Although the mechanism of action for HMB is not known, the primary working theory is that HMB acts by improving cell membrane integrity by supplying adequate substrate for cholesterol synthesis.4 It is clear that HMB is converted to HMG-CoA in the cytosol, which can be used for cholesterol synthesis in cells.4 In all cells, cholesterol is needed for the synthesis of new cell membranes as well as the repair of damaged membranes in maintaining proper cell function and growth.4344 Certain cells, such as muscle cells, require de novo synthesis of cholesterol for cell cholesterol functions. Therefore, during periods of increased stress on cells, such as occurs in muscle during intense exercise, the demand for cholesterol for growth or repair of cellular membranes may exceed that which can be made through normal endogenous production from available cellular HMG-CoA. Thus, supplemental HMB may help meet an increased demand for and maintain maximal cell function by supplying intracellular HMG-CoA for cholesterol synthesis. The cholesterol can then be used to build and stabilize muscle cell membranes. This theory is supported by observations on diverse cell functions such as immune function and milk fat synthesis, which also requires de novo synthesis of cholesterol in the cells.4
Another possible mechanism of action of supplemental HMB on muscle mass is that HMB somehow directly decreases muscle proteolysis or protein breakdown by having a direct effect on transcriptional or translational control of genes, enzyme activities, or other processes involved with proteolysis. When isolated chicken and rat muscles were studied in vitro, HMB addition to the muscle strip media decreased muscle proteolysis.45 Further research in vivo has shown that HMB decreases muscle proteolysis through changes in the activity of the proteolytic enzymes such as thiol cathepsins and calpain II.46 In humans undergoing an intense resistance exercise program, supplementing HMB resulted in a significant decrease in urinary 3-meth-ylhistidine (3-MH), indicating decreased protein degradation during the first 2 weeks of the exercise program (p < 0.04 and p < 0.001 for weeks 1 and 2, respectively).3 Therefore, increasing the circulating levels of HMB through supplementation may decrease the rate of muscle protein breakdown, which would be of benefit in unwanted catabolic conditions such as after heavy exercise or wasting conditions brought about by some diseases.
Both of the mechanisms proposed may contribute to the effects of HMB in helping maintain cellular function. The increase in cell function could be directly through an increase in cellular cholesterol, and thus stabilization of the cell membranes, or through a more positive protein balance by decreasing muscle protein breakdown. Whatever mechanisms are responsible for the effects of HMB, it appears HMB supplementation has a positive effect on minimizing cell damage and protein breakdown.3'6,945
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