Suppression of skeletal muscle lipoprotein lipase activity during physical inactivity: a molecular reason to maintain daily low-intensity activity

Abstract

We have examined the regulation of lipoprotein lipase (LPL) activity in skeletal muscle during physical inactivity in comparison to low-intensity contractile activity of ambulatory controls. From studies acutely preventing ambulatory activity of one or both the hindlimbs in rats, it was shown that approximately 90-95 % of the heparin-releasable (HR) LPL activity normally present in rat muscle with ambulatory activity is lost, and thus dependent on local contractile activity. Similarly, approximately 95 % of the differences in LPL activity between muscles of different fibre types was dependent on ambulatory activity. The robustness of the finding that physical inactivity significantly decreases muscle LPL activity was evident from confirmatory studies with different models of inactivity, in many rats and mice, both sexes, three muscle types and during both acute and chronic (11 days) treatment. Inactivity caused a local reduction of plasma [3H]triglyceride uptake into muscle and a decrease in high density lipoprotein cholesterol concentration. LPL mRNA was not differentially expressed between ambulatory controls and either the acutely or chronically inactive groups. Instead, the process involved a rapid loss of the HR-LPL protein mass (the portion of LPL largely associated with the vascular endothelium) by an actinomycin D-sensitive signalling mechanism (i.e. transcriptionally dependent process). Significant decreases of intracellular LPL protein content lagged behind the loss of HR-LPL protein. Treadmill walking raised LPL activity approximately 8-fold (P < 0.01) within 4 h after inactivity. The striking sensitivity of muscle LPL to inactivity and low-intensity contractile activity may provide one piece of the puzzle for why inactivity is a risk factor for metabolic diseases and why even non-vigorous activity provides marked protection against disorders involving poor lipid metabolism.

Figure 1. Time course for the decrease in muscle LPL activity after inactivity (hindlimb unloading, HU) compared with low-intensity ambulatory activity

Soleus HR-LPL activity was decreased after acute (1 day for 10 h, n = 3) or chronic (11 days of 10 h day⁻¹, n = 8) HU (A). The time course of HR-LPL (B) and intracellular LPL (C) activities in soleus muscle within the first 18 h of HU revealed a delay of ≈4 h and then a precipitous decrease (n = 3–5). Restoring contractile activity for 4 h reversed the decrease in muscle LPL induced by 12 h inactivity. Control rats with normal cage activity (n = 5) and 12 h hindlimb unloaded rats (n = 20) were subjected to 4 h of intermittent treadmill walking (30 min intervals at 8 m min⁻¹ four times separated by 30 min of ‘free in the cage’) and compared with rats with normal ambulatory activity or after 12 h HU. A direct comparison of the time course in the red oxidative slow twitch (soleus) and fast twitch (red quadriceps, RQ) muscles is shown (D). The half-life of LPL activity was calculated from 4 to 10 h using t_1/2 = ln 2/k, where k = −1n (A(t)/A(0))/t. The average k calculated from 4 to 10 h was 0.334 for soleus and 0.341 for RQ. *P < 0.01 between HU and control.

Figure 2. LPL activity in different muscle fibre types after 12 h inactivity compared with low-intensity ambulatory activity

HR-LPL activity was determined in a slow twitch red (STR) soleus (n = 35), fast twitch red (FTR) deep quadriceps (n = 7) and fast twitch white (FTW) or superficial white region of rectus femoris (n = 6) and the diaphragm, which is a mixed skeletal muscle with continual activity (n = 7). *P < 0.01, †P < 0.05 between HU and low-intensity ambulatory control. LPL activity between all three hindlimb muscles was significantly different in controls but not after HU removed the normal contractile activity.

Figure 3. Inactivity decreases both muscle TG uptake and plasma HDL-C

The accumulation of TG-derived fatty acids in the RQ hindlimb muscles and heart (n = 3) was determined 10 min after injection of [³H]triolein-labelled chylomicron-like emulsion in rats following 18 h of HU and compared with rats with normal ambulatory activity (A). Rats with both 1 day (n = 6) and 11 days (n = 8) of intermittent (10–12 h HU day⁻¹) inactivity had a significantly lower plasma HDL-C concentration compared with active controls (B). *P < 0.05 between HU and low-intensity ambulatory control.

Figure 4. Summary of the dose-response relationship between physical activity/inactivity and muscle LPL

Upper panel, summary of oxidative muscle sections (deep RQ and soleus); lower panel, summary of more glycolytic muscle sections (superficial white vastus lateralis and RF). Results for each muscle type are normalized to ambulatory control values. Absolute values for controls are shown in Fig. 2. Treadmill walking was at 8 m min⁻¹. The data on the effects of low-intensity physical activity are from the current results, and those on high-intensity running (56 m min⁻¹ 3.5 h day⁻¹) are from published work (Hamilton et al. 1998). The two studies used the same strain and vendor of rats.