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Growth Horm IGF Res. 2016 Oct - Dec;30-31:1-10. doi: 10.1016/j.ghir.2016.07.002. Epub 2016 Jul 29.

Skeletal muscle-specific overexpression of IGFBP-2 promotes a slower muscle phenotype in healthy but not dystrophic mdx mice and does not affect the dystrophic pathology.

Author information

1
Basic and Clinical Myology Laboratory, Department of Physiology, University of Melbourne, VIC 3010, Australia.
2
Institute for Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), 18196, Dummerstorf, Germany.
3
Muscle Biology and Therapeutics Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
4
F. Hoffmann-La Roche Ltd., pRED, Pharma Research & Early Development, DTA Neuroscience, 4070, Basel, Switzerland.
5
Basic and Clinical Myology Laboratory, Department of Physiology, University of Melbourne, VIC 3010, Australia. Electronic address: gsl@unimelb.edu.au.

Abstract

OBJECTIVE:

The insulin-like growth factor binding proteins (IGFBPs) are thought to modulate cell size and homeostasis via IGF-I-dependent and -independent pathways. There is a considerable dearth of information regarding the function of IGFBPs in skeletal muscle, particularly their role in the pathophysiology of Duchenne muscular dystrophy (DMD). In this study we tested the hypothesis that intramuscular IGFBP-2 overexpression would ameliorate the pathology in mdx dystrophic mice.

DESIGN:

4week old male C57Bl/10 and mdx mice received a single intramuscular injection of AAV6-empty or AAV6-IGFBP-2 vector into the tibialis anterior muscle. At 8weeks post-injection the effect of IGFBP-2 overexpression on the structure and function of the injected muscle was assessed.

RESULTS:

AAV6-mediated IGFBP-2 overexpression in the tibialis anterior (TA) muscles of 4-week-old C57BL/10 and mdx mice reduced the mass of injected muscle after 8weeks, inducing a slower muscle phenotype in C57BL/10 but not mdx mice. Analysis of inflammatory and fibrotic gene expression revealed no changes between control and IGFBP-2 injected muscles in dystrophic (mdx) mice.

CONCLUSIONS:

Together these results indicate that the IGFBP-2-induced promotion of a slower muscle phenotype is impaired in muscles of dystrophin-deficient mdx mice, which contributes to the inability of IGFBP-2 to ameliorate the dystrophic pathology. The findings implicate the dystrophin-glycoprotein complex (DGC) in the signaling required for this adaptation.

KEYWORDS:

Dystrophy; Fiber type; IGFBP-2; Muscle; Muscle function

PMID:
27544574
DOI:
10.1016/j.ghir.2016.07.002
[Indexed for MEDLINE]

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