Human Molecular Genetics Advance Access originally published online on December 12, 2008
Human Molecular Genetics 2009 18(6):997-1005; doi:10.1093/hmg/ddn426
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Delivery of recombinant follistatin lessens disease severity in a mouse model of spinal muscular atrophy
1 Department of Molecular Microbiology and Immunology 2 Department of Veterinary Pathobiology, Life Sciences Center, Room 471G, University of Missouri, Columbia, MO 65211, USA
* To whom correspondence should be addressed. Tel: +1 5738842219; Fax: +1 5738849395; Email: lorsonc{at}missouri.edu
Received August 22, 2008; Revised November 18, 2008; Accepted December 10, 2008
Spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality. SMA is caused by loss of functional survival motor neuron 1 (SMN1), resulting in death of spinal motor neurons. Current therapeutic research focuses on modulating the expression of a partially functioning copy gene, SMN2, which is retained in SMA patients. However, a treatment strategy that improves the SMA phenotype by slowing or reversing the skeletal muscle atrophy may also be beneficial. Myostatin, a member of the TGF-β super-family, is a potent negative regulator of skeletal muscle mass. Follistatin is a natural antagonist of myostatin, and over-expression of follistatin in mouse muscle leads to profound increases in skeletal muscle mass. To determine whether enhanced muscle mass impacts SMA, we administered recombinant follistatin to an SMA mouse model. Treated animals exhibited increased mass in several muscle groups, elevation in the number and cross-sectional area of ventral horn cells, gross motor function improvement and mean lifespan extension by 30%, by preventing some of the early deaths, when compared with control animals. SMN protein levels in spinal cord and muscle were unchanged in follistatin-treated SMA mice, suggesting that follistatin exerts its effect in an SMN-independent manner. Reversing muscle atrophy associated with SMA may represent an unexploited therapeutic target for the treatment of SMA.
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  V. B. Mattis, A. D. Ebert, M. Y. Fosso, C.-W. Chang, and C. L. Lorson Delivery of a read-through inducing compound, TC007, lessens the severity of a spinal muscular atrophy animal model Hum. Mol. Genet., October 15, 2009; 18(20): 3906 - 3913. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Sumner, C. D. Wee, L. C. Warsing, D. W. Choe, A. S. Ng, C. Lutz, and K. R. Wagner Inhibition of myostatin does not ameliorate disease features of severe spinal muscular atrophy mice Hum. Mol. Genet., September 1, 2009; 18(17): 3145 - 3152. [Abstract] [Full Text] [PDF]
|
|