Distinct growth hormone receptor signaling modes regulate skeletal muscle development and insulin sensitivity in mice
Mahendra D. Mavalli, Douglas J. DiGirolamo, Yong Fan, Ryan C. Riddle, Kenneth S. Campbell, Thomas van Groen, Stuart J. Frank, Mark A. Sperling, Karyn A. Esser, Marcas M. Bamman, Thomas L. Clemens
Mahendra D. Mavalli, Douglas J. DiGirolamo, Yong Fan, Ryan C. Riddle, Kenneth S. Campbell, Thomas van Groen, Stuart J. Frank, Mark A. Sperling, Karyn A. Esser, Marcas M. Bamman, Thomas L. Clemens
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Research Article Endocrinology

Distinct growth hormone receptor signaling modes regulate skeletal muscle development and insulin sensitivity in mice

Abstract

Skeletal muscle development, nutrient uptake, and nutrient utilization is largely coordinated by growth hormone (GH) and its downstream effectors, in particular, IGF-1. However, it is not clear which effects of GH on skeletal muscle are direct and which are secondary to GH-induced IGF-1 expression. Thus, we generated mice lacking either GH receptor (GHR) or IGF-1 receptor (IGF-1R) specifically in skeletal muscle. Both exhibited impaired skeletal muscle development characterized by reductions in myofiber number and area as well as accompanying deficiencies in functional performance. Defective skeletal muscle development, in both GHR and IGF-1R mutants, was attributable to diminished myoblast fusion and associated with compromised nuclear factor of activated T cells import and activity. Strikingly, mice lacking GHR developed metabolic features that were not observed in the IGF-1R mutants, including marked peripheral adiposity, insulin resistance, and glucose intolerance. Insulin resistance in GHR-deficient myotubes derived from reduced IR protein abundance and increased inhibitory phosphorylation of IRS-1 on Ser 1101. These results identify distinct signaling pathways through which GHR regulates skeletal muscle development and modulates nutrient metabolism.

Authors

Mahendra D. Mavalli, Douglas J. DiGirolamo, Yong Fan, Ryan C. Riddle, Kenneth S. Campbell, Thomas van Groen, Stuart J. Frank, Mark A. Sperling, Karyn A. Esser, Marcas M. Bamman, Thomas L. Clemens

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Figure 1

GH-induced myoblast proliferation and fusion are mediated by IGF-1 production and intersect the NFATc2/IL-4 pathway.

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GH-induced myoblast proliferation and fusion are mediated by IGF-1 produ...
(A) Primary mouse myoblasts were serum starved for 10 hours before stimulation with GH. Real-time PCR was performed using primers for IGF-1 at indicated times. (B) Myoblasts were serum starved for 10 hours before stimulation with GH or IGF-1 for 8 hours, with BrdU exposure for the full 8 hours of treatment. The percentage of BrdU-positive cells was assessed by flow cytometry. (C) Myoblasts were induced to differentiate and treated with GH for 0–48 hours, 0–24 hours, or 24–48 hours of differentiation. (D) GHR-floxed myoblasts were infected with adenoGFP (control) or adenoCre (ΔGHR) and differentiated in the presence of vehicle, GH, or IGF-1 for 48 hours. (E) IGF-1R–floxed myoblasts were infected with adenoGFP (control) or adenoCre (ΔIGF-1R) as treated in D. (F) Wild-type myoblasts were serum starved for 10 hours before stimulation with vehicle (Veh), GH, or IGF-1 for 1 hour and harvest of nuclear protein extracts. (G) Myoblasts were transfected with an NFAT luciferase reporter construct before induction of differentiation for 24 hours and treatment with vehicle, ionomycin, GH, or IGF-1 for 5 hours. (H) Myoblasts were serum starved for 10 hours before treatment with vehicle or GH for 5 hours. Real-time PCR was performed using primers for IL-4. All data shown is representative of at least 3 separate experiments performed from separate muscle cell preparations. Error bars indicate SEM. *P < 0.05.