Mitochondrial creatine kinase activity and phosphate shuttling are acutely regulated by exercise in human skeletal muscle
Bibliographic record
Abstract
Key point ATP transfer from mitochondria to the cytoplasm occurs mainly through phosphate transfer to creatine by mitochondrial creatine kinase (miCK) but also by transport and/or diffusion of ADP and ATP through specific mitochondrial transport protein complexes. Determining the effect of exercise on phosphate shuttling may require contractile signals in situ and varying creatine concentrations to alter miCK activity. Mitochondrial respiratory sensitivity to ADP was assessed in permeabilized muscle fibre bundles (PmFBs) before and after 2 h cycling exercise in human skeletal muscle. In relaxed PmFBs, ADP sensitivity decreased post‐exercise when miCK phosphate shuttling was low (no creatine) with no change in net ADP sensitivity in the presence of creatine, whereas in contracting fibres post‐exercise ADP sensitivity was higher with creatine. This shows miCK activity is increased post‐exercise, especially during contraction in PmFBs, and suggests exercise regulates phosphate shuttling, which would improve maintenance of energy homeostasis during contraction. Abstract Energy transfer between mitochondrial and cytosolic compartments is predominantly achieved by creatine‐dependent phosphate shuttling (PCr/Cr) involving mitochondrial creatine kinase (miCK). However, ADP/ATP diffusion through adenine nucleotide translocase (ANT) and voltage‐dependent anion carriers (VDACs) is also involved in this process. To determine if exercise alters the regulation of this system, ADP‐stimulated mitochondrial respiratory kinetics were assessed in permeabilized muscle fibre bundles (PmFBs) taken from biopsies before and after 2 h of cycling exercise (60% ) in nine lean males. Concentrations of creatine (Cr) and phosphocreatine (PCr) as well as the contractile state of PmFBs were manipulated in situ . In the absence of contractile signals (relaxed PmFBs) and miCK activity (no Cr), post‐exercise respiratory sensitivity to ADP was reduced in situ (up to 126% higher apparent K m to ADP) suggesting inhibition of ADP/ATP diffusion between matrix and cytosolic compartments (possibly ANT and VDACs). However this effect was masked in the presence of saturating Cr (no effect of exercise on ADP sensitivity). Given that the role of ANT is thought to be independent of Cr, these findings suggest ADP/ATP, but not PCr/Cr, cycling through the outer mitochondrial membrane (VDACs) may be attenuated in resting muscle after exercise. In contrast, in contracted PmFBs, post‐exercise respiratory sensitivity to ADP increased with miCK activation (saturating Cr; 33% lower apparent K m to ADP), suggesting prior exercise increases miCK sensitivity in situ . These observations demonstrate that exercise increases miCK‐dependent respiratory sensitivity to ADP, promoting mitochondrial–cytosolic energy exchange via PCr/Cr cycling, possibly through VDACs. This effect may mask an underlying inhibition of Cr‐independent ADP/ATP diffusion. This enhanced regulation of miCK‐dependent phosphate shuttling may improve energy homeostasis through more efficient coupling of oxidative phosphorylation to perturbations in cellular energy charge during subsequent bouts of contraction.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".