# Perm1 is a Novel Regulator of Cardiac Energetics and Function

> **NIH NIH R01** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2024 · $77,343

## Abstract

PROJECT SUMMARY for parent grant R01 HL 156667
Energy metabolic reprogramming occurs in the developing and diseased hearts. Mitochondria are
responsible for coordinating cellular energy production in response to physiological and pathological
stimuli. The mitochondrial regulatory system is highly regulated by several transcription factors and
coactivators that orchestrate the expression of genes involved in mitochondrial biogenesis, maintenance,
and respiration capacity. However, the transcriptional regulatory machinery in mitochondrial
bioenergetics is complex, and it is still not completely understood how mitochondria coordinately respond
to physiological and pathological stimuli.
Perm1 ("PGC-1 and ERR regulator in muscle 1 ") was recently identified in skeletal muscle, as a
novel muscle-specific protein that regulates mitochondrial oxidative capacity. Perm1 is induced by
exercise, and the increased expression of Perm 1 enhances mitochondrial biogenesis, oxidative capacity,
and fatigue resistance in mouse skeletal muscle. These findings point to a new path towards
understanding mitochondrial myopathies and muscle atrophies. However, the role of Perm1 in the heart
has never been investigated. Moreover, the regulatory mechanism of Perm1 in mitochondrial function is
currently unknown. Our preliminary data suggest the significant role of Perm1 in cardiac
pathophysiology: (1) Perm1 is highly expressed in the heart and is downregulated in the mouse failing
heart and in patients with heart failure; (2) Perm1 expression is increased during differentiation and
maturation in human iPS cell-derived cardiomyocytes; (3) Perm 1 knockdown in cultured cardiomyocytes
leads to reduced mitochondrial respiration capacity. Furthermore, our preliminary data suggest that
Perm1 controls mitochondrial function through the regulation of ERRa, a well-known transcription factor
that orchestrates the expression of genes in mitochondrial bioenergetics.
This application will leverage a genetic animal model and state-of-the art multisystems approach
to conceptually advance our understanding of mitochondrial bioenergetics in the heart. Specifically, this
work is expected to demonstrate that Perm 1 is a critical regulator of mitochondrial biosynthesis and
energetics in the heart through the ERRa pathway. Furthermore, this study will determine if gene
delivery of Perm1 to the heart protects against mitochondrial impairment and cardiac dysfunction in the
setting of pressure-overload-induced heart failure. Conclusive evidence that Perm 1 is a novel
transcriptional cofactor of the mitochondrial regulatory pathway in the heart will profoundly advance our
knowledge of cardiac metabolism, and may suggest new therapeutic approaches for heart failure.

## Key facts

- **NIH application ID:** 10886220
- **Project number:** 3R01HL156667-04S1
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** Stavros George Drakos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $77,343
- **Award type:** 3
- **Project period:** 2020-12-20 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10886220

## Citation

> US National Institutes of Health, RePORTER application 10886220, Perm1 is a Novel Regulator of Cardiac Energetics and Function (3R01HL156667-04S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10886220. Licensed CC0.

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