Muscle Functional Capacity Modifies the Association Between Adiposity and Sarcopenia: Evidence from Two Population-Based Cohorts

Background Whether adiposity is protective against or detrimental to skeletal muscle health in older adults remains unresolved. The conflicting associations between adiposity and sarcopenia, ranging from apparently protective to harmful effects, have been described as the "obesity paradox". We investigated whether this paradox could be explained by heterogeneity in muscle functional capacity, hypothesising that the adiposity-sarcopenia relationship is modified by relative grip strength (RGS). Methods We conducted a cross-sectional analysis of the China Health and Retirement Longitudinal Study (CHARLS; n=15,701), with independent external validation in the US National Health and Nutrition Examination Survey (NHANES; n=10,730). RGS was defined as maximal grip strength divided by body weight. To minimise selective reporting, we performed a prespecified systematic screen of 536 interaction terms derived from 10 anthropometric exposures, 33 functional modifiers, and two sarcopenia outcomes. Core findings were evaluated through cross-metric and cross-outcome replication, sensitivity analyses addressing concerns regarding diagnostic circularity and mathematical coupling, and mediation analyses exploring potential biological pathways. Findings Among 536 tested interactions, 36 met the Bonferroni-corrected significance threshold, and 32 (89%) involved grip-related modifiers. The interaction between waist circumference and RGS for possible sarcopenia was highly significant (p=6.19 x 10(-24)). Stratified analyses showed that higher adiposity was associated with lower odds of sarcopenia, but the magnitude of this association differed substantially by RGS. For BMI, the inverse association was approximately 10-fold stronger among individuals with high RGS than among those with low RGS (OR 0.64, 95% CI 0.60-0.69 vs OR 0.97, 95% CI 0.96-0.98). Similar effect modification patterns were observed across four anthropometric measures and both sarcopenia outcomes, and were independently replicated in NHANES (p<1.0 x 10(-16)). The interaction was no longer evident after restricting analyses to participants with preserved grip strength (p=0.65). Mediation analyses suggested that the association was predominantly direct, with triglycerides accounting for 10.5% of the total effect. Interpretation The association between adiposity and sarcopenia is strongly modified by relative grip strength and appears to be concentrated among individuals with preserved muscle functional capacity. These findings provide a potential explanation for heterogeneity underlying the obesity paradox and suggest that integrating grip strength assessment into adiposity evaluation may improve risk stratification for sarcopenia in older adults.