BackgroundThe potential benefits of gaining body muscle for cardiovascular disease (CVD) susceptibility, and how these compare with the potential harms of gaining body fat, are unknown. We compared associations of early life changes in body lean mass and handgrip strength versus body fat mass with atherogenic traits measured in young adulthood. Methods and findingsData were from 3,227 offspring of the Avon Longitudinal Study of Parents and Children (39% male; recruited in 1991-1992). Limb lean and total fat mass indices (kg/m(2)) were measured using dual-energy X-ray absorptiometry scans performed at age 10, 13, 18, and 25 y (across clinics occurring from 2001-2003 to 2015-2017). Handgrip strength was measured at 12 and 25 y, expressed as maximum grip (kg or lb/in(2)) and relative grip (maximum grip/weight in kilograms). Linear regression models were used to examine associations of change in standardised measures of these exposures across different stages of body development with 228 cardiometabolic traits measured at age 25 y including blood pressure, fasting insulin, and metabolomics-derived apolipoprotein B lipids. SD-unit gain in limb lean mass index from 10 to 25 y was positively associated with atherogenic traits including very-low-density lipoprotein (VLDL) triglycerides. This pattern was limited to lean gain in legs, whereas lean gain in arms was inversely associated with traits including VLDL triglycerides, insulin, and glycoprotein acetyls, and was also positively associated with creatinine (a muscle product and positive control). Furthermore, this pattern for arm lean mass index was specific to SD-unit gains occurring between 13 and 18 y, e.g., -0.13 SD (95% CI -0.22, -0.04) for VLDL triglycerides. Changes in maximum and relative grip from 12 to 25 y were both positively associated with creatinine, but only change in relative grip was also inversely associated with atherogenic traits, e.g., -0.12 SD (95% CI -0.18, -0.06) for VLDL triglycerides per SD-unit gain. Change in fat mass index from 10 to 25 y was more strongly associated with atherogenic traits including VLDL triglycerides, at 0.45 SD (95% CI 0.39, 0.52); these estimates were directionally consistent across sub-periods, with larger effect sizes with more recent gains. Associations of lean, grip, and fat measures with traits were more pronounced among males. Study limitations include potential residual confounding of observational estimates, including by ectopic fat within muscle, and the absence of grip measures in adolescence for estimates of grip change over sub-periods. ConclusionsIn this study, we found that muscle strengthening, as indicated by grip strength gain, was weakly associated with lower atherogenic trait levels in young adulthood, at a smaller magnitude than unfavourable associations of fat mass gain. Associations of muscle mass gain with such traits appear to be smaller and limited to gains occurring in adolescence. These results suggest that body muscle is less robustly associated with markers of CVD susceptibility than body fat and may therefore be a lower-priority intervention target.Author summary Why was this study done? Higher body fat likely causes heart disease, but fat loss remains difficult to maintain. Evidence is less robust on whether gaining body muscle mass or strength would reduce the risk of heart disease, and how the size of potential benefit from muscle or strength gain compares with the expected harm of fat gain.Examining naturally occurring changes in lean mass, grip strength, and fat mass across early stages of life, when ageing-related chronic diseases are rare, should naturally reduce the potential for confounding by subclinical disease and enable less biased estimates of the effect of each body compartment on markers of heart health. What did the researchers do and find? We used data on approximately 3,000 young people from a British birth cohort study to examine repeated measures of body fat and lean mass taken from body scanning performed during childhood, adolescence, and young adulthood, as well as repeated measures of handgrip strength from childhood and young adulthood.We examined associations between these exposures and detailed measures taken from blood samples in young adulthood including apolipoprotein-B-related cholesterol, which reflects susceptibility to heart disease. This enabled us to compare how strongly different body compartments relate to heart health and to pinpoint at what stage of early life (before adulthood) each may be most impactful.We found that gaining lean mass and grip strength were only weakly related to healthier levels of blood markers in young adulthood, and mainly among males, with only lean mass gains occurring in adolescence appearing potentially beneficial. Gaining fat mass was more strongly and consistently related to poorer health in young adulthood, again particularly among males. What do these findings mean? These findings suggest that greater benefits to heart health may be expected from reducing body fat than from gaining body muscle. They further suggest that the regular use of muscle matters more than the volume or intentional building up of muscle for avoiding heart disease.Body muscle is still likely to benefit other functional aspects of health including mobility, and these benefits should still be relayed to patients and the public.