Skeletal muscle properties show collagen organization and immune cell content are associated with resistance exercise response heterogeneity in older persons.

In older individuals, hypertrophy from progressive resistance training (PRT) is compromised in approximately one-third of participants in exercise trials. The objective of this study was to establish novel relationships between baseline muscle features and/or their PRT-induced change in vastus lateralis muscle biopsies with hypertrophy outcomes. Multiple linear regression analyses adjusted for sex were performed on phenotypic data from older adults ( = 48 participants, 70.8 ± 4.5 yr) completing 14 wk of PRT. Results show that baseline muscle size associates with growth regardless of hypertrophy outcome measure [fiber cross-sectional area (fCSA), β = -0.76, Adj. < 0.01; thigh muscle area by computed tomography (CT), β = -0.75, Adj. < 0.01; dual-energy X-ray absorptiometry (DXA) thigh lean mass, β = -0.47, Adj. < 0.05]. Furthermore, loosely packed collagen organization (CO, β = -0.44, Adj. < 0.05) and abundance of CD11b+/CD206- immune cells (β = -0.36, Adj. = 0.10) were negatively associated with whole muscle hypertrophy, with a significant sex interaction on the latter. In addition, a composite hypertrophy score generated using all three measures reinforces significant fiber level findings that changes in myonuclei (MN) (β = 0.67, Adj. < 0.01), changes in immune cells (β = 0.48, Adj. < 0.05; both CD11b+/CD206+and CD11b+/CD206- cells), and capillary density (β = 0.56, Adj. < 0.01) are significantly associated with growth. Exploratory single-cell RNA-sequencing of CD11b+ cells in muscle in response to resistance exercise showed that macrophages have a mixed phenotype. Collagen associations with macrophages may be an important aspect in muscle response heterogeneity. Detailed histological phenotyping of muscle combined with multiple measures of growth response to resistance training in older persons identify potential new mechanisms underlying response heterogeneity and possible sex differences. Extensive analyses of muscle features associated with muscle size and resistance training response in older persons, including sex differences, and evaluation of multiple measures of hypertrophy are discussed. Collagen organization and CD11b-expressing immune cells offer potential new targets to augment growth response in older individuals. A hypertrophy composite score reveals that changes in immune cells, myonuclei, and capillary density are critically important for overall muscle growth while sc-RNAseq reveals evidence for macrophage heterogeneity.