The influence of exercise on inflammation and IGF-1 signaling in diabetes

Diabetes mellitus (DM) is a hyperglycemic condition resulting from impaired insulin signaling which alters metabolism, increases inflammation and leads to progressive complications, including myocardial dysfunction, increased oxidative stress, altered organ mass, bone mineral content (BMC) and skeletal muscle mass. Exercise is commonly prescribed to reduce the progress of DM-related complications, but its ability to normalize intracellular signaling and restore anatomical structure and myocardial function in animals devoid of insulin is not well characterized. Exercise was prescribed either at the onset of, or 4-weeks following, DM induction. Sixty Sprague-Dawley rats were divided into DM and Non-DM groups. Animals from each group (n=10) were assigned to 1 of 3 treatments: (1) sedentary (2) 4-weeks sedentary followed by 4-weeks of exercise (Ex4); or (3) 8-weeks of exercise (Ex8). Exercise training consisted of treadmill running for 1-hour per day, 5-days per week at 27m/min (∼70% VO2max). DM was induced by a low-dose injection of streptozotocin (20mg/kg; i.p.) for 5 consecutive days. We measured organ, BMC and muscle mass changes, whole body oxidative stress, tissue-specific inflammatory signaling via NF-kappaB-DNA binding, delineated myocardial signaling pathways and the expression of structural and functional proteins regulated through insulin-like growth factor-1 (IGF-1), and acquired measures of systolic and diastolic function by echocardiography. Systolic and diastolic function were impaired in DM animals and were not improved by exercise. Skeletal and myocardial mass were reduced, whereas kidney and adrenal mass were increased by DM and not normalized by exercise. In the myocardium, NF-kappaB-DNA binding was increased by DM, exercise, or a combination of both. However, DM increased contents of the inhibitor specific for the pathological p50-p65 heterodimer, IKB-alpha, indicating that DM may increase pathology-related target-gene transcription, which was not improved by exercise. In DM skeletal muscle, NF-kappaB-DNA binding was decreased in the red gastrocnemius muscle (type 1 myosin fibres), but unchanged in the soleus muscle (type 1 myosin fibres), demonstrating a muscle-specific, rather than fibre-type specific inflammatory regulation. Myocardial cellular signaling mediated through the IGF-1-receptor (IGF-1R) was altered by DM measured by increased protein contents of IGF-1R, activated/unphosphorylated GSK-3beta, increased beta-myosin heavy chain, collagen type III, heat shock factor-1, which were not restored by exercise. In contrast, oxidative stress (serum isoprostanes), elevated in DM animals, was normalized by Ex4 and reduced to below normal levels with Ex8 in DM animals only. In addition, exercise increased the cardio-protective heat shock protein 70 (HSP70) in both DM and Non-DM myocardia. In summary, DM induced systolic and diastolic dysfunction, increased kidney and adrenal gland hypertrophy, oxidative stress, and reduced myocardial and skeletal muscle mass and BMC. DM was associated with specific changes to intracellular signaling pathways via IGF-1R and induced increased contents of pathologically associated structural and functional proteins that were not improved or prevented by exercise. These results indicate that DM negatively affects anatomical structure and myocardial function and its progress is unimpeded by exercise; however, exercise reduces mitochondrial oxidative stress and may provide protection against deleterious myocardial events through the protective functions associated with a significant induction of HSP70.