Chronic alterations in growth hormone/insulin-like growth factor-I signaling lead to changes in mouse tendon structure

• Published in: Matrix biology 2014-02, Vol.34, p.96-104
• Main Authors: Nielsen, R.H., Clausen, N.M., Schjerling, P., Larsen, J.O., Martinussen, T., List, E.O., Kopchick, J.J., Kjaer, M., Heinemeier, K.M.
• Format: Article
• Language: English
• Subjects: Acromegaly; Animals; Cattle; Collagen turnover; Collagen Type I - biosynthesis; Connective Tissue - metabolism; Connective Tissue - ultrastructure; GH-deficiency; Growth Hormone - genetics; Growth Hormone - metabolism; IGF-I receptor; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Laron syndrome; Mice; Mice, Transgenic; Muscle, Skeletal - metabolism; Muscle, Skeletal - ultrastructure; Protein Biosynthesis; RNA, Messenger - biosynthesis; Tendons - metabolism
• ISSN: 0945-053X; 1569-1802
• DOI: 10.1016/j.matbio.2013.09.005

The growth hormone/insulin-like growth factor-I (GH/IGF-I) axis is an important stimulator of collagen synthesis in connective tissue, but the effect of chronically altered GH/IGF-I levels on connective tissue of the muscle–tendon unit is not known. We studied three groups of mice; 1) giant transgenic mice that expressed bovine GH (bGH) and had high circulating levels of GH and IGF-I, 2) dwarf mice with a disrupted GH receptor gene (GHR−/−) leading to GH resistance and low circulating IGF-I, and 3) a wild-type control group (CTRL). We measured the ultra-structure, collagen content and mRNA expression (targets: GAPDH, RPLP0, IGF-IEa, IGF-IR, COL1A1, COL3A1, TGF-β1, TGF-β2, TGF-β3, versican, scleraxis, tenascin C, fibronectin, fibromodulin, decorin) in the Achilles tendon, and the mRNA expression was also measured in calf muscle (same targets as tendon plus IGF-IEb, IGF-IEc). We found that GHR−/− mice had significantly lower collagen fibril volume fraction in Achilles tendon, as well as decreased mRNA expression of IGF-I isoforms and collagen types I and III in muscle compared to CTRL. In contrast, the mRNA expression of IGF-I isoforms and collagens in bGH mice was generally high in both tendon and muscle compared to CTRL. Mean collagen fibril diameter was significantly decreased with both high and low GH/IGF-I signaling, but the GHR−/− mouse tendons were most severely affected with a total loss of the normal bimodal diameter distribution. In conclusion, chronic manipulation of the GH/IGF-I axis influenced both morphology and mRNA levels of selected genes in the muscle–tendon unit of mice. Whereas only moderate structural changes were observed with up-regulation of GH/IGF-I axis, disruption of the GH receptor had pronounced effects upon tendon ultra-structure. •We studied tendon and muscle in transgenic mice with GH/IGF-I alterations.•Chronic high and low GH/IGF-I activity affects Achilles tendon ultra structure.•Collagen and IGF-I mRNA expression in tendon and muscle followed systemic levels of GH/IGF-I.•Collagen per total protein in tendon was not affected by GH/IGF-I alterations.•Low GH/IGF-I more dramatically affected tendon than high GH/IGF-I.