The Influence of Acute Beta-Hydroxy Beta-Methylbutyrate (HMB) Ingestion on the Human Skeletal Muscle Transcriptome

Background: Nutritional interventions to mitigate age/disease-related skeletal muscle attrition are much needed given the growing older population. Beta-hydroxy beta-methylbutyrate (HMB), an endogenous metabolite of the essential amino acid leucine, has anabolic properties in skeletal muscle: acutely stimulating muscle protein synthesis and attenuating muscle protein breakdown. While the role of supplemental HMB on muscle protein turnover is established, mechanistic effects on the muscle transcriptome have not been examined. Methods: Total RNA was extracted from m. vastus lateralis muscle biopsies of young males (n = 14) before and ~2.5 h after oral consumption of ~3 g HMB. Global changes in the muscle transcriptome were assessed via RNA sequencing, and differential expression in genes between fasted and 'fed' (HMB) conditions was determined. To identify the functional biology of differentially expressed genes, gene set enrichment and active subnetwork-orientated enrichment analyses was performed. Results: Of 15,982 genes detected, 468 were significantly upregulated and 326 were significantly downregulated in response to HMB. These genes were found to be associated with molecular pathways regulating muscle protein turnover, most notably, JAK-STAT signalling (e.g., STAM), circadian rhythm (e.g., NR1D1, NR1D2, PER2, PER3), TNFα signalling (e.g., TNFRSF1A, CCL2, CXCL2), and protein synthesis (e.g., POLR1A, POLR2A, POLR3A, PIK3RR, SGK1). HMB also regulated the expression of AA transporters, evoking a robust increase in SLC36A1 (PAT1) and SLC7A5 (LAT1). Conclusions: HMB evokes transcriptional events important in the homeostasis of muscle, supporting a role in proteostasis and one akin to protein intake, i.e., upregulation of AA transporters. Future work should further define HMB's transcriptomic/proteomic effects in ageing/disease and synergy with exercise.