Skeletal muscle has recently been identified as an endocrine organ. It has, therefore, been suggested that cytokines and other peptides that are produced, expressed, and released by muscle fibers and exert paracrine, autocrine, or endocrine effects should be classified as "myokines." Recent research demonstrates that skeletal muscles can produce and express cytokines belonging to distinctly different families. However, the first identified and most studied myokine is the gp130 receptor cytokine interleukin-6 (IL-6). IL-6 was discovered as a myokine because of the observation that it increases up to 100-fold in the circulation during physical exercise. Identification of IL-6 production by skeletal muscle during physical activity generated renewed interest in the metabolic role of IL-6 because it created a paradox. On one hand, IL-6 is markedly produced and released in the postexercise period when insulin action is enhanced but, on the other hand, IL-6 has been associated with obesity and reduced insulin action. This review focuses on the myokine IL-6, its regulation by exercise, its signaling pathways in skeletal muscle, and its role in metabolism in both health and disease.

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Muscle as an endocrine organ: focus on muscle-derived interleukin-6.

Chronic diseases are major killers in the modern era. Physical inactivity is a primary cause of most chronic diseases. The initial third of the article considers: activity and prevention definitions; historical evidence showing physical inactivity is detrimental to health and normal organ functional capacities; cause vs. treatment; physical activity and inactivity mechanisms differ; gene-environment interaction [including aerobic training adaptations, personalized medicine, and co-twin physical activity]; and specificity of adaptations to type of training. Next, physical activity/exercise is examined as primary prevention against 35 chronic conditions [Accelerated biological aging/premature death, low cardiorespiratory fitness (VO2max), sarcopenia, metabolic syndrome, obesity, insulin resistance, prediabetes, type 2 diabetes, non-alcoholic fatty liver disease, coronary heart disease, peripheral artery disease, hypertension, stroke, congestive heart failure, endothelial dysfunction, arterial dyslipidemia, hemostasis, deep vein thrombosis, cognitive dysfunction, depression and anxiety, osteoporosis, osteoarthritis, balance, bone fracture/falls, rheumatoid arthritis, colon cancer, breast cancer, endometrial cancer, gestational diabetes, preeclampsia, polycystic ovary syndrome, erectile dysfunction, pain, diverticulitis, constipation, and gallbladder diseases]. The article ends with consideration of deterioration of risk factors in longer-term sedentary groups; clinical consequences of inactive childhood/adolescence; and public policy. In summary, the body rapidly maladapts to insufficient physical activity, and if continued, results in substantial decreases in both total and quality years of life. Taken together, conclusive evidence exists that physical inactivity is one important cause of most chronic diseases. In addition, physical activity primarily prevents, or delays, chronic diseases, implying that chronic disease need not be an inevitable outcome during life.

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Lack of exercise is a major cause of chronic diseases

C-reactive Protein

BACKGROUND\nIncreased physical activity is related to reduced risk of cardiovascular disease, possibly because it leads to improvement in the lipoprotein profile. However, the amount of exercise training required for optimal benefit is unknown. In a prospective, randomized study, we investigated the effects of the amount and intensity of exercise on lipoproteins.\n\n\nMETHODS\nA total of 111 sedentary, overweight men and women with mild-to-moderate dyslipidemia were randomly assigned to participate for six months in a control group or for approximately eight months in one of three exercise groups: high-amount-high-intensity exercise, the caloric equivalent of jogging 20 mi (32.0 km) per week at 65 to 80 percent of peak oxygen consumption; low-amount-high-intensity exercise, the equivalent of jogging 12 mi (19.2 km) per week at 65 to 80 percent of peak oxygen consumption; or low-amount-moderate-intensity exercise, the equivalent of walking 12 mi per week at 40 to 55 percent of peak oxygen consumption. Subjects were encouraged to maintain their base-line body weight. The 84 subjects who complied with these guidelines served as the basis for the main analysis. Detailed lipoprotein profiling was performed by nuclear magnetic resonance spectroscopy with verification by measurement of cholesterol in lipoprotein subfractions.\n\n\nRESULTS\nThere was a beneficial effect of exercise on a variety of lipid and lipoprotein variables, seen most clearly with the high amount of high-intensity exercise. The high amount of exercise resulted in greater improvements than did the lower amounts of exercise (in 10 of 11 lipoprotein variables) and was always superior to the control condition (11 of 11 variables). Both lower-amount exercise groups always had better responses than the control group (22 of 22 comparisons).\n\n\nCONCLUSIONS\nThe highest amount of weekly exercise, with minimal weight change, had widespread beneficial effects on the lipoprotein profile. The improvements were related to the amount of activity and not to the intensity of exercise or improvement in fitness.

Effects of the amount and intensity of exercise on plasma lipoproteins: Editor's comments

1,25-Dihydroxvitamin D3 [1,25(OH)2D3] is the hormonally active form of vitamin D. The genomic mechanism of 1,25(OH)2D3 action involves the direct binding of the 1,25(OH)2D3 activated vitamin D receptor/retinoic X receptor (VDR/RXR) heterodimeric complex to specific DNA sequences. Numerous VDR co-regulatory proteins have been identified, and genome-wide studies have shown that the actions of 1,25(OH)2D3 involve regulation of gene activity at a range of locations many kilobases from the transcription start site. The structure of the liganded VDR/RXR complex was recently characterized using cryoelectron microscopy, X-ray scattering, and hydrogen deuterium exchange. These recent technological advances will result in a more complete understanding of VDR coactivator interactions, thus facilitating cell and gene specific clinical applications. Although the identification of mechanisms mediating VDR-regulated transcription has been one focus of recent research in the field, other topics of fundamental importance include the identification and functional significance of proteins involved in the metabolism of vitamin D. CYP2R1 has been identified as the most important 25-hydroxylase, and a critical role for CYP24A1 in humans was noted in studies showing that inactivating mutations in CYP24A1 are a probable cause of idiopathic infantile hypercalcemia. In addition, studies using knockout and transgenic mice have provided new insight on the physiological role of vitamin D in classical target tissues as well as evidence of extraskeletal effects of 1,25(OH)2D3 including inhibition of cancer progression, effects on the cardiovascular system, and immunomodulatory effects in certain autoimmune diseases. Some of the mechanistic findings in mouse models have also been observed in humans. The identification of similar pathways in humans could lead to the development of new therapies to prevent and treat disease.

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Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects.

Epidemiological studies suggest that physically active individuals have a 30-50% lower risk of developing type 2 diabetes than do sedentary persons and that physical activity confers a similar risk reduction for coronary heart disease. Risk reductions are observed with as little as 30 min of moderate-intensity activity per day. Protective mechanisms of physical activity include the regulation of body weight; the reduction of insulin resistance, hypertension, atherogenic dyslipidemia, and inflammation; and the enhancement of insulin sensitivity, glycemic control, and fibrinolytic and endothelial function. Public health initiatives promoting moderate increases in physical activity may offer the best balance between efficacy and feasibility to improve metabolic and cardiovascular health in largely sedentary populations.

https://www.physiology.org/doi/pdf/10.1152/japplphysiol.00160.2005

Epidemiological evidence for the role of physical activity in reducing risk of type 2 diabetes and cardiovascular disease

Objectives: The purpose is to investigate whether social engagement protects against depressive symptoms in older adults. Method: Three waves of data from a representative cohort study of community-dwelling adults aged 65 years and above from the New Haven Established Populations for the Epidemiologic Study of the Elderly are examined using random effects models. Results: Social engagement (an index combining social and productive activity) is associated with lower CES-D scores after adjustment for age, sex, time, education, marital status, health and functional status, and fitness activities. This association is generally constant with time, suggesting a cross-sectional association. In addition, social engagement is associated with change in depressive symptoms, but only among those with CES-D scores below 16 at baseline. Discussion: Social engagement is independently associated with depressive symptoms cross-sectionally. A longitudinal association is seen only among those not depressed at baseline.

Social Engagement and Depressive Symptoms in Late Life Longitudinal Findings

The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease.

Shari S. Bassuk

Papers

Epidemiological evidence for the role of physical activity in reducing risk of type 2 diabetes and cardiovascular disease

Social Engagement and Depressive Symptoms in Late Life Longitudinal Findings

The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease.

High-sensitivity C-reactive protein: clinical importance.

Vitamin D supplements and prevention of cancer and cardiovascular disease