Muscle-specific activation of Ca2+/calmodulin-dependent protein kinase IV increases whole-body insulin action in mice
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Aerobic exercise increases muscle glucose and improves insulin action through numerous pathways, including activation of Ca2+/calmodulin-dependent protein kinases (CAMKs) and peroxisome proliferator γ coactivator 1α (PGC-1α). While overexpression of PGC-1α increases muscle mitochondrial content and oxidative type I fibres, it does not improve insulin action. Activation of CAMK4 also increases the content of type I muscle fibres, PGC-1α level and mitochondrial content. However, it remains unknown whether CAMK4 activation improves insulin action on glucose metabolism in vivo.
The effects of CAMK4 activation on skeletal muscle insulin action were quantified using transgenic mice with a truncated and constitutively active form of CAMK4 (CAMK4●) in skeletal muscle. Tissue-specific insulin sensitivity was assessed in vivo using a hyperinsulinaemic–euglycaemic clamp and isotopic measurements of glucose metabolism.
The rate of insulin-stimulated whole-body glucose uptake was increased by ∼25% in CAMK4● mice. This was largely attributed to an increase of ∼60% in insulin-stimulated glucose uptake in the quadriceps, the largest hindlimb muscle. These changes were associated with improvements in insulin signalling, as reflected by increased phosphorylation of Akt and its substrates and an increase in the level of GLUT4 protein. In addition, there were extramuscular effects: CAMK4● mice had improved hepatic and adipose insulin action. These pleiotropic effects were associated with increased levels of PGC-1α-related myokines in CAMK4● skeletal muscle.
Activation of CAMK4 enhances mitochondrial biogenesis in skeletal muscle while also coordinating improvements in whole-body insulin-mediated glucose.
KeywordsHyperinsulinaemic–euglycaemic clamp Muscle insulin resistance Myokines
AMP-activated protein kinase
160 kDa substrate of the Akt serine/threonine kinase
Ca2+/calmodulin-dependent protein kinase
Truncated and constitutively active form of CAMK
cAMP response element binding protein
Endogenous glucose production
Extensor digitorum longus
Histone deacetylase 5
Myocyte enhancer factor 2
National Institutes of Health
Novel protein kinase C
Peroxisome proliferator-activated receptor γ coactivator 1α
Protein phosphatase type 2A
Protein phosphatase type 2A catalytic subunit
Akt1 substrate 1 (proline-rich)
Uncoupling protein 1 (mitochondrial, proton carrier)
Voltage-dependent ion channel
White adipose tissue
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