Most of the public health concern is concentrated in the least active 20% to 30% of the population, and the number of very inactive people is growing rapidly. There is a need to identify at the cellular and molecular level the causal links explaining why physical inactivity raises the risk of coronary heart disease (CHD) by negatively impacting disease susceptibility proteins. The trend in recent years has been a shift away from promoting only the stereotypical endurance exercise training paradigm toward physical activity for enhancing health and avoiding the diseases caused by physical inactivity (8). The epidemiologic evidence showing that structured sessions of continuous high-intensity exercise are not essential for preventing disease caused by inactivity actually dates back to the classic vocational studies. What was interesting about some of those studies is that they contrasted disease outcomes between sedentary people with co-workers who were unintentionally exposed to enough repetitive physical activity throughout the course of each day to prevent coronary artery disease and mortality significantly. Those studies are consistent with the consensus statements that recently have de-emphasized the necessity for intense exercise while emphasizing the benefit of maintaining moderate activity every day. There also has been much interest in the idea of accumulating as many minutes of moderate muscular activity throughout the day as possible, sometimes referred to as active living.
Epidemiologic studies of physical inactivity indicate that the greatest disease and mortality rates are in the least active people (Fig. 1), and thus understanding the physiological and molecular responses to inactivity is of high significance. Furthermore, it has been suggested that the steep improvements in disease likely would come from accumulating significant amounts of activity on most days, even if the intensity is moderate enough to reduce chances for injury and recidivism (7). However, there is less research that has sought to provide plausible cellular and molecular mechanisms regulating proteins that modify the risk of metabolic and cardiovascular diseases during inactivity. In this review, a good example of very potent effects of physical inactivity is illustrated.
In this review, we focused on describing the enzyme lipoprotein lipase (LPL) because it is one of the few proteins studied over a wide range of the physical activity continuum and also is linked to a risk for CHD. Although not without controversy regarding the mechanisms, many studies in humans and animals have documented a strong and inverse relationship between LPL activity and CHD. LPL is an enzyme that binds to circulating lipoproteins when present on the vascular endothelium and is essential for hydrolysis of the triglyceride contained in lipoproteins. Compelling evidence by others has shown that the loss of LPL activity at the vascular endothelium impairs optimal tissue-specific uptake of lipoprotein-derived fatty acids and may contribute to the risks frequently observed during metabolic diseases such as obesity, type II diabetes, and most importantly, CHD. Even partial reductions in LPL activity because of specific polymorphisms have been reported to increase significantly the odds ratio for death and greater CHD in human studies as much as fivefold over healthy controls (14). Studies experimentally raising LPL activity provide evidence for less diet-induced atherosclerosis in transgenic rabbits (4), less diabetic hyperlipidemia (11), and less dietary-induced adiposity in transgenic mice overexpressing muscle-specific LPL activity (9). Numerous studies examining a loss of LPL activity have noted other diverse effects caused by genetic mutations in mice, cats, minks, or humans, and after pharmacologic inhibition of LPL activity.
Given that many laboratories have been identifying the functions of LPL and have documented an inverse relationship between LPL activity and CHD, there is now a great need to identify the physiologic processes that determine LPL activity. Herein we summarize a model for recent research regarding significant reductions in skeletal muscle LPL activity during acute and chronic inactivity (2), with aging (1,6), and how it is increased significantly by walking (2) and run training (5). In keeping with the guidelines of this journal, we discuss a novel integrative concept and hypothesis regarding physical activity and inactivity that is supported by two to three recent peer-reviewed papers, and thus do not intend to slight valuable historical contributions by others.
REGULATION OF LPL BY ACUTE AND CHRONIC PHYSICAL INACTIVITY
A recent study (2) tested the hypothesis that one reason why physical inactivity may impair lipid metabolism is because of reduced LPL activity in weight-bearing skeletal muscles that otherwise could be prevented by maintaining the nonfatiguing contractions that can occur during normal ambulatory activities in rats. The study found that the amount of LPL activity in skeletal muscles is remarkably sensitive to physical inactivity and activity (Fig. 2). This is especially evident in the capillary beds of oxidative muscle sections that are known from EMG and blood flow studies to be recruited at the lower intensities frequently occurring in everyday life. In these studies, there was no muscle atrophy. The reduction in muscle LPL activity during physical inactivity, experimentally robust because it occurs during both acute and chronic inactivity, is evident in both rats and mice and was induced using two different models of decreased contractile activity (hindlimb unloading and acute unilateral tenotomy). A general conclusion to draw from this is that there is a potent regulatory process at the lower end of the physical activity continuum controlling LPL activity (2).
The marked reduction of skeletal muscle LPL activity during inactivity does not involve a decreased expression of LPL messenger RNA (mRNA) in those same muscles (Fig. 2). Furthermore, the low muscle LPL activity after inactivity can be reversed after a single session of treadmill walking at a moderate intensity (8 meters·min−1, ≤50% of o2 max, performed intermittently with 30 min of rest each hour over 4 h). The increase in LPL activity during walking does not involve an increase in LPL mRNA concentration (2). LPL activity within the capillary beds increases several fold after walking exercise even when transcription is pharmacologically suppressed (2).
The known steps involved in regulating LPL activity during inactivity in young rats are very similar to the decreases in skeletal muscle LPL activity in older rats (1). Aged rats have significantly lower LPL specifically in the postural muscles (both capillary and total LPL activity and protein). As also seen in sedentary young rats, aged animals do not have a decrease in LPL mRNA concentration. Aged humans and rats develop relatively greater postprandial hypertriglyceridemia (6). Less physical activity (spontaneous activity) is a common stereotype of the aged in all species of which we are aware. Potential reversal of some of the negative effects of aging on LPL and plasma lipid metabolism with exercise in humans has been reviewed (6).
Distribution of Functional LPL Protein in Muscle
LPL protein is distributed spatially between the site of synthesis (myocyte) and the critical site for physiologic interactions with circulating lipoproteins (capillary endothelium). Total LPL is measured in tissue homogenates. The LPL protein and activity richly concentrated in the capillary beds can be extracted rapidly when small pieces of muscle are bathed in a heparin-containing medium (2) or when the vasculature of the intact rat hindlimb is perfused with heparin (Hutchins, K.C., and M.T. Hamilton, unpublished observations, 2004). Importantly, during physical inactivity, there is a more rapid onset and greater percentage decrease in LPL associated with the capillary pool compared with the LPL in whole muscle (Fig. 3), suggesting a possible posttranslational regulation of the distribution of LPL. The LPL protein in capillaries decreases approximately 50% before the total LPL begins to decrease, and the LPL mRNA does not decrease at any point up to even 11 d (2).
The loss of LPL activity is localized to skeletal muscles with reduced contractile activity (2). The most oxidative muscle regions with normally the greatest amount of LPL activity experience approximately a 95% loss of the capillary LPL activity after physical inactivity (Table 1, Fig. 2). Thus, very important processes that determine the functional capillary LPL require a sufficient volume of moderate intensity contractile activity.
LPL is the essential enzyme for lipolysis of triglycerides in circulating lipoproteins and can have a variety of effects on metabolism (4,9,12,13). Thus, it is not surprising that there is a large decrease in radiolabeled triglyceride lipoprotein uptake locally into skeletal muscle with low LPL activity (2). Sometimes, the removal of normal ambulatory activities decreases plasma HDL cholesterol concentration, with two studies reporting approximately 20% reductions (2,15). Importantly, human CHD is greatest in the individuals who are the least physically active (Fig. 1), and LPL may provide one reason for this.
CONTRASTING THE EFFECTS OF INACTIVITY WITH THE EFFECTS OF INTENSE EXERCISE
There are many contrasts for LPL regulation between the effects of running intensely (56 ± 1 m·min−1, 11 km·d−1, 2–3 wk, ≥80% o2 max) and the reversible effects of physical inactivity or walking slowly (Table 1). In contrast to the effect of inactivity, high-intensity running (Fig. 4) certainly can increase LPL mRNA expression significantly (approximately twofold to threefold increases in all examined white glycolytic muscles in the leg) (5). As a contrast between the low and high end of the physical activity spectrum (Table 1), there is an apparent threshold for the processes increasing LPL mRNA, because LPL mRNA did not change in any muscle type when comparing inactivity with lower intensity ambulatory activity (Figs. 2 and 4). However, it also is important to note that there is not an apparent threshold intensity for the process regulating capillary LPL activity, because even the normal ambulatory activity in the cage or walking at 8 meters·min−1 maintains LPL activity many fold more compared with the LPL activity in the inactive muscle (Fig. 2). All muscle types in the rat (especially oxidative muscles) had greater LPL activity during control ambulatory activity than when sedentary.
In contrast, the running only increased LPL activity and protein in the fast white muscles and had no effect on any of the oxidative muscle sections (5). The differences listed in Table 1 are important to note because they illustrate differences at the two ends of the physical activity continuum for the type of myocytes affected, and they show differences in molecular processes such as differential expression of LPL mRNA.
There are now several sets of data pointing to local signals regulating skeletal muscle over the entire range of the dose-response continuum (2,5). This is in contrast to the long-held speculation that hormones are sufficient to change muscle LPL with exercise. Taken together, local contractile activity likely is sufficient and necessary to explain both the decreases in LPL activity during inactivity and the increases in LPL activity during training.
A CONCEPT OF INACTIVITY PHYSIOLOGY: ACUTE AND CHRONIC RESPONSES TO PHYSICAL INACTIVITY
Inactivity physiology includes the study of the biological responses to physical inactivity and is critical for elucidating the mechanisms operating at the key lower end of this continuum where most of the change in disease occurs. As suggested by Figure 1, persons with an average level of physical activity (the median quintile in the center of the graph) are expected to have a significant increase in cardiovascular disease and mortality when becoming more physically inactive (moving toward the steep left side of the graph). The least active people and people in the middle quintile for physical activity and fitness generally do not report exercising regularly. We introduce the concept that responses to physical inactivity (inactivity physiology) can cause significant negative effects on many specific cellular and molecular processes important for disease-related proteins, and sometimes these processes are qualitatively different from what is known about more intense exercise training. Although this is not currently a well-appreciated concept gauging from the number of research publications, we expect it will be a fruitful area of future research.
Behaviors involving nonfatiguing muscle contractions that are not part of intentional exercise raise skeletal muscle energy demand locally in the working muscle fibers more than an order of a magnitude. These nonexercise behaviors are sometimes called active living in epidemiologic studies, and the influence on whole body metabolic rate has been called nonexercise activity thermogenesis (10). Nonexercise activity thermogenesis primarily is the result of low- to moderate-intensity ambulatory activity (≤50% of o2 max), can account for a large percentage of the 24-hr metabolic rate, is highly variable between individuals, and can be sufficient to prevent diet-induced obesity (10). We propose that even independent of body fat, accumulation of contractile activity in an active lifestyle may stimulate some potent biochemical and molecular processes important for preventing the effects of inactivity on chronic metabolic diseases (e.g., process A in Fig. 1). Regulation of the fraction of capillary LPL in muscle may be one such mechanism, because removing the normal intermittent ambulatory activity caused a precipitous decrease in LPL activity (Fig. 2), which was reversible by reestablishing moderate ambulatory activity.
Cellular Signals Stimulated by Physical Inactivity
A common misconception we have noted from discussions with students and colleagues is that the reduction in the concentration of specific proteins during contractile inactivity likely is part of a generalized effect in concert with atrophy. However, LPL protein decreases in acute and chronic models of reduced contractile activity that do not cause any atrophy (2). Many mRNAs, proteins, and signal pathways are stimulated by contractile inactivity. One recent study (3) examined the expression of thousands of genes soon after becoming sedentary and found that there were at least as many genes that were upregulated in muscle as there were downregulated genes. Therefore, correcting this misconception is sometimes important to elucidate the signals causing the effects of inactivity. As an example, recent data have led to the novel hypothesis that there is a regulatory factor upregulated during inactivity that suppresses the amount of capillary LPL in muscle (2) (Fig. 5).
Hypothesis That a Short-Lived Inhibitor Protein Decreases LPL in Sedentary Muscle
Because LPL activity apparently decreases in the capillaries of muscle because of a posttranslational process (Table 1), we sought to begin to explore the hypothesis that there is an inhibitor expressed in sedentary muscle that can decrease LPL function rapidly (Fig. 5). Treatment of rats for 6 h with actinomycin D (a transcriptional inhibitor) did not decrease LPL mRNA in either white or red muscle (2). Actinomycin D treatment also did not change LPL activity in ambulatory control rats, nor did it attenuate an eightfold increase in LPL activity during treadmill walking for 4 h after physical inactivity. However, in sedentary rats, the transcriptional inhibition prevented the decrease in capillary LPL activity (2). This implies that a short-lived inhibitor protein for posttranslational regulation of LPL is induced only by physical inactivity stimuli.
There is much to be learned from new insights regarding the molecular and physiological mechanisms responsible for the relationship between different diseases and physical inactivity and activity. Because epidemiologic studies demonstrate that inactivity contributes significantly to chronic metabolic diseases, we envision that there will be an emergence of “inactivity physiology” studies identifying additional key cellular mechanisms responsible for regulating disease-susceptibility proteins. Using LPL as an example, it is possible that some of the most potent processes regulating proteins modulating risk for disease will be evident at the low end of the physical activity continuum, and qualitatively different processes also may be operating during structured programs of more intense exercise training.
Supported by the National Space Biomedical Research Institute.
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Keywords:©2004 The American College of Sports Medicine
dose response; coronary heart disease (CHD); transcription; posttranslational; signaling; sedentary; aging