Abstract
The transcriptional coactivator peroxisome proliferator-activator receptor γ coactivator (PGC)-1α is required for full hypoxic induction of vascular endothelial growth factor (VEGF) in skeletal muscle cells. Under normoxic conditions, PGC-1α also strongly induces mitochondrial biogenesis, but PGC-1α does not activate this program under hypoxic conditions. How this specificity is achieved is not known. We show here that hypoxia specifically induces alternatively spliced species encoding for truncated forms of PGC-1α: NT-PGC-1α and PGC-1α4. NT-PGC-1α strongly induces VEGF expression, whereas having little effect on mitochondrial genes. Conditioned medium from cells expressing NT-PGC-1α robustly induces endothelial migration and tube formation, hallmarks of angiogenesis. Transgenic expression of PGC-1α4 in skeletal muscle in mice induces angiogenesis in vivo. Finally, knockdown of these PGC-1α isoforms and hypoxia-inducible factor-1α (HIF-1α) abrogates the induction of VEGF in response to hypoxia. NT-PGC-1α and/or PGC-1α4 thus confer angiogenic specificity to the PGC-1α-mediated hypoxic response in skeletal muscle cells.
Highlights
Peroxisomal proliferator activator receptor ␥ coactivator (PGC)-1␣ induces both mitochondrial biogenesis and angiogenesis in skeletal muscle
Alternative Splicing of PGC-1␣ Is Preferentially Induced by Hypoxia in Skeletal Muscle Cells—Oligonucleotides were generated to amplify exon 6/7 alternative splice forms of PGC-1␣, including both NT-PGC-1␣ and PGC-1␣4, by quantitative real-time PCR (qPCR) (Fig. 1A). qPCR of plasmids encoding each specific isoform demonstrated the specificity of the qPCR primers (Fig. 1B)
We show here that N-truncated forms of PGC-1␣, as compared with FL-PGC-1␣, preferentially induce an angiogenic program over a mitochondrial program in skeletal muscle cells
Summary
Peroxisomal proliferator activator receptor ␥ coactivator (PGC)-1␣ induces both mitochondrial biogenesis and angiogenesis in skeletal muscle. Results: Hypoxic induction of an alternative spliced form of PGC-1␣ induces only angiogenesis in skeletal muscle, and not mitochondrial biogenesis. The transcriptional coactivator peroxisome proliferator-activator receptor ␥ coactivator (PGC)-1␣ is required for full hypoxic induction of vascular endothelial growth factor (VEGF) in skeletal muscle cells. Transgenic expression of PGC-1␣4 in skeletal muscle in mice induces angiogenesis in vivo Knockdown of these PGC-1␣ isoforms and hypoxia-inducible factor-1␣ (HIF-1␣) abrogates the induction of VEGF in response to hypoxia. PGC-1␣ expression is induced by hypoxia in muscle cells and is required for full hypoxic induction of angiogenic genes such as VEGF. We further hypothesized that alternative splicing at the exon 6/7 boundary of PGC-1␣ may be induced by hypoxia, conferring specificity to the PGC-1␣ hypoxic response
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