Biological Mechanisms of Strength Preservation During Calorie Restriction-Induced Weight Loss Among Young- to Middle-Aged Adults without Obesity

ABSTRACT Purpose Weight loss is often pursued to improve cardiometabolic health and quality of life. However, rapid weight loss can lead to reductions in lean soft tissue mass and strength to compromise body composition and functional ability. Thus, identifying molecular predictors of muscular strength preservation during weight loss is critical to mitigating these effects. Methods We conducted a secondary analysis of the CALERIE TM (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) trial, a two-year randomized controlled study of caloric restriction (CR) or ad-libitum intake in healthy adults without obesity. Among 198 participants, changes in whole-body mass and knee extensor strength were assessed over the first 12 months of the study which was primarily characterized by weight loss. Transcriptomic profiling was conducted in a subset of 42 participants who provided skeletal muscle samples. Linear regression was used to model the relationship between strength change and gene expression change, while controlling for changes in whole-body mass. Gene set enrichment analysis (GSEA) was performed using Hallmark pathways. Individual-level pathway analysis was performed via gene set variation analysis (GSVA). Results We identified 96 out of 198 individuals (48.5%) who maintained or improved strength relative to body mass during weight loss ( i.e. individuals with residuals > 0). Transcriptomics analysis on a subset of 42 individuals revealed 151 genes significantly associated with change in strength after accounting for change in whole-body mass ( p < 0.01). Hub genes were identified as HSP90AA1 (β = 34.45, SE = 7.32, p <0.001), EIF3A (β = 36.14, SE = 10.27, p < 0.001), EIF5B (β = 49.94, SE = 11.28, p < 0.001), and H3C1 (β = −15.87, SE = 4.85, p < 0.001). GSEA revealed significant involvement of pathways related to cellular proliferation, immune regulation, protein secretion, and checkpoint control processes. GSVA identified a similar set of pathways. Conclusions These findings highlight molecular pathways supporting strength retention during CR-induced weight loss. Heat-shock protein, HSP90AA1 , warrants further investigation as a candidate target for preserving muscle strength during interventions aimed at weight reduction.