Chronic alterations in growth hormone/insulin-like growth factor-I signaling lead to changes in mouse tendon structure.
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.
Institute of Sports Medicine, Department of Orthopedics Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Electronic address: rieharboenielsen@gmail.com.
R H
RH
Nielsen
Institute of Sports Medicine, Department of Orthopedics Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
N M
NM
Clausen
Institute of Sports Medicine, Department of Orthopedics Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
P
P
Schjerling
Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
J O
JO
Larsen
Department of Biostatistics, University of Copenhagen, Denmark.
T
T
Martinussen
Edison Biotechnology Institute, Department of Biological Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United States.
E O
EO
List
Edison Biotechnology Institute, Department of Biological Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United States.
J J
JJ
Kopchick
Institute of Sports Medicine, Department of Orthopedics Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
M
M
Kjaer
Institute of Sports Medicine, Department of Orthopedics Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
K M
KM
Heinemeier
D000818:Animals; D002417:Cattle; D024042:Collagen Type I / Q000096:biosynthesis*; D003238:Connective Tissue / Q000378:metabolism / Q000648:ultrastructure; D013006:Growth Hormone / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000648:ultrastructure; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D013710:Tendons / Q000378:metabolism
D024042:Collagen Type I; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone
Acromegaly; Collagen turnover; GH-deficiency; IGF-I receptor; Laron syndrome