The effect of dietary creatine and supplementation on skeletal muscle creatine accumulation and subsequent degradation and on urinary creatinine excretion was investigated in 31 male subjects who ingested creatine in different quantities over varying time periods. Muscle total creatine concentration increased by approximately 20% after 6 days of creatine supplementation at a rate of 20 g/day. This elevated concentration was maintained when supplementation was continued at a rate of 2 g/day for a further 30 days. In the absence of 2 g/day supplementation, total creatine concentration gradually declined, such that 30 days after the cessation of supplementation the concentration was no different from the presupplementation value. During this period, urinary creatinine excretion was correspondingly increased. A similar, but more gradual, 20% increase in muscle total creatine concentration was observed over a period of 28 days when supplementation was undertaken at a rate of 3 g/day. In conclusion, a rapid way to "creatine load" human skeletal muscle is to ingest 20 g of creatine for 6 days. This elevated tissue concentration can then be maintained by ingestion of 2 g/day thereafter. The ingestion of 3 g creatine/day is in the long term likely to be as effective at raising tissue levels as this higher dose.

Skeletal muscle contraction during ischemia, such as that experienced by peripheral vascular disease patients, is characterized by rapid fatigue. Using a canine gracilis model, we tested the hypothesis that a critical factor determining force production during ischemia is the metabolic response during the transition from rest to steady state. Dichloroacetate (DCA) administration before gracilis muscle contraction increased pyruvate dehydrogenase complex activation and resulted in acetylation of 80% of the free carnitine pool to acetylcarnitine. After 1 min of contraction, phosphocreatine (PCr) degradation in the DCA group was approximately 50% lower than in the control group (P < 0.05) during conditions of identical force production. After 6 min of contraction, steady-state force production was approximately 30% higher in the DCA group (P < 0.05), and muscle ATP, PCr, and glycogen degradation and lactate accumulation were lower (P < 0.05 in all cases). It appears, therefore, that an important determinant of contractile function during ischemia is the mechanisms by which ATP regeneration occurs during the period of rest to steady-state transition.

The metabolic effects of partial ischemia on canine skeletal muscle were examined during 20 min of isometric contraction. A reduction in blood flow of approximately 75% resulted in an approximate 40% reduction in contractile function. Muscle lactate accumulation and phosphocreatine (PCr) hydrolysis were greater during ischemia, indicating a greater reliance on anaerobic ATP regeneration. Pyruvate dehydrogenase transformation to its active form (PDCa) during contraction was not affected by ischemia, such that PDCa did not appear to be a determinant of skeletal muscle fatigue. Acetylcarnitine concentration was greater during ischemic contraction and inversely correlated with PCr concentration (r = -0.79, P<0.01). Furthermore, acetylcarnitine accumulation and PCr degradation correlated with the degree of skeletal muscle fatigue (r = 0.56, P<0.05 and r = 0.70, P<0.01, respectively). Thus the greater the acetyl group oxidation, the lesser the contribution from anaerobic ATP provision and, subsequently, the smaller the degree of muscle fatigue observed. The metabolic characteristics of this model of ischemic muscle contraction are indistinguishable from the normal metabolic responses observed with increasing contractile intensity.

The 'Cell-cell Lactate Shuttle' hypothesis posited that together with blood glucose, glycogen reserves in diverse tissues are mobilized to provide lactate, a metabolic intermediate that is either used within cells of formation or transported to adjacent and anatomically distributed cells for utilization. Hence, lactate was conceived to be a quantitatively important oxidizable substrate and gluconeogenic recursor. First with rats and 14C-tracers, then with humans and P3C-tracers we showed rapid lactate turnover during exercise with oxidation accounting for 75-80% of disposal. Further, the predominant site of lactate removal and oxidation in men is working muscle. During exercise, lactate contributes significantly to glucose production, but gluconeogenesis accounts for only about 20-25% of lactate disposal. We and others have shown that myocyte lactate exchange is mediated by lactate/pyruvate (monocarboxylate) transporters. More recently, we posited a role for the 'Intracellular Lactate Shuttle' in regulation of redox when lactate is exchanged for, or converted to its more oxidized analog, pyruvate. Thus, during exercise and other conditions lactate may become a pseudo hormone, a "lactonone." Beyond human exercise examples of lactate shuttles are found in yeast, sperm, glutamate-mediated synaptic transmission in brain, and within cellular organelles such as mitochondria and peroxisomes. Rather than a dead-end metabolite formed as the result of cell O2 insufficiency, lactate production, exchange and oxidation fulfills important functions in maintaining energy substrate supply and in coordinating metabolic pathways.c7 Adipose tissue, the immune system and exercise fatigue: how activated lymphocytes compete for lipids c J 5 J h c -

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