The adaptation of mitochondrial ATP production rate (MAPR) to training and detraining was evaluated in nine healthy men. Muscle samples (approximately 60 mg) were obtained before and after 6 wk of endurance training and after 3 wk of detraining. MAPR was measured in isolated mitochondria by a bioluminometric method. In addition, the activities of mitochondrial and glycolytic enzymes were determined in skeletal muscle. In response to training, MAPR increased by 70%, with a substrate combination of pyruvate + palmitoyl-L-carnitine + alpha-ketoglutarate + malate, by 50% with only pyruvate + malate, and by 92% with palmitoyl-L-carnitine + malate. With detraining MAPR decreased by 12-28% from the posttraining rate (although not significantly for all substrates). No differences were found when MAPR was related to the protein content in the mitochondrial fraction. The largest increase in mitochondrial enzyme activities induced by training was observed for cytochrome-c oxidase (78%), whereas succinate cytochrome c reductase showed only an 18% increase. The activity of citrate synthase increased by 40% and of glutamate dehydrogenase by 45%. Corresponding changes in maximal O2 uptake were a 9.6% increase by training and a 6.0% reversion after detraining. In conclusion, both MAPR and mitochondrial enzyme activities are shown to increase with endurance training and to decrease with detraining.

Muscle metabolism, including the role of pyruvate dehydrogenase (PDH) in muscle lactate (Lac−) production, was examined during incremental exercise before and after 7 days of submaximal training on a cycle ergometer [2 h daily at 60% peak O2 uptake (V˙o 2 max)]. Subjects were studied at rest and during continuous steady-state cycling at three stages (15 min each): 30, 65, and 75% of the pretraining V˙o 2 max. Blood was sampled from brachial artery and femoral vein, and leg blood flow was measured by thermodilution. Biopsies of the vastus lateralis were obtained at rest and during steady-state exercise at the end of each stage. V˙o 2 max, leg O2 uptake, and the maximum activities of citrate synthase and PDH were not altered by training; muscle glycogen concentration was higher. During rest and cycling at 30% V˙o 2 max, muscle Lac− concentration ([Lac−]) and leg efflux were similar. At 65%V˙o 2 max, muscle [Lac−] was lower (11.9 ± 3.2 vs. 20.0 ± 5.8 mmol/kg dry wt) and Lac− efflux was less [−0.22 ± 0.24 (one leg) vs. 1.42 ± 0.33 mmol/min] after training. Similarly, at 75%V˙o 2 max, lower muscle [Lac−] (17.2 ± 4.4 vs. 45.2 ± 6.6 mmol/kg dry wt) accompanied less release (0.41 ± 0.53 vs. 1.32 ± 0.65 mmol/min) after training. PDH in its active form (PDHa) was not different between conditions. Calculated pyruvate production at 75%V˙o 2 max fell by 33%, pyruvate reduction to lactate fell by 59%, and pyruvate oxidation fell by 24% compared with before training. Muscle contents of coenzyme A and phosphocreatine were higher during exercise after training. Lower muscle lactate production after training resulted from improved matching of glycolytic and PDHafluxes, independently of changes in muscle O2 consumption, and was associated with greater phosphorylation potential.

We evaluated a 22-yr-old Swedish man with lifelong exercise intolerance marked by premature exertional muscle fatigue, dyspnea, and cardiac palpitations with superimposed episodes lasting days to weeks of increased muscle fatigability and weakness associated with painful muscle swelling and pigmenturia. Cycle exercise testing revealed low maximal oxygen uptake (12 ml/min per kg; healthy sedentary men = 39±5) with exaggerated increases in venous lactate and pyruvate in relation to oxygen uptake (V02) but low lactate/pyruvate ratios in maximal exercise. The severe oxidative limitation was characterized by impaired muscle oxygen extraction indicated by subnormal systemic arteriovenous oxygen difference (a-v 02 diff) in maximal exercise (patient = 4.0 ml/dl, normal men = 16.7±2.1) despite normal oxygen carrying capacity and Hgb-02 PSO. In contrast maximal oxygen delivery (cardiac output, Q) was high compared to sedentary healthy men (Q..: patient = 303 ml/min per kg, normal men 238±36) and the slope of increase in Q relative to V02 (i.e., A&Q/AVO2) from rest to exercise was exaggerated (A&Q/AVO2, patient = 29, normal men = 4.7±0.6) indicating uncoupling of the normal approximately 1:1 relationship between oxygen delivery and utilization in dynamic exercise. Studies of isolated skeletal muscle mitochondria in our patient revealed markedly impaired succinate oxidation with normal glutamate oxidation implying a metabolic defect at the level of complex II of the mitochondrial respiratory chain. A defect in Complex H in skeletal muscle was confirmed by the finding ofdeficiency ofsuccinate dehydrogenase as determined histochemically and biochemically. Immunoblot analysis showed low amounts of the 30-kD (iron-sulfur) and 13.5-kD proteins with near normal levels of the 70-kD protein of complex II. Deficiency of succinate dehydrogenase was associated with decreased levels of mitochondrial aconitase assessed enzymatically and immunologically whereas activities of other tricarboxylic acid cycle enzymes were increased compared to normal subjects. The exercise findings are consistent with the hypothesis that this defect impairs muscle oxidative metabolism by limiting the rate of NADH production by the tricarboxylic acid cycle. (J. Clin.

Seven subjects cycled to exhaustion [58 +/- 7 (SE) min] at approximately 75% of their maximal oxygen uptake (VO2max). Needle biopsy samples were taken from the quadriceps femoris muscle at rest, after 3, 10, and 40 min of exercise, at exhaustion, and after 10 min of recovery. After 3 min of exercise, a nearly complete transformation of the pyruvate dehydrogenase complex (PDC) into active form had occurred and was maintained throughout the exercise period. The total in vitro activated PDC was unchanged during exercise. The muscle concentration of acetyl-CoA increased from a resting value of 8.4 +/- 1.0 to 31.6 +/- 3.3 mumol/kg dry wt at exhaustion and that of acetylcarnitine from 2.9 +/- 0.7 to 15.6 +/- 1.6 mmol/kg dry wt. This was accompanied by corresponding decreases in reduced CoA (CoASH) from 45.3 +/- 3.1 to 25.9 +/- 3.1 mumol/kg dry wt and in free carnitine from 18.8 +/- 0.7 to 5.7 +/- 0.5 mmol/kg dry wt. Acetyl group accumulation, in the form of acetyl-CoA and acetylcarnitine, was maintained throughout exercise to exhaustion while the glycogen content decreased by 90%. This suggests that availability of acetyl groups was not limiting to exercise performance despite the nearly total depletion of the glycogen store. The increased acetyl-CoA-to-CoASH ratio during exercise caused inhibition of neither the PDC transformation nor the calculated catalytic activity of active PDC.