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.

/pdf/muscle-as-an-endocrine-organ-focus-on-muscle-derived-3c7h8gsq1u.pdf

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

Stable isotope tracers and indirect calorimetry were used to evaluate the regulation of endogenous fat and glucose metabolism in relation to exercise intensity and duration. Five trained subjects were studied during exercise intensities of 25, 65, and 85% of maximal oxygen consumption (VO2max). Plasma glucose tissue uptake and muscle glycogen oxidation increased in relation to exercise intensity. In contrast, peripheral lipolysis was stimulated maximally at the lowest exercise intensity, and fatty acid release into plasma decreased with increasing exercise intensity. Muscle triglyceride lipolysis was stimulated only at higher intensities. During 2 h of exercise at 65% VO2max plasma-derived substrate oxidation progressively increased over time, whereas muscle glycogen and triglyceride oxidation decreased. In recovery from high-intensity exercise, although the rate of lipolysis immediately decreased, the rate of release of fatty acids into plasma increased, indicating release of fatty acids from previously hydrolyzed triglycerides. We conclude that, whereas carbohydrate availability is regulated directly in relation to exercise intensity, the regulation of lipid metabolism seems to be more complex.

Regulation of endogenous fat and carbohydrate metabolism in relation to exercise intensity and duration.

Endocrine Regulation of the Fasting Response by PPARα-Mediated Induction of Fibroblast Growth Factor 21

Physical inactivity is recognized as a risk factor for coronary artery disease. Regular aerobic physical activity increases exercise capacity and plays a role in both primary and secondary prevention of cardiovascular disease.1 2 3 4 5 The known benefits of regular aerobic exercise and current recommendations for implementation of exercise programs are described in this revised report.6 

Exercise training increases cardiovascular functional capacity and decreases myocardial oxygen demand at any level of physical activity in apparently healthy persons as well as in most subjects with cardiovascular disease. Regular physical activity is required to maintain these training effects. The potential risk of physical activity can be reduced by medical evaluation, risk stratification, supervision, and education.4 

Exercise can help control blood lipid abnormalities, diabetes, and obesity. In addition, aerobic exercise adds an independent blood pressure–lowering effect in certain hypertensive groups with a decrease of 8 to 10 mm Hg in both systolic and diastolic blood pressure measurements.7 8 9 10 There is a direct relation between physical inactivity and cardiovascular mortality, and physical inactivity is an independent risk factor for the development of coronary artery disease.11 12 13 14 There is a dose-response relation between the amount of exercise performed from approximately 700 to 2000 kcal of energy expenditure per week and all-cause mortality and cardiovascular disease mortality in middle-aged and elderly populations.14 15 The greatest potential for reduced mortality is in the sedentary who become moderately active.15 Most beneficial effects of physical activity on cardiovascular disease mortality can be attained through moderate-intensity activity (40% to 60% of maximal oxygen uptake, depending on age).14 15 16 The activity can be accrued through formal training programs or leisure-time physical activities. Although most of the supporting data are based on studies in men, more recent findings …

/pdf/statement-on-exercise-benefits-and-recommendations-for-2nlrxdcf98.pdf

Statement on Exercise: Benefits and Recommendations for Physical Activity Programs for All Americans A Statement for Health Professionals by the Committee on Exercise and Cardiac Rehabilitation of the Council on Clinical Cardiology, American Heart Association

Physical exercise can be an important adjunct in the treatment of both non-insulin-dependent diabetes mellitus and insulin-dependent diabetes mellitus. Over the past several years, considerable progress has been made in understanding the molecular basis for these clinically important effects of physical exercise. Similarly to insulin, a single bout of exercise increases the rate of glucose uptake into the contracting skeletal muscles, a process that is regulated by the translocation of GLUT4 glucose transporters to the plasma membrane and transverse tubules. Exercise and insulin utilize different signaling pathways, both of which lead to the activation of glucose transport, which perhaps explains why humans with insulin resistance can increase muscle glucose transport in response to an acute bout of exercise. Exercise training in humans results in numerous beneficial adaptations in skeletal muscles, including an increase in GLUT4 expression. The increase in muscle GLUT4 in trained individuals contributes to an increase in the responsiveness of muscle glucose uptake to insulin, although not all studies show that exercise training in patients with diabetes improves overall glucose control. However, there is now extensive epidemiological evidence demonstrating that long-term regular physical exercise can significantly reduce the risk of developing non-insulin-dependent diabetes mellitus.

Exercise, glucose transport, and insulin sensitivity.

A B S T R A C T To determine the plasma epinephrine thresholds for its metabolic and hemodynamic actions and plasma epinephrine metabolic clearance rates, 60-min intravenous epinephrine infusions at nominal rates of0.1, 0.5, 1.0, 2.5, and 5.0,ug/min were performed in each of six normal human subjects. These 30 infusions resulted in steady-state plasma epinephrine concentrations ranging from 24 to 1,020 pg/ml. Plasma epinephrine thresholds were 50-100 pg/ml for increments in heart rate, 75-125 pg/ml for increments in blood glycerol and systolic blood pressure, 150-200 pglml for increments in plasma glucose (the resultant ofincrements in glucose production and decrements in glucose clearance), blood lactate, blood f3-hydroxybutyrate, and diastolic blood pressure, and >400 pg/ml for early decrements in plasma insulin. Changes in blood alanine, plasma glucagon, plasma growth hormone, and plasma cortisol were not detected. At steadystate plasma epinephrine concentrations of 24-74 pg/ml, values overlapping the basal normal range, the mean (±SE) plasma metabolic clearance rate of epinephrine was 52±4 ml min-l kg-l; this value rose to 89±6 ml * min-' kg-' (P < 0.01) at steady-state epinephrine concentrations of 90-1,020 pg/ml. We con

/pdf/rates-and-physiologic-thresholds-for-metabolic-and-53dro9tm02.pdf

Rates and Physiologic Thresholds for Metabolic and Hemodynamic Actions in Man

To determine the plasma epinephrine thresholds for its metabolic and hemodynamic actions and plasma epinephrine metabolic clearance rates, 60-min intravenous epinephrine infusions at nominal rates of 0.1, 0.5, 1.0, 2.5, and 5.0 microgram/min were performed in each of six normal human subjects. These 30 infusions resulted in steady-state plasma epinephrine concentrations ranging from 24 to 1,020 pg/ml. Plasma epinephrine thresholds were 50-100 pg/ml for increments in heart rate, 75-125 pg/ml for increments in blood glycerol and systolic blood pressure, 150-200 pg/ml for increments in plasma glucose (the resultant of increments in glucose production and decrements in glucose clearance), blood lactate, blood beta-hydroxybutyrate, and diastolic blood pressure, and greater than 400 pg/ml for early decrements in plasma insulin. Changes in blood alanine, plasma glucagon, plasma growth hormone, and plasma cortisol were not detected. At steady-state plasma epinephrine concentrations of 24-74 pg/ml, values overlapping the basal normal range, the mean (+/-SE) plasma metabolic clearance rate of epinephrine was 52 +/- 4 ml x min-1 x kg-1; this value rose to 89 +/- 6 ml x min-1 x kg-1 (P less than 0.01) at steady-state epinephrine concentrations of 90-1,020 pg/ml. We conclude that in human subjects: (a) the plasma epinephrine thresholds for its hemodynamic and metabolic actions lie within the physiologic range, (b) epinephrine and norepinephrine accelerate their own metabolic clearance, and (c) epinephrine is 10 times more potent than norepinephrine.

/pdf/epinephrine-plasma-metabolic-clearance-rates-and-physiologic-2hfv1pwcf4.pdf

Epinephrine plasma metabolic clearance rates and physiologic thresholds for metabolic and hemodynamic actions in man.

To determine the plasma epinephrine thresholds for its lipolytic effect, 60-min epinephrine infusions at nominal rates of 0.1, 0.5, 1.0, 2.5, and 5.0 micrograms/min were performed in each of four normal young adult men while they also received a simultaneous infusion of [1-13C]palmitic acid to estimate inflow transport of plasma free fatty acids. These 20 infusions resulted in steady-state plasma epinephrine concentrations ranging from 12 to 870 pg/ml. Plasma epinephrine thresholds for changes in blood glucose, lactate, and beta-hydroxybutyrate were in the 150--200-pg/ml range reported by us previously (Clutter, W. E., D. M. Bier, S. D. Shah, and P. E. Cryer. 1980. J. Clin. Invest. 66: 94--101.). Increments in plasma glycerol and free fatty acids and in the inflow and outflow transport of palmitate, however, occurred at lower plasma epinephrine thresholds in the range of 75 to 125 pg/ml. Palmitate clearance was unaffected at any steady-state epinephrine level produced. These data indicate that (a) the lipolytic effects of epinephrine occur at plasma levels approximately threefold basal values and (b) lipolysis is more sensitive than glycogenolysis to increments in plasma epinephrine.

/pdf/epinephrine-plasma-thresholds-for-lipolytic-effects-in-man-3lqrnwjjhb.pdf

Epinephrine Plasma Thresholds for Lipolytic Effects in Man MEASUREMENTS OF FATTY ACID TRANSPORT WITH

Insulin action is enhanced in people who exercise regularly and vigorously. In the present study, the hyperinsulinemic, euglycemic clamp procedure was used to determine whether this enhanced insulin action is due to an increased sensitivity and/or an increased responsiveness to insulin. To avoid the variability that exists between individuals and complicates cross-sectional studies, the same subjects were studied in the trained exercising state and again after 10 days of physical inactivity. When the plasma insulin concentration was maintained at approximately 78 microU.ml-1 (a submaximal level), glucose disposal rate averaged 8.7 +/- 0.5 mg.kg-1.min-1 before and 6.7 +/- 0.6 mg.kg-1.min-1 after 10 days of activity (P less than 0.001). When the plasma insulin concentration was maintained at approximately 2,000 microU.ml-1 (a maximally effective concentration), the rate of glucose disposal was not significantly different before (15.3 +/- 0.5 mg.kg-1.min-1) compared with after (14.5 +/- 0.4 mg.kg-1.min-1) 10 days without exercise. These results provide evidence that the reversal of enhanced insulin action that occurs within a few days when exercise-trained individuals stop exercising is due to a decrease in sensitivity to insulin, not to a decrease in insulin responsiveness.

Effects of exercise and lack of exercise on insulin sensitivity and responsiveness.

/pdf/epinephrine-plasma-thresholds-for-lipolytic-effects-in-man-1hfh0h3ctr.pdf

P. E. Cryer

Papers

Rates and Physiologic Thresholds for Metabolic and Hemodynamic Actions in Man

Epinephrine plasma metabolic clearance rates and physiologic thresholds for metabolic and hemodynamic actions in man.

Epinephrine Plasma Thresholds for Lipolytic Effects in Man MEASUREMENTS OF FATTY ACID TRANSPORT WITH

Effects of exercise and lack of exercise on insulin sensitivity and responsiveness.

Epinephrine plasma thresholds for lipolytic effects in man: measurements of fatty acid transport with [l-13C]palmitic acid.