Distinct growth hormone receptor signaling modes regulate skeletal muscle development and insulin sensitivity in mice
Mahendra D. Mavalli, … , Marcas M. Bamman, Thomas L. Clemens
Mahendra D. Mavalli, … , Marcas M. Bamman, Thomas L. Clemens
Published October 1, 2010
Citation Information: J Clin Invest. 2010;120(11):4007-4020. https://doi.org/10.1172/JCI42447.
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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 2

GHR is required for normal myofiber specification, myonuclei accumulation, and muscle function.

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GHR is required for normal myofiber specification, myonuclei accumulatio...
mRNA was harvested from the gastrocnemius muscles of control and ΔGHR mice, and real-time PCR was performed using primers for (A) Ghr, (B) Igf1r, and (C) Igf1. (D–G) Sections of medial gastrocnemius from control and ΔGHR mice were visualized using antibodies directed against MHC type I and laminin and counterstained with Hoechst 33258 to visualize myonuclei. Scale bars: 80 μm. (H–M) Histomorphometric analyses of myonuclei per 100 myofibers, percentage myofiber distribution, and myofiber diameter (CSA) were performed on sections described above for (H–J) 6-week-old and (K–M) 16-week-old control and ΔGHR mice. Muscle performance in 26-week-old control and ΔGHR mice was assessed by (N) grip strength and (O and P) rotarod testing, as described in Methods. For all studies shown, n = 6 for control and ΔGHR at all time points. Error bars indicate SEM. *P < 0.05.