Recovery Of Glucose-6-Phosphate But Not ATP Following Fatiguing Skeletal Muscle Contractions In Humans

Abstract

Intramyocellular ATP depletion can occur during intense muscle contractions if ATP demand exceeds ATP production. If conditions are sufficiently severe, this can lead to a loss of total adenine nucleotides (TAN) in the irreversible step from adenosine monophosphate (AMP) to inosine monophosphate (IMP). The occurrence and bioenergetic implications of ATP depletion during and following intense contractions in vivo are not clear. PURPOSE: To understand the evolution and resolution of changes in vivo in ATP, phosphomonoesters (PME; glucose-6-phosphate (G6P) + IMP), and TAN during fatiguing contractions in humans. METHODS: After providing written informed consent, 9 adults (35 ± 2 yr; 6F) performed 120 maximal isotonic contractions (1 every 2 s) at 20% of peak torque on a non-magnetic knee extension ergometer in a 3 tesla magnetic resonance (MR) system. Phosphorus MR spectra (2-s repetition time) were collected from the vastus lateralis muscle during rest, 4 min of contractions, and 10 min of recovery. Metabolites (ATP; inorganic phosphate, Pi; PME; and phosphocreatine, PCr) were fit using jMRUI and concentrations calculated assuming ATP = 8.2 mM at rest. Standard equations were used to calculate ADP, AMP, IMP and G6P. Statistics: paired t-tests and Pearson correlation. RESULTS: Peak power decreased to 65 ± 17% (mean ± SD) of baseline during contractions (p < 0.01), indicating substantial muscle fatigue. PCr declined rapidly from 32 ± 2 to 7 ± 5 mM (p < 0.01). ATP was maintained during the first 60 s of contractions, then declined steadily to 6.9 ± 0.9 mM (p < 0.01), and was associated with fatigue (r = 0.62 ± 0.3). G6P, ADP, AMP, and IMP increased (p ≤ 0.01, all), and TAN decreased (p < 0.01) throughout the protocol. Intracellular pH fell to 6.72 ± 0.20 (p < 0.01), indicating moderate acidosis. G6P and pH returned to baseline by 10 min recovery, whereas PCr, ATP, IMP and TAN did not (p ≤ 0.01, all). CONCLUSIONS: Intense, dynamic contractions deplete ATP to the point of impaired bioenergetic recovery due to the accumulation of IMP and consequent loss of TAN. In contrast, full recovery of G6P suggests no long-term inhibition of glycolysis under these conditions. The results have important implications for understanding long-duration fatigue and the bioenergetic preparedness of muscle for subsequent bouts of work. Funding: NIH R01-AG058607