Short (<10 days) periods of muscle disuse, often necessary for recovery from illness or injury, lead to various negative health consequences. The current study investigated mechanisms underlying disuse-induced insulin resistance, taking into account muscle atrophy. Ten healthy, young males (age: 23 +/- 1 years; BMI: 23.0 +/- 0.9 kg . m(-2)) were subjected to 1 week of strict bed rest. Prior to and after bed rest, lean body mass (dual-energy X-ray absorptiometry) and quadriceps cross-sectional area (CSA; computed tomography) were assessed, and peak oxygen uptake (VO(2)peak) and leg strength were determined. Whole-body insulin sensitivity was measured using a hyperinsulinemic-euglycemic clamp. Additionally, muscle biopsies were collected to assess muscle lipid (fraction) content and various markers of mitochondrial and vascular content. Bed rest resulted in 1.4 +/- 0.2 kg lean tissue loss and a 3.2 +/- 0.9% decline in quadriceps CSA (both P <0.01). VO(2)peak and one-repetition maximum declined by 6.4 +/- 2.3 (P <0.05) and 6.9 +/- 1.4% (P <0.01), respectively. Bed rest induced a 29 +/- 5% decrease in whole-body insulin sensitivity (P <0.01). This was accompanied by a decline in muscle oxidative capacity, without alterations in skeletal muscle lipid content or saturation level, markers of oxidative stress, or capillary density. In conclusion, 1 week of bed rest substantially reduces skeletal muscle mass and lowers whole-body insulin sensitivity, without affecting mechanisms implicated in high-fat diet-induced insulin resistance.