The lab focuses on the gene regulatory events underlying cardiovascular
metabolism. The heart and skeletal muscle are highly metabolically
active tissues. Their rates of energy consumption, choice of substrates,
and method of catabolism can vary widely. Aberrant generation or
use of energy in these tissues can lead to various diseases, including
myopathies and heart failure. Conversely, optimal handling of energy
improves exercise performance, and can have beneficial impact on
chronic diseases like diabetes.
Energy in the cell is most efficiently generated by complete oxidation,
in the mitochondria, of substrates like sugars and fat. ATP is abundantly
generated in the process, while free oxygen is obligatorily reduced
to water. The generation and regulation of mitochondria is complex
and highly regulated. Importantly, the proper delivery of oxygen
and nutrients must also be closely coordinated with mitochondrial
function. Accordingly, highly oxidative tissues are almost invariably
also highly vascular. The gene regulatory networks underlying these
processes are only beginning to be understood.
Transcriptional co-activators are proteins that interact with DNA-bound
transcription factors to regulate gene expression. It is likely
that most if not all transcription factors require co-activators.
Certain co-activators are highly regulated and integrate extracellular
cues to affect gene regulation. Probably the best example of this
is the small family of PGC-1 co-activators (PGC-1α, PGC-1β, and
PRC). The PGC-1’s interact with a number of chromatin-bound transcription
factors, including most nuclear receptors. The PGC-1’s assist in
the activation of the basal transcriptional machinery, including
the mediator complex; assist in the recruitment of chromatin-modifying
enzymes such as histone acetylases like p300; and help coordinate
transcription with the splicing machinery. The result is robust
The PGC-1’s control various biological pathways in different tissues.
Common to these functions, is the regulation of mitochondrial biogenesis
and activity. The exogenous addition of PGC-1’s is sufficient to
drive the formation of fully functional mitochondria, both in cell
culture and in vivo. Conversely, deletion of either PGC-1α or β
leads to mitochondrial defects in numerous tissues. To do this,
the PGC-1’s must coordinate the activation of 100’s of genes, both
on the nuclear and mitochondrial genomes. This occurs in part through
co-activation of the nuclear respiratory factors (NRF-1 and 2),
the orphan nuclear receptors ERRα and γ, and likely a number of
other transcription factors.
We have recently shown that PGC-1α also regulates angiogenesis.
PGC-1α regulates a broad angiogenic program, including the expression
of VEGF and a number of other angiogenic factors, leading to a dramatic
increase in vasculature density in PGC-1α transgenic animals. The
induction of VEGF by PGC-1α requires the co-activation of ERRα on
conserved binding sites found in the promoter and in a newly identified
enhancer within the first intron of the VEGF gene. Hence, PGC-1α
and ERRα, major regulators of mitochondrial function in response
to exercise and other stimuli, also control a novel angiogenic pathway
that delivers needed oxygen and substrates.
In addition, PGC-1α also appears to play a specific role in the
response to ischemia. PGC-1α is induced by withdrawal of nutrients
and oxygen, and full induction of VEGF by these conditions requires
PGC-1α. PGC-1α -/- mice show a striking failure to normally reconstitute
blood flow to the limb after an ischemic insult. Conversely, transgenic
expression of PGC-1α in skeletal muscle is protective. Hence, PGC-1α
plays a critical role in the regulation of angiogenesis, both in
health and disease.
The lab currently focuses on addressing a number of questions:
1. What is the role of PGC-1 coactivators in regulating angiogenesis
in various physiological and pathophysiological contexts?
2. What is the role of PGC-1 coactivators in regulating cardiac
and skeletal muscle metabolism?
3. How are genes of oxidative phosphorylation and mitochondrial
biology regulated during hypoxia and ischemia?
4. What transcriptional networks regulate metabolic changes and
angiogenesis in cardiac and skeletal muscle?
We take a multidisciplinary approach to these questions, ranging
from molecular biology and high-throughput genomics to cell biology
and mouse physiology. Our goal is to understand the gene regulatory
events that underlie physiological and pathological metabolic adaptations
in both heart and skeletal muscle.