PUBLICATION
Metabolic consequences of PGC-1α dysregulation in adult zebrafish muscle
- Authors
- Kurchaba, N., Charette, J.M., LeMoine, C.M.R.
- ID
- ZDB-PUB-220608-6
- Date
- 2022
- Source
- American journal of physiology. Regulatory, integrative and comparative physiology 323(3): R319-R330 (Journal)
- Registered Authors
- Keywords
- CRISPR, Metabolism, co-activator, mitochondria, respirometry
- MeSH Terms
-
- Animals
- Energy Metabolism/genetics
- Lipids
- Mammals/metabolism
- Muscle, Skeletal*/metabolism
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism
- Transcription Factors/genetics
- Transcription Factors/metabolism
- Zebrafish*/genetics
- Zebrafish*/metabolism
- PubMed
- 35670765 Full text @ Am. J. Physiol. Regul. Integr. Comp. Physiol.
Citation
Kurchaba, N., Charette, J.M., LeMoine, C.M.R. (2022) Metabolic consequences of PGC-1α dysregulation in adult zebrafish muscle. American journal of physiology. Regulatory, integrative and comparative physiology. 323(3):R319-R330.
Abstract
The peroxisome proliferator activated receptor gamma co-activator 1 alpha (PGC-1α) is central to the regulation of cellular and mitochondrial energy homeostasis in mammals, but its role in other vertebrates remains unclear. Indeed, previous work suggests extensive structural and functional divergence of PGC-1α in teleosts but this remains to be directly tested. Here, we describe the initial characterization of heterozygous PGC-1α mutant zebrafish lines created by CRISPR-Cas9 disruptions of an evolutionarily conserved regulatory region of the PGC-1α proximal promoter. Using qPCR, we confirmed the disruption of PGC-1α gene expression in striated muscle, leading to a simultaneous 4-fold increase in mixed skeletal muscle PGC-1α mRNA levels and an opposite 4-fold downregulation in cardiac muscle. In mixed skeletal muscle, most downstream effector genes were largely unaffected yet two mitochondrial lipid transporters, carnitine palmitoyltransferase 1 and 2, were strongly induced. Conversely, PGC-1α depression in cardiac muscle reduced the expression of several transcriptional regulators (estrogen related receptor alpha, nuclear respiratory factor 1 and PGC-1β) without altering metabolic gene expression. Using high resolution respirometry, we determined that white muscle exhibited increased lipid oxidative capacity with little difference in markers of mitochondrial abundance. Finally, using whole animal intermittent respirometry, we show that mutant fish exhibit a 2-fold higher basal metabolism than their wildtype counterparts. Altogether, this new model confirms a central but complex role for PGC-1α in mediating energy utilization in zebrafish and we propose its use as a valuable tool to explore the intricate regulatory pathways of energy homeostasis in a popular biomedical model.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping