Exercise physiology versus inactivity physiology: an essential concept for understanding lipoprotein lipase regulation

Abstract

Some health-related proteins such as lipoprotein lipase may be regulated by qualitatively different processes over the physical activity continuum, sometimes with very high sensitivity to inactivity. The most powerful process known to regulate lipoprotein lipase protein and activity in muscle capillaries may be initiated by inhibitory signals during physical inactivity, independent of changes in lipoprotein lipase messenger RNA.

Figure 1

Relationship between physical activity and the risk for death, and two hypothetical processes that influence this risk. Summary of two studies (□ref. (11);■ref. (7)) that demonstrate that those with the lowest fitness and activity are at a much greater risk for death and CHD. The most salient molecular and cellular underlying processes responsible for the causal links between increased CHD and physical inactivity likely will be found by studying candidate processes over a range of inactivity and activity that includes the most physically inactive (process A). Theoretically, process A may be operative at higher levels of activity as well. Process B hypothetically would buttress health further (i.e., moderately high intensity exercise), but it is not necessarily the same mechanism as process A. If this is indeed true that sometimes there are distinct mechanisms regulating disease-related proteins across the physical activity continuum, then exercise studies only examining the effect of moderately high exercise intensity may not detect some of the most potent processes (e.g., process A) responsible for the strong association of physical inactivity with CHD. The key concept is that the middle quintile (“average person”) generally does not formally exercise train, but health is strongly impacted by becoming less active because of the physiologic responses to inactivity (“inactivity physiology”).

Figure 2

LPL activity and mRNA (inset) in different muscle fiber types after reduced physical activity compared with normal control ambulatory activity. LPL activity was determined in a rat slow-twitch red soleus muscle known to be most extensively recruited during low to moderate ambulatory activity (■; N = 35), fast-twitch red quadriceps (; N = 7), and fast-twitch white quadriceps muscle sections least recruited (□; N = 6) during ambulatory activity (2). *P < 0.05 indicates significant difference between reduced activity and ambulatory activity. †P < 0.05 indicates significantly lower LPL mRNA in fast-twitch white muscle than in red oxidative soleus muscle. NS, no significant difference in LPL mRNA between inactivity and ambulatory activity measured by Northern blotting (2) and by real-time polymerase chain reaction (3).

Figure 3

Skeletal muscle LPL mass and activity in response to physical inactivity. Measurement of the temporal changes in LPL mRNA, protein mass, and activity in both the capillary pool and total tissue at the onset and throughout a day of physical inactivity gives insight into the underlying mechanisms triggering the changes in LPL activity. After an initial lag period of approximately 4 h, there is a precipitous loss of capillary LPL protein that is closely paralleled by a simultaneous decrease in capillary LPL activity (measured in both soleus and red quadriceps muscles at many time points) (2). Coincident with the early events, there is likely a decrease in intracellular-specific LPL activity because total tissue LPL protein does not change initially, yet total tissue LPL activity decreases. Eventually, total LPL protein decreases. Importantly, the loss of LPL activity during physical inactivity does not require a decrease in LPL mRNA concentration (Fig. 4).

Figure 4

Pretranslational process increasing LPL mRNA is activated in white glycolytic muscle by intense run training and electrical stimulation. This pretranslational process (increased LPL mRNA) is activated by intense run training or intense electrical stimulation of a motor neuron, but this effect requires intense contractions and occurs only in predominantly fast-twitch muscles (5). The run training averaged 56 ± 1 m·min⁻¹ (>80%V̇O₂max) for 3.4 hr·d⁻¹ and was compared with the same muscles of nonrunning ambulatory control rats. In other rats, a muscle was electrically stimulated for 4 hr·d⁻¹ to mimic run training. The run training stimuli did not increase LPL mRNA in a muscle that is not used in locomotion (masseter). Note that LPL mRNA was altered only at the high end of the physical activity continuum and did not decrease at the low end of the continuum.

Figure 5

Potential steps involved in decreasing LPL during contractile inactivity. The decrease in muscle LPL does not occur because of less LPL mRNA concentration (Figure 2). The pharmacologic inhibition of transcription prevented the decrease in LPL activity in sedentary muscle, but did not affect LPL activity in muscle of ambulatory and exercising rats (2). There is also potentially a reduction in intracellular LPL specific activity that may be involved. Conversely, the decrease in intracellular LPL mass may be a consequence of a process that causes a rapid loss of LPL mass at the capillary endothelium. Light or intense muscle contractions can prevent the upregulation or activation of a gene(s) that suppresses capillary LPL mass and activity (as described in text) (2). Loss of capillary LPL activity can reduce plasma triglyceride uptake and plasma HDL cholesterol concentration in some conditions and likely has other ensuing effects on lipid and carbohydrate metabolism.