Abstract
BackgroundIn 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.MethodsThe 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.ResultsTotal 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.ConclusionsThese 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.
Highlights
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
Due to limited soleus tissue, Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5) analyses were only completed in a subset of wild type (WT) (n = 5) and bovine GH (bGH) (n = 4) mice; similar trends were observed in the soleus as in the gastrocnemius
Mice overexpressing GH demonstrated increased phosphorylation of the p70 S6 kinase (Fig. 3e–f ), a protein critical for the activation of downstream targets responsible for the translation of elongation factors and cell growth [47]. While these results clearly provide evidence that aspects of the Akt1 signaling pathway are upregulated in the skeletal muscle of bGH mice, we provide novel findings demonstrating that portions of this pathway are unaffected (i.e., glycogen synthase kinase 3β (GSK3β) and FOXO1) or even negatively affected, as is the case for the gastrocnemius (i.e., Akt2 and mechanistic target of rapamycin (mTOR), Figs. 2c and 3a), which would contradict previous observations in the liver of bGH mice [48,49,50]
Summary
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. Consitt et al Skeletal Muscle (2017) 7:17 in skeletal muscle have been attributed to the indirect effects of insulin-like growth factor-1 (IGF-1) [9], acute GH infusion studies have provided compelling evidence that this hormone has a direct role in stimulating skeletal muscle protein synthesis [10, 11]. The MAPK signaling cascade, especially the p42/p44 and p38 pathways, are known to have an important role in skeletal muscle proliferation and differentiation [18,19,20]
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