Conducted Capillary Signaling Enables Oxygen Responses in Skeletal Muscle Independent of Metabolite Production
Bibliographic record
Abstract
Red blood cell (RBC) flow through the microvasculature is closely matched to tissue O 2 requirements. At a fundamental level, O 2 demand‐supply coupling entails the sensing of PO 2 , and the generation of a stimulus that alters upstream arteriolar tone. However, where and how O 2 needs are sensed in the microcirculation is presently contested. One idea centers on hypoxia triggering the release of K + , activating endothelial K IR 2.1 channels and initiating a hyperpolarization that conducts upstream via gap junctions, comprised of connexins (Cx). We tested this idea in skeletal muscle where we controlled the local tissue O 2 environment using live animal imaging in Cx40 ‐/‐ and endothelial K IR 2.1 ‐/‐ mice. The extensor digitorum longus muscle positioned overtop a gas control chamber allowed second‐by‐second monitoring of capillary RBC flow responses as O 2 was altered around its physiological set point of 53 mmHg. A stepwise drop in PO 2 at the muscle surface (53 to 15 or 0 mmHg) increased RBC supply rate in control capillaries while elevated chamber O 2 elicited the opposite response; these capillaries robustly expressed Cx40. The RBC flow responses were rapid and tightly coupled to O 2 levels as readily observed when chamber O 2 was oscillated in a sinusoidal manner. In contrast, this blood flow response was significantly diminished in Cx40 ‐/‐ mice and translated into lower capillary RBC O 2 saturation. K IR 2.1 ‐/‐ mice, on the other hand, had normal resting RBC O 2 saturation and reacted normally to O 2 changes, albeit an oscillation or a sustained stepwise decrease. Furthermore, we confirmed that RBC flow responses are conserved in endothelial K IR 2.1 ‐/‐ mice even when the low O 2 challenge is applied to a restricted number of surface capillaries in the muscle; interestingly, these responses were dominated by capillary hematocrit changes in both control and endothelial K IR 2.1 ‐/‐ mice. Modelling this phenomenon supported the idea that the number of capillaries stimulated is indeed tied to conduction distance and tissue RBC distribution. In conclusion, we demonstrate that microvascular O 2 responses depend on coordinated electrical signaling via gap junctions comprised of Cx40 and that endothelial K IR 2.1channels do not drive the initiating electrical event. These findings reconceptualize our understanding of blood flow regulation and how O 2 initiates this process at the capillary level independent of metabolite production.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 source (direct Gemma or distilled Codex), 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".