Skeletal Muscle Transcriptomic Responses to Concurrent Training With Polyphenols in Ageing Adults: A Randomized Trial

Background: Transcriptomic adaptations of ageing skeletal muscle to concurrent resistance training (RT) and high-intensity interval training (HIIT) remain insufficiently characterized. We investigated the effects of a 12-week concurrent RT + HIIT intervention on the vastus lateralis transcriptome in middle-aged and older adults and whether polyphenol supplementation modulated these responses. Methods: Thirty-eight adults (55–70 years; 17 polyphenol [PP], 21 placebo [PLA]) with paired skeletal muscle RNA-sequencing data participated in a randomized, double-blind trial. Participants completed a 30-day supplementation phase followed by a 12-week supervised RT + HIIT programme with continued supplementation. Muscle biopsies were obtained before (PRE) and after (POST) training. Differential expression analyses were adjusted for age, sex and muscle fibre type composition. Differential expression was assessed using FDR ≤ 0.05, with |log2FC| > 1 applied as an additional effect-size criterion. Results: Baseline transcriptomic differences between PP and PLA groups were minimal, with three FDR-significant transcripts, of which only HMOX1 additionally exceeded |log2FC| > 1 (FDR = 0.011; log2FC = 1.16). The group-by-time interaction analysis identified 14 FDR-significant transcripts, of which eight additionally exceeded |log2FC| > 1; these signals were characterized by low or sparse expression and high inter-individual variability, without a coherent supplementation-related transcriptional response. In the pooled paired PRE–POST analysis, 60 transcripts reached FDR significance, of which seven additionally exceeded |log2FC| > 1, including upregulation of CLLU1 (log2FC = 3.10; FDR = 0.0155), PRND (log2 log2FC = 2.60; FDR = 0.02) and LOX, and downregulation of MYH1 (log2FC = −1.3; FDR = 0.0001). Most FDR-significant transcripts showed relatively small estimated effect sizes, and functional enrichment analyses did not identify robust pathway-level adaptations. Conclusions: In middle-aged and older adults, 12 weeks of concurrent RT + HIIT induced a predominantly low-magnitude skeletal muscle transcriptional response. Selected transcript-level changes were consistent with processes related to extracellular matrix remodelling and contractile regulation; however, the absence of robust pathway-level enrichment limits conclusions regarding coordinated biological pathway adaptations. Polyphenol supplementation did not meaningfully influence the transcriptional response to exercise training. © 2026 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.