Abnormal oxidative metabolism and O₂ transport in muscle phosphofructokinase deficiency

Humans who lack availability of carbohydrate fuels may provide important models for the study of physiological control mechanisms. We compared seven patients who had unavailability of muscle glycogen and blood glucose as oxidative fuels due to muscle phosphofructokinase deficiency (PFKD) with five patients who had a selective defect in long-chain fatty acid oxidation due to carnitine palmitoyltransferase deficiency (CPTD) and with six healthy subjects. Peak cycle exercise work rate, peak O₂ uptake (V̇O₂), and arteriovenous O₂ difference were markedly lower (P < 0.001) for PFKD patients (23 ± 6 W, 14 ± 2 ml·min^-1·kg^-1, and 7.1 ± 0.5 ml/dl, respectively) than for CPTD patients (142 ± 33 W, 31 ± 4 ml·min^-1·kg^-1, and 15.0 ± 0.8 ml/dl, respectively) or healthy subjects (171 ± 17 W, 36 ± 1 ml·min^-1·kg^-1, and 16.4 ± 0.7 ml/dl, respectively). Peak cardiac output (Q̇) was similar (P > 0.05) in all three groups, but the slope of increase in Q̇ (l/min) on V̇O₂ (l/min) from rest to exercise (ΔQ̇/ΔV̇O₂) was more than twofold greater (P < 0.001) for PFKD patients (11.2 ± 1.2) than for CPTD patients (4.6 ± 0.6) and healthy subjects (4.6 ± 0.2). Increasing availability of blood-borne oxidative substrates capable of metabolically bypassing the defect at phosphofructokinase (by fasting plus prolonged moderate exercise to increase plasma free fatty acids or by iv lactate infusion) increased peak work rate, V̇O₂, and arteriovenous O₂ difference, lacked consistent effect on peak Q̇, and normalized ΔQ̇/ΔV̇O₂ in PFKD patients. The results extend our previous observations in patients with a block in muscle glycogen but not blood glucose oxidation due to phosphorylase deficiency and imply that specific unavailability of muscle glycogen as an oxidizable fuel is primarily responsible for abnormal muscle oxidative metabolism and associated exercise intolerance and exaggerated ΔQ̇/ΔV̇O₂ in muscle PFKD. The findings also endorse the concept that factors closely linked with muscle oxidative phosphorylation participate in regulating ΔQ̇/ΔV̇O₂, likely via activation of metabolically sensitive muscle afferents.