Improved aerobic exercise capacity (VO2max) has emerged as one of the most important health benefits of aerobic exercise training. However, hyperglycemia is associated with low VO2max in humans, even when physical activity levels are matched. To determine how glycemia influences aerobic adaptations with exercise training, we induced moderate hyperglycemia (+50-70 mg/dL vs. control) in mouse models that mimic the pathologies of type 1 or type 2 diabetes: 1) Low-dose Streptozotocin treatment (STZ), or 2) Western diet (WD) feeding. Normoglycemic mice acted as controls (CON). All mice completed ∼500 km of voluntary wheel running over an 8-wk aerobic training period, and achieved the expected metabolic benefits from exercise training. However, metabolic improvements were uncoupled from aerobic adaptation in hyperglycemic WD and STZ mice, who failed to improve VO2max beyond the level of sedentary controls. In contrast, CON mice had a 2-fold increase in VO2max in response to the same training intervention. In hyperglycemic models, blunted improvements in VO2max were associated with structural changes to muscle, including glucose-induced modifications to the extracellular matrix (e.g., glycation and collagen accretion), and reduced exercise-induced angiogenesis and oxidative fiber-type shifts. Thus, our data provide evidence that aerobic muscle remodeling, which is critical for augmenting VO2max, is impaired by hyperglycemia. In addition, we show that chronic hyperglycemia causes hyper-activation of a JNK/SMAD2 signaling network in muscle with acute aerobic exercise, which is a known molecular mechanism that inhibits aerobic adaptation. Accordingly, in human subjects, we show that impaired glucose tolerance strongly predicts hyper-activation of this inhibitory signaling network in conjunction with low VO2max. Taken together, we demonstrate that hyperglycemia, regardless of etiology, may interfere with fundamental adaptations to aerobic exercise training and negatively regulate improvements in VO2max.
T. MacDonald: None. P. Pathak: None. N.M. Fernandez: None. E.C. Freitas: None. S. Hafida: None. J. Mitri: Consultant; Spouse/Partner; Janssen Pharmaceuticals, Inc., kymera. Consultant; Self; national dairy council/local dairy council. Research Support; Spouse/Partner; AbbVie Inc., beigene, Janssen Pharmaceuticals, Inc. Research Support; Self; Kowa Pharmaceuticals America, Inc., national dairy council. Research Support; Spouse/Partner; pharma cyclic, TG therapeutics. S.J. Lessard: None.
American Heart Association (19POST34381036)