Biological Pathways of Strength Preservation During Calorie Restriction‐Induced Weight Loss Among Adults Without Obesity

OBJECTIVE: Weight loss is often pursued to improve cardiometabolic health and quality of life. However, weight loss can lead to reductions in lean soft tissue mass and strength, compromising 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 trial, a 2-year randomized controlled study of caloric restriction or ad libitum intake in healthy adults without obesity. Changes in whole-body mass and knee extensor strength were assessed over the first 12 months of the study. Transcriptomic profiling was conducted in a subset who provided skeletal muscle samples. The relationship between strength change and gene expression change was modeled, controlling for whole-body mass change. RESULTS: 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, including HSP90AA1 and EIF3A. Pathway analyses revealed significant involvement of pathways related to cellular proliferation, immune regulation, and protein secretion. CONCLUSIONS: These findings highlight molecular pathways and genes supporting strength retention during caloric restriction-induced weight loss. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00427194 www. CLINICALTRIALS: gov.