Exercise attenuates bed rest-induced increases in insulin resistance while α-klotho increases in 55 to 65 year-old women and men.

We evaluated the efficacy of combined aerobic, high intensity interval (HIIT) and resistive exercises during Head-Down Bed Rest (HDBR) in preventing metabolic derangement. Twenty-two participants (control: F (5) BMI: 22.1 ± 2.1, M (6) BMI: 25.7 ± 2.2, exercise F (6) BMI: 24.3 ± 3.2, M (5) BMI: 27.5 ± 1.2; Average age: 59 ± 3 years; weight: 70.1 ± 14.2 kg; height: 1.67 ± 0.09 m; BMI: 24.9 ± 3.0 kg/m)) confined to 6° HDBR for 14-days were randomly assigned to either EX (1 h/day head-down exercise including HIIT every other day) or CONT (passive movement). Oral glucose tolerance tests (OGTT) at baseline, day 9 HDBR (HDT 9) and 13 HDBR (HDT 13) were matched to fasted biomarker analyses and Vastus lateralis biopsies. HDBR increased area under the curve for glucose (p < 0.01, interaction between groups; group × bed rest; p = 0.07) and insulin (p < 0.01). Matsuda index fell in CONT alone, FGF-23 increased in EX correlating with elevations to circulating levels of C reactive protein; a negative correlation existed between FGF-23 and HOMA-IR in CONT. A novel finding was that α-klotho increased in all participants (p < 0.0001), starting higher and rising faster in women, whilst negatively correlating with Matsuda index in CONT alone. Undercarboxylated-osteocalcin ratio fell in CONT (p = 0.05). Neither IGF-1, nor GLUT1/4 protein content changed during HDBR. HDBR promoted insulin resistance with increases in circulating α-klotho; FGF-23 increased only in EX. Differing Matsuda index responses indicate benefits imparted by multimodal exercise despite elevations in α-klotho and FGF-23.Clinical Trial Registration Number: NCT04964999.