Disuse-induced insulin resistance susceptibility coincides with a dysregulated skeletal muscle metabolic transcriptome.

Short-term muscle disuse is characterized by skeletal muscle insulin resistance, although this response is divergent across subjects. The mechanisms regulating inactivity-induced insulin resistance between populations that are more or less susceptible to disuse-induced insulin resistance are not known. RNA sequencing was conducted on vastus lateralis muscle biopsies from subjects before and after bed rest (n = 26) to describe the transcriptome of inactivity-induced insulin resistance. Subjects were separated into Low (n = 14) or High (n = 12) Susceptibility Groups based on the magnitude of change in insulin sensitivity after 5 days of bed rest. Both groups became insulin-resistant after bed rest, and there were no differences between groups in nonmetabolic characteristics (body mass, body mass index, fat mass, and lean mass). The High Susceptibility Group had more genes altered >1.5-fold (426 high versus 391 low) and more than twofold (73 high versus 55 low). Twenty-four genes were altered more than twofold in the High Susceptibility Group that did not change in the Low Susceptibility Group. 95 gene changes correlated with the changes in insulin sensitivity; 6 of these genes changed more than twofold in the High Susceptibility Group. Participants in the High Susceptibility Group were uniquely characterized with muscle gene responses described by a decrease in pathways responsible for lipid uptake and oxidation, decreased capacity for triglyceride export (APOB), increased lipogenesis (i.e., PFKFB3, FASN), and increased amino acid export (SLC43A1). These transcriptomic data provide a comprehensive examination of pathways and genes that may be useful biomarkers, or novel targets to offset muscle disuse-induced insulin resistance. NEW & NOTEWORTHY Short-term muscle disuse results in skeletal muscle insulin resistance through mechanisms that are not fully understood. Following a 5-day bed rest intervention, subjects were divided into High and Low Susceptibility Groups to inactivity-induced insulin resistance. This was followed by a genome-wide transcriptional analysis on muscle biopsy samples to gain insight on divergent insulin sensitivity responses. Our primary finding was that the skeletal muscle of subjects who experienced the most inactivity-induced insulin resistance (high susceptibility) was characterized by a decreased preference for lipid oxidation, increased lipogenesis, and increased amino acid export.