PGC-1alpha regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy.
The coactivator PGC-1alpha mediates key responses of skeletal muscle to motor nerve activity. We show here that neuregulin-stimulated phosphorylation of PGC-1alpha and GA-binding protein (GABP) allows recruitment of PGC-1alpha to the GABP complex and enhances transcription of a broad neuromuscular junction gene program. Since a subset of genes controlled by PGC-1alpha and GABP is dysregulated in Duchenne muscular dystrophy (DMD), we examined the effects of transgenic PGC-1alpha in muscle of mdx mice. These animals show improvement in parameters characteristic of DMD, including muscle histology, running performance, and plasma creatine kinase levels. Thus, control of PGC-1alpha levels in skeletal muscle could represent a novel avenue to prevent or treat DMD.
Handschin
Christoph
C
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Kobayashi
Yvonne M
YM
Chin
Sherry
S
Seale
Patrick
P
Campbell
Kevin P
KP
Spiegelman
Bruce M
BM
D000818:Animals; D001665:Binding Sites; D051268:GA-Binding Protein Transcription Factor / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation; D011950:Receptors, Cholinergic / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014162:Transfection
D051268:GA-Binding Protein Transcription Factor; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D011950:Receptors, Cholinergic; D015534:Trans-Activators; D014157:Transcription Factors