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Genes & Dev. 19 (14): 1715-1722

Copyright © 2005 by Cold Spring Harbor Laboratory Press.


RESEARCH PAPER

Runx1 prevents wasting, myofibrillar disorganization, and autophagy of skeletal muscle

Xiaoxia Wang1, Chris Blagden1, Jihua Fan1, Scott J. Nowak1, Ichiro Taniuchi2, Dan R. Littman2, and Steven J. Burden1,3

1 Molecular Neurobiology Program, 2 Molecular Pathogenesis Program and Howard Hughes Medical Institute, Skirball Institute of Biomolecular Medicine, New York University Medical School, New York, New York 10016, USA

Abstract: Disruptions in the use of skeletal muscle lead to muscle atrophy. After short periods of disuse, muscle atrophy is reversible, and even after prolonged periods of inactivity, myofiber degeneration is uncommon. The pathways that regulate atrophy, initiated either by peripheral nerve damage, immobilization, aging, catabolic steroids, or cancer cachexia, however, are poorly understood. Previously, we found that Runx1 (AML1), a DNA-binding protein that is homologous to Drosophila Runt and has critical roles in hematopoiesis and leukemogenesis, is poorly expressed in innervated muscle, but strongly induced in muscle shortly after denervation. To determine the function of Runx1 in skeletal muscle, we generated mice in which Runx1 was selectively inactivated in muscle. Here, we show that Runx1 is required to sustain muscle by preventing denervated myofibers from undergoing myofibrillar disorganization and autophagy, structural defects found in a variety of congenital myopathies. We find that only 29 genes, encoding ion channels, signaling molecules, and muscle structural proteins, depend upon Runx1 expression, suggesting that their misregulation causes the dramatic muscle wasting. These findings demonstrate an unexpected role for electrical activity in regulating muscle wasting, and indicate that muscle disuse induces compensatory mechanisms that limit myofiber atrophy. Moreover, these results suggest that reduced muscle activity could cause or contribute to congenital myopathies if Runx1 or its target genes were compromised.

Key Words: Atrophy • myopathy • acute myeloid leukemia • hematopoiesis • denervation

Received for publication March 25, 2005. Accepted for publication May 26, 2005.


Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1318305.

3 Corresponding author.

E-MAIL burden{at}saturn.med.nyu.edu; FAX (212) 263-2842.


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