Increased IGF-1 in muscle modulates the phenotype of severe SMA mice
| Autor: | Celeste E. Lipkes, Dong W. Choe, Marta Bosch-Marce, Charlotte J. Sumner, Lingling Kong, Claribel D. Wee, Tara Martinez, James P. Van Meerbeke, Antonio Musarò |
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| Přispěvatelé: | Department of Neurology, Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU)-Johns Hopkins University (JHU), Department of Anatomy, Histology, Forensic Medicine and Orthopedic [Roma] (DAHFMO), Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] |
| Rok vydání: | 2011 |
| Předmět: |
Male
Myoblast proliferation MESH: Insulin-Like Growth Factor I SMN1 MESH: Mice Knockout Muscle hypertrophy Mice 0302 clinical medicine MESH: Muscular Atrophy Spinal MESH: Up-Regulation MESH: Animals Insulin-Like Growth Factor I Genetics (clinical) Mice Knockout 0303 health sciences MESH: Muscle Skeletal SMN Complex Proteins General Medicine Articles SMA MESH: Motor Activity Up-Regulation medicine.anatomical_structure Female medicine.drug medicine.medical_specialty Biology Motor Activity MESH: SMN Complex Proteins Muscular Atrophy Spinal 03 medical and health sciences Internal medicine Genetics medicine Animals Humans Muscle Skeletal Molecular Biology MESH: Mice 030304 developmental biology MESH: Humans Skeletal muscle Spinal muscular atrophy Motor neuron medicine.disease MESH: Male Disease Models Animal Trichostatin A Endocrinology MESH: Disease Models Animal MESH: Female 030217 neurology & neurosurgery [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology |
| Zdroj: | Human Molecular Genetics Human Molecular Genetics, Oxford University Press (OUP), 2011, 20 (9), pp.1844-53. ⟨10.1093/hmg/ddr067⟩ Human Molecular Genetics; Vol 20 |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddr067⟩ |
| Popis: | Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by the mutation of the survival motor neuron 1 (SMN1) gene and deficiency of the SMN protein. Severe SMA mice have abnormal motor function and small, immature myofibers early in development suggesting that SMN protein deficiency results in retarded muscle growth. Insulin-like growth factor 1 (IGF-1) stimulates myoblast proliferation, induces myogenic differentiation and generates myocyte hypertrophy in vitro and in vivo. We hypothesized that increased expression of IGF-1 specifically in skeletal muscle would attenuate disease features of SMAΔ7 mice. SMAΔ7 mice overexpressing a local isoform of IGF-1 (mIGF-1) in muscle showed enlarged myofibers and a 40% increase in median survival compared with mIGF-1-negative SMA littermates (median survival = 14 versus 10 days, respectively, log-rank P = 0.025). Surprisingly, this was not associated with a significant improvement in motor behavior. Treatment of both mIGF-1(NEG) and mIGF-1(POS) SMA mice with the histone deacetylase inhibitor, trichostatin A (TSA), resulted in a further extension of survival and improved motor behavior, but the combination of mIGF-1 and TSA treatment was not synergistic. These results show that increased mIGF-1 expression restricted to muscle can modulate the phenotype of SMA mice indicating that therapeutics targeted to muscle alone should not be discounted as potential disease-modifying therapies in SMA. IGF-1 may warrant further investigation in mild SMA animal models and perhaps SMA patients. |
| Databáze: | OpenAIRE |
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