Central Suppression of the GH/IGF Axis and Abrogation of Exercise-Related mTORC1/2 Activation in the Muscle of Phenotype-Selected Male Marathon Mice (DUhTP)

Abstract

The somatotropic axis is required for a number of biological processes, including growth, metabolism, and aging. Due to its central effects on growth and metabolism and with respect to its positive effects on muscle mass, regulation of the GH/IGF-system during endurance exercise is of particular interest. In order to study the control of gene expression and adaptation related to physical performance, we used a non-inbred mouse model, phenotype-selected for high running performance (DUhTP). Gene expression of the GH/IGF-system and related signaling cascades were studied in the pituitary gland and muscle of sedentary males of marathon and unselected control mice. In addition, the effects of three weeks of endurance exercise were assessed in both genetic groups. In pituitary glands from DUhTP mice, reduced expression of Pou1f1 (p = 0.002) was accompanied by non-significant reductions of Gh mRNA (p = 0.066). In addition, mRNA expression of Ghsr and Sstr2 were significantly reduced in the pituitary glands from DUhTP mice (p ≤ 0.05). Central downregulation of Pou1f1 expression was accompanied by reduced serum concentrations of IGF1 and coordinated downregulation of multiple GH/IGF-signaling compounds in muscle (e.g., Ghr, Igf1, Igf1r, Igf2r, Irs1, Irs2, Akt3, Gskb, Pik3ca/b/a2, Pten, Rictor, Rptor, Tsc1, Mtor; p ≤ 0.05). In response to exercise, the expression of Igfbp3, Igfbp 4, and Igfbp 6 and Stc2 mRNA was increased in the muscle of DUhTP mice (p ≤ 0.05). Training-induced specific activation of AKT, S6K, and p38 MAPK was found in muscles from control mice but not in DUhTP mice (p ≤ 0.05), indicating a lack of mTORC1 and mTORC2 activation in marathon mice in response to physical exercise. While hormone-dependent mTORC1 and mTORC2 pathways in marathon mice were repressed, robust increases of Ragulator complex compounds (p ≤ 0.001) and elevated sirtuin 2 to 6 mRNA expression were observed in the DUhTP marathon mouse model (p ≤ 0.05). Activation of AMPK was not observed under the experimental conditions of the present study. Our results describe coordinated downregulation of the somatotropic pathway in long-term selected marathon mice (DUhTP), possibly via the pituitary gland and muscle interaction. Our results, for the first time, demonstrate that GH/IGF effects are repressed in a context of superior running performance in mice.

Sex-based differences in IGF1 signaling pathways in response to PAPP-A2 deficiency

“…However, as GH is secreted in a pulsatile fashion, a single plasma measurement does not necessarily re ect its total integrated levels, nor the e ciency of the pulsatile pattern to promote growth. Several studies reported that there is not always a perfect correlation between IGF1 and GH actions, suggesting that IGF1 production depends on additional factors that modulate this axis [30,31,32]. In agreement, mice with liver IGF1 de ciency (LID) have reduced circulating total IGF1 levels and a consequent increase in plasma GH levels, whereas mice with Igfals gene deletion (ALSko) have reduced levels of circulating total IGF1 with normal GH levels [30].…”

Sex-based differences in growth-related IGF1 signaling in response to PAPP-A2 deficiency: comparative effects of rhGH, rhIGF1 and rhPAPP-A2 treatments

“…However, as GH is secreted in a pulsatile fashion, a single plasma measurement does not necessarily reflect its total integrated levels, nor the efficiency of the pulsatile pattern to promote growth. Several studies reported that there is not always a perfect correlation between IGF1 and GH actions, suggesting that IGF1 production depends on additional factors that modulate this axis [ 33 – 35 ]. In agreement, mice with liver IGF1 deficiency (LID) have reduced circulating total IGF1 levels and a consequent increase in plasma GH levels, whereas mice with Igfals gene deletion (ALSko) have reduced levels of circulating total IGF1 with normal GH levels [ 33 ].…”

The Multiple Faces of the GH/IGF Axis

“…Human GH is used by some athletes as a performance-enhancing drug, despite its illegality. Brenmoehl et al [ 9 ] examined the physiological role of pituitary GH in skeletal muscle in DUhTP “marathon” mice selected for high running performance compared to sedentary DUhTP mice to explore GH/IGF1 axis action in skeletal muscle during exercise. After 3 weeks of endurance exercise, pituitary Pou1 (Pit1), a pituitary-specific transcription factor for GH, as well as mTORC1 and mTORC2 pathways were suppressed, with downregulation of multiple GH/IGF1 signaling compounds in muscle including Ghr, Igf1, Igf1r, Irs1 and 2, Akt3, Rictor, Rptor, and others.…”