Sci. Signal., 18 August 2009
Neurodegenerative Disorders Muscle Doping
Science Signaling, AAAS, Washington, DC 20005, USA
Spinal and bulbar muscular atrophy (SBMA) is caused by expansion of a CAG repeat in the gene encoding the androgen receptor (AR), which is found in neurons and muscle. The resulting mutant receptor contains an extended stretch of polyglutamine residues and is prone to aggregation. People with this neurodegenerative disorder exhibit loss of motor neurons and muscle atrophy, although it is unclear whether the muscle pathology is primary or secondary to neurodegeneration. Antiandrogen therapy ameliorates the symptoms of SBMA but may have undesirable side effects. Based on their previous finding that Akt phosphorylation of the AR reduces ligand binding, Palazzolo et al. reasoned that insulin-like growth factor 1 (IGF-1), which activates Akt, could be a potential therapeutic for SBMA. In cells transfected with mutant AR with 65 glutamine residues (AR65Q), IGF-1 treatment increased Akt phosphorylation of AR65Q, an effect that led to reduced AR65Q aggregation and increased proteasomal degradation of AR65Q. Mice that expressed human AR with 97 glutamine residues (AR97Q) were crossed with mice that overexpressed the muscle-specific isoform of IGF-1 (mIGF-1) only in muscle. These AR97Q/mIGF-1 mice exhibited increased Akt-mediated phosphorylation of AR97Q at Ser215 and decreased AR97Q aggregation in muscle. Furthermore, they had better muscle strength, fewer gait abnormalities, fewer histological signs of muscle denervation, and longer survival times compared with AR97Q mice. Moreover, AR97Q/mIGF-1 mice were protected from the motor neuron loss and decrease in neuronal cross-sectional area seen in AR97Q mice. In their commentary, Papanikolaou and Ellerby advocate further investigation of the mechanism by which IGF-1 prevents muscle atrophy.
I. Palazzolo, C. Stack, L. Kong, A. Musaro, H. Adachi, M. Katsuno, G. Sobue, J. P. Taylor, C. J. Sumner, K. H. Fischbeck, M. Pennuto, Overexpression of IGF-1 in muscle attenuates disease in a mouse model of spinal and bulbar muscular atrophy. Neuron 63, 316–328 (2009). [Online Journal]
T. Papanikolaou, L. M. Ellerby, IGF-1: Elixir for motor neuron diseases. Neuron 63, 277–278 (2009). [Online Journal]
Citation: W. Wong, Muscle Doping. Sci. Signal. 2, ec274 (2009).
Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882