TY - JOUR

T1 - Insulin resistance induced by physical inactivity is associated with multiple transcriptional changes in skeletal muscle in young men

AU - Alibegovic, A C

AU - Sonne, M P

AU - Højbjerre, L

AU - Bork-Jensen, Jette

AU - Jacobsen, S

AU - Nilsson, E

AU - Faerch, K

AU - Hiscock, N

AU - Mortensen, B

AU - Friedrichsen, M

AU - Stallknecht, Bente Merete

AU - Dela, F

AU - Vaag, A

PY - 2010/11/1

Y1 - 2010/11/1

N2 - Physical inactivity is a risk factor for insulin resistance. We examined the effect of 9 days of bed rest on basal and insulin-stimulated expression of genes potentially involved in insulin action by applying hypothesis-generating microarray in parallel with candidate gene real-time PCR approaches in 20 healthy young men. Furthermore, we investigated whether bed rest affected DNA methylation in the promoter region of the peroxisome proliferator-activated receptor-¿ coactivator-1a (PPARGC1A) gene. Subjects were reexamined after 4 wk of retraining. We found that bed rest induced insulin resistance and altered the expression of more than 4,500 genes. These changes were only partly normalized after 4 wk of retraining. Pathway analyses revealed significant downregulation of 34 pathways, predominantly those of genes associated with mitochondrial function, including PPARGC1A. Despite induction of insulin resistance, bed rest resulted in a paradoxically increased response to acute insulin stimulation in the general expression of genes, particularly those involved in inflammation and endoplasmatic reticulum (ER) stress. Furthermore, bed rest changed gene expressions of several insulin resistance and diabetes candidate genes. We also observed a trend toward increased PPARGC1A DNA methylation after bed rest. We conclude that impaired expression of PPARGC1A and other genes involved in mitochondrial function as well as a paradoxically increased response to insulin of genes involved in inflammation and ER stress may contribute to the development of insulin resistance induced by bed rest. Lack of complete normalization of changes after 4 wk of retraining underscores the importance of maintaining a minimum of daily physical activity.

AB - Physical inactivity is a risk factor for insulin resistance. We examined the effect of 9 days of bed rest on basal and insulin-stimulated expression of genes potentially involved in insulin action by applying hypothesis-generating microarray in parallel with candidate gene real-time PCR approaches in 20 healthy young men. Furthermore, we investigated whether bed rest affected DNA methylation in the promoter region of the peroxisome proliferator-activated receptor-¿ coactivator-1a (PPARGC1A) gene. Subjects were reexamined after 4 wk of retraining. We found that bed rest induced insulin resistance and altered the expression of more than 4,500 genes. These changes were only partly normalized after 4 wk of retraining. Pathway analyses revealed significant downregulation of 34 pathways, predominantly those of genes associated with mitochondrial function, including PPARGC1A. Despite induction of insulin resistance, bed rest resulted in a paradoxically increased response to acute insulin stimulation in the general expression of genes, particularly those involved in inflammation and endoplasmatic reticulum (ER) stress. Furthermore, bed rest changed gene expressions of several insulin resistance and diabetes candidate genes. We also observed a trend toward increased PPARGC1A DNA methylation after bed rest. We conclude that impaired expression of PPARGC1A and other genes involved in mitochondrial function as well as a paradoxically increased response to insulin of genes involved in inflammation and ER stress may contribute to the development of insulin resistance induced by bed rest. Lack of complete normalization of changes after 4 wk of retraining underscores the importance of maintaining a minimum of daily physical activity.

KW - Adult

KW - Bed Rest

KW - DNA Methylation

KW - Epigenesis, Genetic

KW - Gene Expression Profiling

KW - Gene Expression Regulation

KW - Glucose Clamp Technique

KW - Heat-Shock Proteins

KW - Humans

KW - Insulin Resistance

KW - Male

KW - Muscle, Skeletal

KW - Oligonucleotide Array Sequence Analysis

KW - RNA

KW - Statistics, Nonparametric

KW - Transcription Factors

KW - Young Adult

U2 - 10.1152/ajpendo.00590.2009

DO - 10.1152/ajpendo.00590.2009

M3 - Journal article

C2 - 20739510

VL - 299

SP - E752-63

JO - American Journal of Physiology - Endocrinology and Metabolism

JF - American Journal of Physiology - Endocrinology and Metabolism

SN - 0193-1849

IS - 5

ER -