posted on 2020-05-21, 20:06authored byAda AdminAda Admin, Louise Lantier, Ashley S. Williams, Ian M.Williams, Amanda Guerin, Deanna P. Bracy, Mickael Goelzer, Marc Foretz, Benoit Viollet, Curtis C. Hughey, David H. Wasserman
Insulin resistance
due to overnutrition places a burden on energy-producing pathways in skeletal
muscle (SkM). Nevertheless, energy state is not compromised. The hypothesis that
the energy sensor AMP-activated protein kinase (AMPK) is necessary to offset
the metabolic burden of overnutrition was tested using chow-fed and high fat
(HF)-fed SkM-specific AMPKa1a2 knockout (mdKO) mice and AMPKa1a2lox/lox
littermates (WT). Lean mdKO and WT mice were phenotypically similar. HF-fed
mice were equally obese and maintained lean mass regardless of genotype. Results
did not support the hypothesis that AMPK is protective during overnutrition.
Paradoxically, mdKO mice were more insulin sensitive. Insulin-stimulated SkM glucose uptake was ~two-fold
greater in mdKO mice in vivo. Furthermore, insulin signaling, SkM GLUT4
translocation, hexokinase activity, and glycolysis were increased. AMPK and
insulin signaling intersect at mTOR, a critical node for cell proliferation and
survival. Basal mTOR activation was reduced by 50% in HF-fed mdKO mice, but was
normalized by insulin-stimulation. Mitochondrial function was impaired in mdKO
mice, but energy charge was preserved by AMP deamination. Results show a surprising
reciprocity between SkM AMPK signaling and insulin action that manifests with diet-induced
obesity, as insulin action is preserved to protect fundamental energetic
processes in the muscle.
Funding
This work was supported by National Institute of Health grant DK054902, the European Commission integrated project (LSHM-CT-2004- 005272), Agence Nationale de la Recherche (PHYSIO 2006 R06428KS), and Association Française contre les Myopathies (grant 14138).