Regulation and role of hormone-sensitive lipase activity in human skeletal muscle.

Hormone-sensitive lipase (HSL) is believed to play a regulatory role in initiating the degradation of intramuscular triacylglycerol (IMTG) in skeletal muscle. A series of studies designed to characterise the response of HSL to three stimuli: exercise of varying intensities and durations; adrenaline infusions; altered fuel supply have recently been conducted in human skeletal muscle. In an attempt to understand the regulation of HSL activity the changes in the putative intramuscular and hormonal regulators of the enzyme have also been measured. In human skeletal muscle at rest there is a high constitutive level of HSL activity, which is not a function of biopsy freezing. The combination of low adrenaline and Ca(2+) levels and resting levels of insulin appear to dictate the level of HSL activity at rest. During the initial minute of low and moderate aerobic exercise HSL is activated by contractions in the apparent absence of increases in circulating adrenaline. During intense aerobic exercise, adrenaline may contribute to the early activation of HSL. The contraction-induced activation may be related to increased Ca(2+) and/or other unknown intramuscular activators. As low- and moderate-intensity exercise continues beyond a few minutes, activation by adrenaline through the cAMP cascade may also occur. With prolonged moderate-intensity exercise beyond 1-2 h and sustained high-intensity exercise, HSL activity decreases despite continuing increases in adrenaline, possibly as a result of increasing accumulations of free AMP, activation of AMP kinase and phosphorylation of inhibitory sites on HSL. The existing work in human skeletal muscle also suggests that there are numerous levels of control involved in the regulation of IMTG degradation, with control points downstream from HSL also being important. For example, it must be remembered that the actual flux (IMTG degradation) through HSL may be allosterically inhibited during prolonged exercise as a result of the accumulation of long-chain fatty acyl-CoA.