Growth differentiation factor 15 (GDF15) is a secreted protein whose cellular expression increases in response to a variety of stimuli, including mitochondrial dysfunction. Plasma GDF15 levels increase with advanced age and positively associate with sarcopenia. The prevalence of type 2 diabetes (T2D) increases with age and the incidence of sarcopenia is elevated in patients with T2D. Despite these established associations, the relationship between skeletal muscle mitochondrial function and changes in GDF15 expression, as well as how they may contribute to sarcopenia and T2D in the context of aging, remain poorly defined. We hypothesized that mitochondrial dysfunction in skeletal muscle would be positively associated with increased GDF15 expression and plasma levels in aged mice, and that muscle function and insulin sensitivity would be impaired also. Lean mass as a percentage of body weight was significantly reduced in aged (52 months) male C57BL6 compared with young (4 months) mice. Skeletal muscle function and mobility, assessed as peak and max sustained speeds achieved during voluntary wheel running, were significantly impaired in aged mice. Hyperinsulinemic euglycemic clamps demonstrated impaired insulin sensitivity in skeletal muscle, adipose and liver of aged mice. High-resolution respirometry studies using permeabilized muscle fibers detected significant reductions in the respiratory control ratio (RCR) in aged mice that was due to increased state 4 or leak respiration. Muscle GDF15 gene expression was significantly elevated in old mice, as were plasma levels of circulating GDF15. Our data suggests that skeletal muscle is a significant contributor to increased plasma GDF15 levels seen during aging, and that changes in mitochondrial function may contribute to increased skeletal muscle GDF15 expression. Elevated GDF15 may therefore serve as a strong predictor of mitochondrial pathology and subsequent risk of T2D in aging.
J.Chen: None. F.Bello: None. J.Kastroll: None. A.Vandevender: None. M.Pangburn: None. A.A.Gil silva: None. I.J.Sipula: None. J.Alder: None. M.J.Jurczak: None.