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

Abstract

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.

Recurrent training rejuvenates and enhances transcriptome and methylome responses in young and older human muscle

“…Globally, detraining mainly induced hypermethylation compared to post-training and more genes were downregulated (54) compared to upregulated (40) (Figure 6a-b). Eleven of these 94 DEGs were transcriptionally altered in the same direction as a five-day bed rest study in elderly men 56 Table 1, File S2e-g). The majority of the pathways influenced by training, were also differentially methylated following detraining and/or retraining, whereas 34 pathways were uniquely affected by retraining (Figure 6c), suggesting that the methylome was more responsive to retraining.…”

“…The training and immobilization data of the younger men was, respectively, cross-referenced with RT studies of 10 to 20 weeks (n = 58) 50-55 (File S4h) and immobilization/bed rest studies of 5 to 21 days (n = 42) 10, [56][57][58][59] (File S4i) in healthy, sedentary/active, lean/overweight, younger men. MetaMEx does not include retraining studies.…”

“…We cross-referenced the (re-)training data of the older men with RT studies of 12 to 24 weeks in healthy, sedentary and active, lean or overweight, elderly men (n = 66) 50,52,54,60-62 (File S2h, S2j). MetaMEx does not include detraining studies, instead the detraining data of the older men is compared to a five-day bed rest study in elderly men (n = 10) 56 (File S2i).…”

Absence of MyD88 from Skeletal Muscle Protects Female Mice from Inactivity‐Induced Adiposity and Insulin Resistance

“…Total RNA was isolated from visceral fat and the red portion of the gastrocnemius muscle as described previously, with differences described in online Supporting Information Methods . Sequencing was performed using Illumina NovaSeq (Illumina, San Diego, California), and a 2 × 51 cycle paired end sequence run was performed (NovaSeq 2 × 50 bp Sequencing_100 M Read‐Pairs) using a NovaSeq 6000 SP Reagent Kit (20027465).…”

“…Although energy surplus is the primary culprit for fat accumulation , the principles governing energy expenditure and storage are multifactorial. One such factor is genetic susceptibility to obesogenic environmental influences that may signal through inflammation pathways , such as xenobiotic exposure and ultraprocessed food consumption , which can, for example, drive the extent of metabolic disruption. Much research has been done to understand how energy consumption (diet) interacts with inflammation, but less attention has been given to the interaction between reduced energy expenditure (physical inactivity), inflammation, and obesity.…”