# Role of a novel PGC-1α isoform in gene transcription

> **NIH NIH R21** · UNIVERSITY OF ROCHESTER · 2022 · $192,500

## Abstract

Peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α) is a transcriptional coactivator that
is critical for the metabolic adaptation of mammalian cells to diverse physiological stresses. In addition to this
well-described function in the control of cell metabolism, the number of reports describing a protective role for
PGC-1α against inflammation is on the rise. I report here a novel stress-dependent pro-inflammatory PGC-1α
variant that I have identified in vitro in C2C12 mouse myoblasts and in vivo in mouse skeletal muscle.
 My unpublished results indicate that, compared to the canonical PGC-1α isoform (also known as
PGC-1α(1)), the structure of this novel 72-kDa PGC-1α isoform, which I will call PGC-1α(72), is typified by its
lack of the C-terminal 15 amino acids. The deleted C-terminal sequence encompasses a 9-amino-acid alpha
helix that I previously reported to be essential for PGC-1α(1) to bind to the cap-binding protein (CBP)80 and to
transactivate pro-myogenic PGC-1α-dependent genes. In contrast to PGC-1α(1), PGC-1α(72) lacks the
CBP80-binding motif (CBM) and, as my data indicate, activates the transcription of pro-inflammatory genes. In
the first aim of my research strategy, I propose to use C2C12 myoblasts to fully characterize the sequence of
this novel PGC-1α(72) isoform, identify those transcription factors and RNA-binding proteins that regulate its
expression in response to stress, and comprehensively determine the transcriptional network that it activates.
 In the second aim, I will take advantage of my finding that functional inhibition of the PGC-1α CBM
phenocopies PGC-1α(72)-dependent expression of pro-inflammatory chemoattractants such as the chemokine
CCL2. Elevated CCL2 plasma levels, which are observed with aging, have been recognized as important risk
factors for numerous inflammatory diseases, including cardiac fibrosis, atherosclerosis and cancers.
Mechanistically, CCL2 has been found to function in monocyte recruitment onto the endothelium of blood
vessels and in monocyte infiltration into inflamed tissues. I will breed our newly characterized PGC-1αCBMmut
mice with the Dystrophin-deficient Dmdmdx muscle inflammatory and premature aging mouse model and use
derived primary myoblasts to infer the functional consequences of PGC-1α(72) expression, in particular those
attributable to its lacking the CBM, to inflammation. In particular, I will determine how PGC-1αCBMmut triggers the
CCL2-dependent recruitment of monocytes onto endothelial cells, their infiltration into cardiac tissues, and
development of cardiac fibrosis in aging mice as a function of sex, i.e. in males vs. females.
 I view demonstrating the contribution of PGC-1αCBMmut to cardiac fibrosis as a proof of concept. It will
provide fertile grounds to study the function of skeletal muscle PGC-1α(72) in the development of other aging-
related inflammatory diseases. I hypothesize that understanding PGC-1α(72)-dependent gene regulation and its
conse...

## Key facts

- **NIH application ID:** 10525004
- **Project number:** 1R21AG075368-01A1
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Xavier Rambout
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $192,500
- **Award type:** 1
- **Project period:** 2022-08-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10525004

## Citation

> US National Institutes of Health, RePORTER application 10525004, Role of a novel PGC-1α isoform in gene transcription (1R21AG075368-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10525004. Licensed CC0.

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