Molecular Signatures Underlying Heterogenous Hypertrophy Responsiveness to Resistance Training in Older Men and Women: a Within-Subject Design

We showed that higher resistance training (RT) volume (4-sets) offsets muscle hypertrophy nonresponsiveness to single-set RT (1 set) while enhancing hypertrophic response among responders. Here, we investigated molecular traits underpinning RT-related hypertrophic variability via targeted (ribosome density and biogenesis) and untargeted approaches [RNA-Seq gene ontology (GO) and Pathway-Level Information ExtractoR (PLIER)]. Twenty-seven older (69 ± 3 yr) participants in the parental trial had one leg randomly allocated to 1 set and the contralateral leg allocated to 4-sets of RT for 10-wk, 2 times/week. Pre- and postintervention, participants underwent magnetic resonance imaging (MRI) and muscle biopsies. We selected participants based on quadriceps muscle cross-sectional area (qCSA) changes and used the MRI typical error (2 × TE = 3.27%) to allocate those in distinct hypertrophy phenotype: low responders: blunted hypertrophy, regardless of RT volume; medium responders: hypertrophy only following the higher RT volume; and high responders: hypertrophy following both RT volume. The qCSA was higher for 4-sets compared with 1 set for medium and high responders only. Higher RT volume, regardless of responsiveness groups, was followed by increased Frizzled-1 protein expression. RNA-Seq showed that high responders' robust hypertrophy was followed by up-regulation of pathways linked with protein turnover metabolism, RT-related metabolic response, and protein-folding biological processes. Hypertrophy in medium responders was marked by downregulation of pathways linked with muscle catabolism (proteasome and spliceosome), modulations on distinct RT-related metabolic response, and biological processes associated with hormone- and steroid-related pathways. Low responders, on the other hand, did not show measurable changes in any molecular pathways, regardless of RT volume manipulation. Overall, these finding reveal differential molecular signatures across the spectrum of RT responsiveness among older individuals.NEW & NOTEWORTHY We showed that higher RT volume increased total protein expression of Frizzled-1. High responder's robust hypertrophy was followed by upregulation of pathways linked with protein turnover metabolism and RT-related metabolic response. Hypertrophy in medium responders, on the other hand, was marked by downregulation of pathways associated with proteasome and spliceosome, and upregulation of lipoproteins metabolisms and genes was associated with membrane trafficking and intracellular protein transport. These findings reveal differential molecular signatures across the spectrum of RT responsiveness among older individuals in response to different RT volume manipulations.