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- Title
Coupling of Oxidative Metabolism to Muscular Work in Healthy and Insulin Resistant Conscious Mice: Role of AMPK Signaling.
- Authors
Lee-Young, Robert S.; Ayala, Julio E.; Birnbaum, Morris J.; Wasserman, David H.
- Abstract
Oxidative capacity of the body is determined, in part, by mitochondrial function, which is associated with insulin resistance. The aim of this study was to test (1) the capacity of normal and insulin-resistant muscles to use oxygen in conscious C57B16/J mice, and (2) the dependence of work capacity and oxygen uptake (VO[sub 2]) on AMP-activated protein kinase (AMPK) signaling. AMPK dominant negative (AMPK-DN) mice and wild type littermates (WT) were fed chow (CH) or made insulin resistant using a high fat (HF) diet. Mice underwent an incremental exercise stress test at 16 wks of age. Mice on a HF diet increased body mass by ∼50% and fat mass by ∼3-fold compared to CH, although no genotype effects were observed. In WT mice, a HF diet resulted in impaired work capacity (running speed at exhaustion of 30±1 for HF vs 38±1 m⋅min[sup -1] for CH; P<0.05), and the change in VO[sub 2] from rest to exhaustion (ΔVO[sub 2max]) was also attenuated (34±6 vs 142±9 ml⋅g lean mass[sup -1]⋅.min[sup -1]; P<0.001). In WT mice fed CH, exercise increased AMPK activation ∼2-fold, whilst no increase was observed for HF fed WT mice. Thus, AMPK-DN mice were then used to test the role of impaired AMPK signaling in regards to oxidative capacity. Compared to WT mice on CH, AMPK-DN mice on CH had reduced work capacity (22±1 m⋅min[sup -1]) and ΔVO[sub 2max] was also impaired at exhaustion (64±24 ml⋅g lean mass[sup -1]⋅min[sup -1]). A HF diet reduced the work capacity of AMPK-DN mice (18±1 m⋅min[sup -1]) to a greater extent than either HF (i.e. WT vs AMPK-DN) or AMPK-DN independently. Remarkably, there was no increase in VO[sub 2] at exhaustion when AMPK-DN mice on a HF diet were exercised (ΔVO[sub 2max] = 1±4 ml⋅g lean mass[sup -1]⋅min[sup -1]). In conclusion, the increases in AMPK activation and oxidative capacity during exercise are both suppressed by a HF diet in WT mice. The impaired oxidative capacity of AMPK-DN mice underscores the essential role of AMPK signaling during exercise. The demonstration that HF diet reduces exercise capacity and ΔVO[sub 2max] in AMPK-DN mice indicates that the impaired exercise response with HF feeding is AMPK-independent ADA-Funded Research
- Subjects
OXYGEN; METABOLISM; MUSCLES; INSULIN resistance; PROTEIN kinases
- Publication
Diabetes, 2007, Vol 56, pA63
- ISSN
0012-1797
- Publication type
Article