binding protein and Transferrin receptor.

Non-alcoholic steatohepatitis (NASH) is characterized by steatosis, lobular inflammation, and enlargement of the diameter of hepatocytes (ballooning hepatocytes), with or without fibrosis. It affects 20% of patients with non-alcoholic fatty liver disease (NAFLD). Due to liver dysfunction and the numerous metabolic changes that commonly accompany the condition (obesity, insulin resistance, type 2 diabetes, and metabolic syndrome), the secretion of organokines is modified, which may contribute to the pathogenesis or progression of the disease. In this sense, this study aimed to perform a review of the role of organokines in NASH. Thus, by combining descriptors such as NASH, organokines, oxidative stress, inflammation, insulin resistance, and dyslipidemia, a search was carried out in the EMBASE, MEDLINE-PubMed, and Cochrane databases of articles published in the last ten years. Insulin resistance, inflammation and mitochondrial dysfunction, fructose, and intestinal microbiota were fact...

In recent years, the prevalence of obesity continues to increase, leading to a public health problem. Therefore, the obesity problem needs serious attention and treatment approaches. Exercise is one of the treatment approach to combat obesity because exercise plays a role in beiging/browning process. Beiging is a differentiation process from white adipocyte to beige adipocyte, which has similar characteristics to brown adipocyte and is marked with an increase of UCP-1 expression. Irisin plays a role in increasing UCP-1 expression by activating p38 mitogen-activated protein kinase (MAPK) and extracellular-signal regulated kinase (ERK) signaling. Muscle contraction during exercise can activate PGC-1α, which leads to the synthesis of irisin. Exercise may increase irisin levels in skeletal muscle and consequently, play as a mediator of beiging process in adipose tissue.

Muscle and bone are intimately linked by bi-directional signals regulating both muscle and bone cell gene expression and proliferation. It is generally accepted that muscle cells secrete factors (myokines) that influence adjacent bone cells, but these myokines are yet to be identified. We have previously shown that osteocyte-specific deletion of the co-receptor subunit utilized by IL-6 family cytokines, glycoprotein 130 (gp130), resulted in impaired bone formation in the trabecular bone, but enhanced periosteal expansion, suggesting a gp130dependent periosteum-specific inhibition of osteoblast function, potentially induced by the local muscle fibres. We report here that differentiated primary calvarial osteoblasts cultured in myotube-conditioned media (CM) from myogenic C2C12 cells show reduced mRNA levels of genes associated with osteoblast differentiation. Alkaline phosphatase protein activity and all mRNA markers of osteoblast differentiation in the tested panel (runx2, osterix, alkaline phosphatase, parathyroid hormone (PTH) receptor, osteoprotegerin, osteocalcin, sclerostin) were reduced following culture with myotube CM. The exception was RANKL, which was significantly elevated in differentiated primary osteoblast cultures expressing osteocytic genes. A cytokine array of the C2C12 myotube-conditioned media identified TIMP-1 and MCP-1 as the most abundant myokines, but treatment with recombinant TIMP-1 or MCP-1 did not inhibit osteoblast gene expression. Rather, the IL-6 family cytokine ciliary neurotrophic factor (CNTF), which we found abundantly expressed by mouse muscle at the transcript and protein level, reduced osteoblast gene expression, although not to the same extent as the myotubeconditioned media. These data indicate that muscle cells secrete abundant TIMP-1, MCP-1, and CNTF, and that of these, only CNTF has the ability to suppress osteoblast function and gene expression in a similar manner to myotube-conditioned medium. This suggests that CNTF is an inhibitory myokine for osteoblasts.

Background. Recently, high-intensity intermittent training (HIIT) appears to have the same beneficial effects or even superior to those of continuous moderate-intensity training (CMIT) on body fat mass reduction. Exercise may induce myokine secretion such as irisin, which plays a role as a mediator of beiging process, and thus might contribute as treatment of obesity. However, the effects of those exercise formulas on irisin level changes as beiging agent are not known. In addition, metabolic states may affect the irisin responses to those exercise formulas. Therefore, this study was aimed to determine the different effects of exercises using HIIT and CMIT on circulating and tissue irisin levels in normal and abnormal metabolic conditions (obese). Methods. Sixteen male Sprague-Dawley rats (8 weeks of age) were randomized to 4 groups according to training regimens (HIIT and CMIT) and metabolic conditions (normal and abnormal/obese). The groups are (1) HIIT on normal metabolic (n=4), (2) CMIT on normal metabolic (n=4), (3) HIIT on abnormal metabolic (n=4), and (4) CMIT on abnormal metabolic (n=4). Abnormal metabolic condition was induced with high fat diet (19% fat) for 8 weeks in obese rats. Irisin levels in serum, skeletal muscle, and white adipose tissue were evaluated by ELISA. Results. Serum irisin levels were shown significantly higher in normal metabolic compared to abnormal metabolic condition (P<0.001). The effect of interaction between metabolic condition and exercise formula was found (P<0.01) on adipose irisin levels. The effect of HIIT was shown significantly more effective on adipose irisin levels, compared with CMIT in abnormal metabolic conditions. However, no significant differences of skeletal muscle irisin levels were found in both normal and abnormal metabolic subjects (P>0.05). Regarding exercise formula, no different effects were found between HIIT and CMIT on skeletal muscle irisin levels in both metabolic conditions (P>0.05). The similar findings were observed in serum irisin levels (P>0.05). Conclusions. The exercise effects in abnormal metabolic condition might be more adaptable in maintaining the irisin levels in skeletal muscle and induce the irisin uptake from circulation into adipose tissue. In addition, HIIT might be more involved to induce irisin uptake into adipose tissue; thus it might have the significant role in beiging process. However, further research about how the HIIT formula affects the regulation mechanisms of irisin uptake into adipose tissue is still warranted.

Muscle and bone are intimately linked by bi-directional signals regulating both muscle and bone cell gene expression and proliferation. It is generally accepted that muscle cells secrete factors (myokines) that influence adjacent bone cells, but these myokines are yet to be identified. We have previously shown that osteocyte-specific deletion of the co-receptor subunit utilized by IL-6 family cytokines, glycoprotein 130 (gp130), resulted in impaired bone formation in the trabecular bone, but enhanced periosteal expansion, suggesting a gp130dependent periosteum-specific inhibition of osteoblast function, potentially induced by the local muscle fibres. We report here that differentiated primary calvarial osteoblasts cultured in myotube-conditioned media (CM) from myogenic C2C12 cells show reduced mRNA levels of genes associated with osteoblast differentiation. Alkaline phosphatase protein activity and all mRNA markers of osteoblast differentiation in the tested panel (runx2, osterix, alkaline phosphatase, parathyroid hormone (PTH) receptor, osteoprotegerin, osteocalcin, sclerostin) were reduced following culture with myotube CM. The exception was RANKL, which was significantly elevated in differentiated primary osteoblast cultures expressing osteocytic genes. A cytokine array of the C2C12 myotube-conditioned media identified TIMP-1 and MCP-1 as the most abundant myokines, but treatment with recombinant TIMP-1 or MCP-1 did not inhibit osteoblast gene expression. Rather, the IL-6 family cytokine ciliary neurotrophic factor (CNTF), which we found abundantly expressed by mouse muscle at the transcript and protein level, reduced osteoblast gene expression, although not to the same extent as the myotubeconditioned media. These data indicate that muscle cells secrete abundant TIMP-1, MCP-1, and CNTF, and that of these, only CNTF has the ability to suppress osteoblast function and gene expression in a similar manner to myotube-conditioned medium. This suggests that CNTF is an inhibitory myokine for osteoblasts.