Insulinlike growth factor (IGF)-1 administration ameliorates disease manifestations in a mouse model of spinal and bulbar muscular atrophy

• Published in: Molecular medicine (Cambridge, Mass.) Mass.), 2012, Vol.18 (9), p.1261-1268
• Main Authors: Rinaldi, Carlo, Bott, Laura C, Chen, Ke-lian, Harmison, George G, Katsuno, Masahisa, Sobue, Gen, Pennuto, Maria, Fischbeck, Kenneth H
• Format: Article
• Language: English
• Subjects: Androgens; Animals; Digital video; Disease; Disease Models, Animal; Enzyme Activation - drug effects; Fitness equipment; Gene expression; Growth factors; Humans; Insulin-Like Growth Factor I - administration & dosage; Insulin-Like Growth Factor I - pharmacology; Insulin-Like Growth Factor I - therapeutic use; Kinases; Laboratory animals; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Motor Activity - drug effects; Motor Neurons - drug effects; Motor Neurons - pathology; Muscles - drug effects; Muscles - metabolism; Muscles - pathology; Muscles - physiopathology; Muscular Disorders, Atrophic - drug therapy; Muscular Disorders, Atrophic - enzymology; Muscular Disorders, Atrophic - pathology; Muscular Disorders, Atrophic - physiopathology; Musculoskeletal system; Mutant Proteins - metabolism; Phosphorylation; Phosphorylation - drug effects; Protein Structure, Quaternary; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Receptors, Androgen - metabolism; Sodium; Spinal cord; Survival analysis; Toxicity; Variance analysis; Weight Loss - drug effects; Wire
• ISSN: 1076-1551; 1528-3658; 1528-3658
• DOI: 10.2119/molmed.2012.00271

Spinal and bulbar muscular atrophy is an X-linked motor neuron disease caused by polyglutamine expansion in the androgen receptor. Patients develop slowly progressive proximal muscle weakness, muscle atrophy and fasciculations. Affected individuals often show gynecomastia, testicular atrophy and reduced fertility as a result of mild androgen insensitivity. No effective disease-modifying therapy is currently available for this disease. Our recent studies have demonstrated that insulinlike growth factor (IGF)-1 reduces the mutant androgen receptor toxicity through activation of Akt in vitro, and spinal and bulbar muscular atrophy transgenic mice that also overexpress a noncirculating muscle isoform of IGF-1 have a less severe phenotype. Here we sought to establish the efficacy of daily intraperitoneal injections of mecasermin rinfabate, recombinant human IGF-1 and IGF-1 binding protein 3, in a transgenic mouse model expressing the mutant androgen receptor with an expanded 97 glutamine tract. The study was done in a controlled, randomized, blinded fashion, and, to reflect the clinical settings, the injections were started after the onset of disease manifestations. The treatment resulted in increased Akt phosphorylation and reduced mutant androgen receptor aggregation in muscle. In comparison to vehicle-treated controls, IGF-1-treated transgenic mice showed improved motor performance, attenuated weight loss and increased survival. Our results suggest that peripheral tissue can be targeted to improve the spinal and bulbar muscular atrophy phenotype and indicate that IGF-1 warrants further investigation in clinical trials as a potential treatment for this disease.