Abstract
ABSTRACT
Aim
The Na,K‐ATPase is important for energy demanding cellular processes, including essential components of substrate metabolism and metabolic flexibility. Mice heterozygous for the hemiplegic migraine‐related mutation, G301R, of the Na,K‐ATPase α
2
isoform (α
2
+/G301R
) demonstrated altered metabolism in the heart. We hypothesized that mitochondrial dysfunction in α
2
+/G301R
mice is associated with abnormal systemic glucose metabolism.
Methods
3‐ and 8‐month‐old α
2
+/G301R
and wild type (WT) mice of both sexes were metabolically phenotyped. Glucose uptake in peripheral tissues was assessed by [
18
F]‐2‐fluoro‐2‐deoxyglucose (FDG) MRI. Mitochondrial function in liver was assessed with high‐resolution respirometry. Protein expression was assessed by proteomics and Western blot. Glycated hemoglobin (HbA1c) was measured with immunoassay.
Results
The 3‐month‐old α
2
+/G301R
mice had normal responses to glucose tolerance test, but males showed a reduced insulin response. The 8‐month‐old α
2
+/G301R
mice exhibited glucose intolerance associated with impaired glucose uptake in the liver while unaltered in skeletal muscle associated with unchanged GLUT‐4 and insulin receptor levels. Insulin secretion and insulin sensitivity were similar between 8‐month‐old genotypes. In the liver, 8‐month‐old α
2
+/G301R
mice of both sexes showed reduced expression of the α
2
Na,K‐ATPase and several key mitochondrial proteins from the electron transport chain. Accordingly, mitochondrial oxygen consumption was reduced in 8‐month‐old α
2
+/G301R
males, and 8‐month‐old α
2
+/G301R
females showed a complex I‐mediated dysfunction in the liver mitochondria.
Conclusions
Migraine‐associated mutation of the Na,K‐ATPase α
2
isoform was associated with impaired mitochondrial respiratory capacity in the liver. Hence, α
2
+/G301R
mice exhibited reduced capacity of ATP‐demanding metabolic pathways in the liver resulting in age‐dependent impaired glucose homeostasis.