Exploring the multifactorial causes and therapeutic strategies for anabolic resistance in sarcopenia: A systems modeling study
Bibliographic record
Abstract
Abstract Background Sarcopenia is the progressive loss of skeletal muscle mass, strength, and function with age, driven by dysregulation in the rates of muscle protein synthesis (MPS) and breakdown (MPB). Although MPB contributes to net protein balance (NB), a primary contributor of sarcopenia is anabolic resistance , defined as the blunted MPS response to anabolic stimuli such as feeding. While candidate mechanisms of anabolic resistance have been identified, none singularly accounts for the observed reduction in MPS. Instead, multiple mechanisms likely act simultaneously and interactively to suppress MPS. Studying these interactions experimentally is challenging. Mathematical modeling is well suited to analyzing complex biological phenomena such as anabolic resistance. Methods We analyzed a previously developed kinetic model of leucine-mediated signaling and protein metabolism in human skeletal muscle to systematically investigate potential mechanisms contributing to anabolic resistance. Using global sensitivity analysis, we identified key controllers of MPS, MPB, and NB. We then simulated amino acid feeding in older adults, classified the responses as either anabolic sensitive or resistant, and compared the resulting parameter distributions of the two groups. We next performed targeted analysis to evaluate the effects of individual and combined putative mechanisms of anabolic resistance on muscle metabolism. Finally, we simulated therapeutic interventions aimed at restoring muscle metabolism. Results The sensitivity analysis revealed that MPS and MPB are primarily controlled by their proximal signaling processes, while NB is largely driven by MPS dynamics. Exploratory simulations showed that several parameters and signaling protein concentrations, particularly those controlling MPS, differed significantly between anabolic sensitive and resistant groups. The targeted simulations indicated that multiple dysregulated mechanisms were required to account for the experimentally observed reductions in MPS in older adults. Therapy simulations showed that single-target interventions could largely restore MPS when isolated mechanisms were perturbed (e.g., increasing mTORC1 sensitivity, enhancing p70S6K levels), but a multifactorial approach was required to recover muscle metabolism when all anabolic resistance mechanisms were present. Conclusion This study highlights the multifactorial nature of anabolic resistance and the implications for therapy. Specifically, the results motivate new hypotheses regarding the mechanisms most likely to be impaired and argue for multi-target therapeutic strategies to help restore muscle protein metabolism in aging.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".