Deletion of muscle IGF-I transiently impairs growth and progressively disrupts glucose homeostasis in male mice

Abstract

Insulin-like growth factors (IGFs) are essential for local skeletal muscle growth and organismal physiology, but these actions are entwined with glucose homeostasis through convergence with insulin signaling. The objective of thisworkwas to determinewhether the effects of IGF-I on growth andmetabolismcould be separated. Wegeneratedmuscle-specific IGF-I-deficient (MID) mice that afford inducible deletion of Igf1 at any age.After Igf1 deletion at birth or in young adultmice, evaluations ofmuscle physiology and glucose homeostasiswere performed up to 16wk of age.MIDmice generated at birth had lowermuscle and circulating IGF-I,decreasedmuscle and body mass, and impairedmuscle force production. Eight-wk-oldmaleMID had heightened insulin levels with trends of elevated fasting glucose. This phenotype progressed to impaired glucose handling and increased fat deposition without significant musclemass loss at 16wk of age. The same phenotype emerged in 16-wk-oldMIDmice induced at 12 wk of age, compounded with heightened muscle fatigability and exercise intolerance.We assert that muscle IGF-I independently modulates anabolismandmetabolismin an age-dependentmanner, thus positioningmuscle IGF-Imaintenance to be critical for bothmuscle growth andmetabolic homeostasis.