Mice overexpressing growth hormone exhibit increased skeletal muscle myostatin and MuRF1 with attenuation of muscle mass

Leslie A. Consitt, Alicson Saneda, Gunjan Saxena, Edward O. List, John J. Kopchick

In contrast to the acute effects of growth hormone (GH) on skeletal muscle protein synthesis, long-term GH treatment appears to have negligible effects on muscle mass. Despite this knowledge, little is known regarding the chronic effects of GH on skeletal muscle protein synthesis and atrophy signaling pathways. The purpose of this study was to determine if protein synthesis pathways are attenuated and/or muscle atrophy intracellular signaling pathways are altered in the skeletal muscle of transgenic bovine GH (bGH) mice. The gastrocnemius and soleus from 5-month-old male bGH mice (n = 9) and wild type (WT) controls (n = 9) were harvested and analyzed for proteins involved in the protein synthesis (Akt/mTOR), growth and proliferation (MAPK), and muscle atrophy (MuRF1 and myostatin) pathways. Total body mass was significantly increased in bGH mice compared to WT controls (49%, P < 0.0001). When expressed relative to total body mass, the gastrocnemius (- 28%, P < 0.0001), but not the soleus, was significantly lower in mice overexpressing GH, compared to controls. Transgenic bGH mice had elevated phosphorylation levels of protein kinase b (Akt1), 4E-binding protein 1 (4E-BP1), p70 S6 kinase, p42/44, and p38 (P < 0.05) compared to WT littermates. Mature myostatin (26 kDa), premature myostatin (52 kDa), and activin receptor type IIB (AcvR2B) protein levels were increased in bGH mice (P < 0.05), along with elevated phosphorylation levels of mothers against decapentaplegic homolog (Smad2) (59%, P < 0.0001). Mice overexpressing GH had increased MuRF1 expression (30%, P < 0.05) and insulin receptor substrate 1 (IRS1) serine phosphorylation (44%, P < 0.05) in the gastrocnemius, but not the soleus, when compared to controls. These findings demonstrate that chronic elevations in circulating GH have a critical impact on signaling pathways involved in skeletal muscle protein synthesis and atrophy, and suggest that MuRF1, myostatin, and IRS1 serine phosphorylation may act to inhibit exaggerated glycolytic muscle growth, in environments of chronic GH/IGF-1 excess.