Gene expression-based screening identifies microtubule inhibitors as inducers of PGC-1alpha and oxidative
Zoltan Arany1, Bridget K Wagner, Yanhong Ma
1Dana Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Abstract:
The transcriptional coactivator PGC-1alpha is a potent regulator of several metabolic pathways, including, in particular, the activation of oxidative phosphorylation and mitochondrial biogenesis. Recent evidence suggests that increasing PGC-1alpha activity may have beneficial effects in various conditions, including muscular dystrophy, diabetes, and neurodegenerative diseases. We describe here a high-throughput screen to identify small molecules that induce PGC-1alpha expression in skeletal muscle cells. A number of drug classes are identified, including glucocorticoids, microtubule inhibitors, and protein synthesis inhibitors. These drugs induce PGC-1alpha mRNA, and the expression of a number of genes known to be regulated by PGC-1alpha. No induction of these target genes is seen in PGC-1alpha -/- cells, demonstrating that the drugs act through PGC-1alpha. These data demonstrate the feasibility of high-throughput screening for inducers of PGC-1alpha. Moreover, the data identify microtubule inhibitors and protein synthesis inhibitors as modulators of PGC-1alpha and oxidative phosphorylation.
Insights
Researchers screened for drugs that boost PGC-1alpha, a key metabolic regulator. They found that microtubule and protein synthesis inhibitors effectively increase PGC-1alpha expression and related gene activity in muscle cells.
Area of Science:
- Molecular Biology
- Cellular Metabolism
- Drug Discovery
Background:
- Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) is a master regulator of cellular energy metabolism.
- PGC-1alpha activation is linked to improved outcomes in metabolic and neurodegenerative diseases.
- Targeting PGC-1alpha offers therapeutic potential for conditions like muscular dystrophy and diabetes.
Purpose of the Study:
- To develop and implement a high-throughput screening (HTS) method for identifying small molecules that upregulate PGC-1alpha expression.
- To validate the identified compounds' mechanism of action through PGC-1alpha-dependent gene expression.
- To discover novel drug classes that modulate PGC-1alpha activity.
Main Methods:
- A high-throughput screening assay was designed to measure PGC-1alpha induction in skeletal muscle cells.
- Identified compounds were tested for their ability to increase PGC-1alpha mRNA levels.
- Target gene expression, regulated by PGC-1alpha, was assessed in both wild-type and PGC-1alpha knockout cells.
Main Results:
- The screen successfully identified several classes of small molecules that induce PGC-1alpha expression.
- Glucocorticoids, microtubule inhibitors, and protein synthesis inhibitors were among the identified drug classes.
- Drug-induced PGC-1alpha target gene expression was confirmed to be PGC-1alpha-dependent.
Conclusions:
- High-throughput screening is a feasible approach for discovering PGC-1alpha inducers.
- Microtubule inhibitors and protein synthesis inhibitors represent novel modulators of PGC-1alpha.
- These findings open new avenues for therapeutic strategies targeting metabolic and mitochondrial function.
