Skeletal Muscle Pyruvate Dehydrogenase Phosphorylation and Lactate Accumulation During Sprint Exercise in Normoxia and Severe Acute Hypoxia: Effects of Antioxidants.

David Morales-Alamo,Miriam Gelabert-Rebato,Cecilia Dorado,Alfredo Santana,José A L Calbet,Borja Guerra,Marcos Martin-Rincon

doi:10.3389/fphys.2018.00188

Abstract

Compared to normoxia, during sprint exercise in severe acute hypoxia the glycolytic rate is increased leading to greater lactate accumulation, acidification, and oxidative stress. To determine the role played by pyruvate dehydrogenase (PDH) activation and reactive nitrogen and oxygen species (RNOS) in muscle lactate accumulation, nine volunteers performed a single 30-s sprint (Wingate test) on four occasions: two after the ingestion of placebo and another two following the intake of antioxidants, while breathing either hypoxic gas (PIO2 = 75 mmHg) or room air (PIO2 = 143 mmHg). Vastus lateralis muscle biopsies were obtained before, immediately after, 30 and 120 min post-sprint. Antioxidants reduced the glycolytic rate without altering performance or VO2. Immediately after the sprints, Ser293- and Ser300-PDH-E1α phosphorylations were reduced to similar levels in all conditions (~66 and 91%, respectively). However, 30 min into recovery Ser293-PDH-E1α phosphorylation reached pre-exercise values while Ser300-PDH-E1α was still reduced by 44%. Thirty minutes after the sprint Ser293-PDH-E1α phosphorylation was greater with antioxidants, resulting in 74% higher muscle lactate concentration. Changes in Ser293 and Ser300-PDH-E1α phosphorylation from pre to immediately after the sprints were linearly related after placebo (r = 0.74, P < 0.001; n = 18), but not after antioxidants ingestion (r = 0.35, P = 0.15). In summary, lactate accumulation during sprint exercise in severe acute hypoxia is not caused by a reduced activation of the PDH. The ingestion of antioxidants is associated with increased PDH re-phosphorylation and slower elimination of muscle lactate during the recovery period. Ser293 re-phosphorylates at a faster rate than Ser300-PDH-E1α during the recovery period, suggesting slightly different regulatory mechanisms.

Highlights

During sprint exercise in normoxia lactate accumulates in the recruited skeletal muscles (Jones et al, 1985; Cheetham et al, 1986; Parolin et al, 1999; Morales-Alamo et al, 2012), indicating that the flux through the pyruvate dehydrogenase (PDH) is not sufficient to avoid pyruvate accumulation and its corresponding reduction to lactate (Howlett et al, 1999)
Compared to normoxia, during sprint exercise in severe acute hypoxia the glycolytic rate is increased leading to greater muscle lactate accumulation, acidification and oxidative stress (Morales-Alamo et al, 2012)
We show that this increased accumulation of lactate is not due to a lower level of PDH activation during the sprint in hypoxia, pointing toward a mitochondrial limitation of the rate of pyruvate decarboxylation to acetyl-CoA and subsequent oxidation of acetyl groups

Summary

Introduction

During sprint exercise in normoxia lactate accumulates in the recruited skeletal muscles (Jones et al, 1985; Cheetham et al, 1986; Parolin et al, 1999; Morales-Alamo et al, 2012), indicating that the flux through the pyruvate dehydrogenase (PDH) is not sufficient to avoid pyruvate accumulation and its corresponding reduction to lactate (Howlett et al, 1999). Animal experiments have shown that excessive RNOS production may reduce PDH activity (Churchill et al, 2005). It remains unknown whether the increased lactate production during sprint exercise in severe acute hypoxia is due, at least in part, to reduced activation of PDH. We have recently shown that during the last 15 s of a 30-s isokinetic sprint in severe acute hypoxia skeletal muscle VO2 is limited by O2 delivery (Calbet et al, 2015). During submaximal exercise at 55% of the VO2max in acute hypoxia (FiO2: = 0.11), the level of PDH activation after 1 min cycling was lower than in normoxia (Parolin et al, 2000)

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