IMP2 increases mouse skeletal muscle mass and voluntary activity by enhancing autocrine IGF2 production and optimizing muscle metabolism

ABSTRACT

The IGF2 mRNA binding protein2/IMP2 was selectively deleted from adult mouse muscle; two phenotypes were observed: decreased accrual of skeletal muscle mass after weaning and reduced wheel running activity but normal forced treadmill performance. Reduced wheel running occurs when fed a high fat diet but is normalized consuming standard chow. The two phenotypes are due to altered abundance of different IMP2 client mRNAs. The reduced fiber size of IMP2 deficient muscle is attributable, in part, to diminished autocrine Igf2 production; basal tyrosine phosphorylation of the Insulin and IGF1 receptors is diminished and Akt1 activation is selectively reduced. Gsk3α is disinhibited and eIF2Bϵ[lsqb]S536[rsqb] hyperphosphorylated. Protein synthesis is reduced despite unaltered MTOR complex1 activity. The diet dependent reduction in voluntary exercise is likely due to altered muscle metabolism, as contractile function is normal. IMP2-deficient muscle exhibits reduced fatty acid oxidation, due to reduced abundance of PPARα mRNA, an IMP2 client, and PPARα protein. IMP2 deficient muscle fibers treated with mitochondrial uncoupler to increase electron flux, as occurs with exercise, exhibit reduced oxygen consumption from fatty acids with higher oxygen consumption from glucose. The greater dependence on muscle glucose metabolism during increased oxygen demand may promote central fatigue and thereby diminish voluntary activity.