Endocrine Abstracts (2003) 6 OC16

Overexpression of insulin-like growth factor binding protein-5 (Igfbp5) in mice results in compromised muscle development

DAM Salih, C Holding, G Tripathi, LJ Cobb, I Gonzalez, EJ Carter, FA Lovett & JM Pell

Signalling Programme, Babraham Institute, Cambridge, UK.

Igfbp5 is the most conserved of the six members of the Igfbp family, which orchestrate the actions of the insulin-like growth factors (IGFs) systemically via blood and locally within tissues. Igfbp5 is upregulated in key lineages during development (e.g. muscle) and pathologies (e.g. rhabdomyosarcoma).

To highlight the range and extent of Igfbp5 actions in vivo, we generated novel lines of transgenic mice that ubiquitously overexpressed myc-tagged Igfbp5 at low, intermediate and high levels consistently using a hybrid CMV enhancer/beta-actin regulatory sequence. The phenotype severity observed between transgenic lines was in direct positive correlation with the Igfbp5 mRNA dose (muscle levels increased by up to 17-fold and serum IGFBP-5 levels increased by up to 6-fold in the highest expressing line).

Transgenic animals were severely growth retarded, with a birth weight down to 63.7 plus/minus 1.1% of wild-type mice. The highest expressers were lethal within 24 h of birth. The reduction in bodyweight could be partially attributed to decreased muscle development. In surviving adult mice, muscle weight (represented by the gastrocnemius, plantaris and soleus fibres) relative to bodyweight was reduced by up to 29.9 plus/minus 3.1% in comparison with wild-type siblings. Histology of e18.5 transgenic embryos highlighted a thinner diaphragm and generalised disorganisation of many muscle groups. Myofibres demonstrated a decrease in cross sectional area (atrophy) and a decrease in myofibre separation.

Future studies will concentrate on attributing the muscle phenotype to alterations in myoblast proliferation, differentiation and survival. Overall these mice provide convincing in vivo evidence that IGFBP-5, by either IGF-dependent or -independent mechanisms, is indeed important in coordinating the cellular fate of myoblasts.

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