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

The Igf2 mRNA binding protein2/Imp2 was selectively deleted from adult mouse muscle; two phenotypes were observed: modestly decreased accrual of skeletal muscle mass after weaning and reduced wheel running activity but normal forced treadmill performance. Reduced voluntary activity occurs when fed a high fat diet but is normalized when consuming standard chow. The reduced muscle mass is due to diminished autocrine Igf2 production, reduced Akt1 activation, disinhibition of Gsk3a and reduced protein synthesis, without altered mTOR complex1 activity. The diet-dependent reduction in spontaneous exercise is accompanied by suboptimal muscle fatty acid oxidation, caused by reduced PPARa mRNA and protein, the former an Imp2 client. Nevertheless, in contrast to global Imp2 deficiency, muscle specific Imp2 inactivation does not alter glucose tolerance or the hypoglycemic effect of insulin. Imp2 deficiency in skeletal muscle reduces autocrine production of Igf2 and fiber growth and disorders nutrient metabolism so as to reduce voluntary physical activity. Overall design: The function of IMP2 in adult muscle has been investigated by creating the IMP2 muscle specific knockout mice. The metabolism of these mice at the whole body level, cellular lever, molecular level have been studied.

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Regué L, Ji F, Flicker D, Kramer D, Pierce W, Davidoff T, Widrick JJ, Houstis N, Minichiello L, Dai N, Avruch J