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 versus 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 (V o 2 max), sarcopenia, metabolic syndrome, obesity, insulin resistance, prediabetes, type 2 diabetes, nonalcoholic 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, pre‐eclampsia, 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. © 2012 American Physiological Society. Compr Physiol 2:1143‐1211, 2012.

The unweighting model is a unique whole animal model that will permit the future delineation of the mechanism(s) by which gravity maintains contractile mass in postural (slow-twitch) skeletal muscle. Since the origination of the model of rodent hindlimb unweighting almost one decade ago, about half of the 59 refereed articles in which this model was utilized have been published in the Journal of Applied Physiology. Thus the purpose of this review is to provide, for those researchers with an interest in the hindlimb unweighting model, a summation of the data derived from this model to data and hopefully to stimulate research interest in aspects of the model for which data are lacking. The stress response of the animal to hindlimb unweighting is transient, minimal in magnitude, and somewhat variable. After 1 wk of unweighting, the animal exhibits no chronic signs of stress. The atrophy of the soleus muscle, a predominantly slow-twitch muscle, is emphasized because unweighting preferentially affects it compared with other calf muscles, which are mainly fast-twitch muscles. The review considers the following information about the unweighted soleus muscle: electromyogram activity, amount and type of protein lost, capillarization, oxidative capacity, glycolytic enzyme activities, fiber cross section, contractile properties, glucose uptake, sensitivity to insulin, protein synthesis and degradation rates, glucocorticoid receptor numbers, responses of specific mRNAs, and changes in metabolite concentrations.

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of exercise. Obesity. 2006;14:345-356. Voluntary physical activity and exercise training can favorably influence brain plasticity by facilitating neurogenerative, neuroadaptive, and neuroprotective processes. At least some of the processes are mediated by neurotrophic factors. Motor skill training and regular exercise enhance executive functions of cognition and some types of learning, including motor learning in the spinal cord. These adaptations in the central nervous system have implications for the prevention and treatment of obesity, cancer, depression, the decline in cognition associated with aging, and neurological disorders such as Parkinson's disease, Alzheimer's dementia, ischemic stroke, and head and spinal cord injury. Chronic voluntary physical activity also attenuates neural responses to stress in brain circuits responsible for regulating peripheral sympathetic activity, suggesting constraint on sympathetic responses to stress that could plausibly contribute to reductions in clinical disorders such as hypertension, heart failure, oxidative stress, and suppression of immunity. Mechanisms explaining these adaptations are not as yet known, but metabolic and neurochemical pathways among skeletal muscle, the spinal cord, and the brain offer plausible, testable mechanisms that might help explain effects of physical activity and exercise on the central nervous system.

This review proposes that physical inactivity could be considered a behavior selected by evolution for resting, and also selected to be reinforcing in life-threatening situations in which exercise would be dangerous. Underlying the notion are human twin studies and animal selective breeding studies, both of which provide indirect evidence for the existence of genes for physical inactivity. Approximately 86% of the 325 million in the United States (U.S.) population achieve less than the U.S. Government and World Health Organization guidelines for daily physical activity for health. Although underappreciated, physical inactivity is an actual contributing cause to at least 35 unhealthy conditions, including the majority of the 10 leading causes of death in the U.S. First, we introduce nine physical inactivity-related themes. Next, characteristics and models of physical inactivity are presented. Following next are individual examples of phenotypes, organ systems, and diseases that are impacted by physical inactivity, including behavior, central nervous system, cardiorespiratory fitness, metabolism, adipose tissue, skeletal muscle, bone, immunity, digestion, and cancer. Importantly, physical inactivity, itself, often plays an independent role as a direct cause of speeding the losses of cardiovascular and strength fitness, shortening of healthspan, and lowering of the age for the onset of the first chronic disease, which in turn decreases quality of life, increases health care costs, and accelerates mortality risk.