# Perm1 in skeletal muscle dysfunction induced by disuse and heart failure

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2023 · —

## Abstract

Project Summary/Abstract
Skeletal muscle (SkM) atrophy is a significant health problem associated with muscle disuse. It can frequently
occur in association with diseases or treatments of any type that require bed rest or full immobilization. It can
result nervous supply injury, or result from chronic diseases, such as cancer, AIDS, diabetes, and importantly, a
focus of this proposal, chronic heart failure (HF). Increased physical activity and exercise reduce muscle atrophy
or even accelerate its recovery, by causing SkM to undergo metabolic, contractile and morphological adaptations.
These adaptations rely on signaling pathways that lead to changes in gene expression and enzymatic activity.
Therefore, understanding the molecular mechanisms underlying muscle activity-induced signaling may provide
novel basic information about muscle function and adaptation and ultimately could provide new approaches for
treating muscle dysfunction, including muscle dysfunction in heart failure.
We note that the transcriptional coactivator PGC-1 has been shown to be induced and activated by exercise,
and regulate muscle metabolic programs. By using a microarray screen with a myotube model transduced with
PGC-1 (PPARgamma coactivator 1) and ERR (Estrogen-related receptor) transcription factors, we identified a
novel PGC-1 / ERR target gene, termed Perm1 (PGC-1 and ERR-induced regulator, muscle 1). Our published
and preliminary data show that striated muscle protein (Perm1) impacts muscle bioenergetics, is induced by
exercise, regulates expression of metabolic genes, and modifies muscle mitochondrial (Mito) biogenesis. Perm1
is also down-regulated in SkM with disuse and the presence of heart failure.
Based on this strong preliminary data, we propose the central hypothesis that Perm1 integrates activity-induced
signals and enhances muscle mitochondrial biogenesis and function. A corollary to this is that Perm1 acts by
modulating activity/contraction–induced kinase signaling (CaMKII, calcium/calmodulin dependent protein kinase
II). Through activity-induced signal integration, Perm1 may prevent disuse and HF - induced SkM dysfunction.
To address this hypothesis, we have generated two novel mouse models in which Perm1 is either specifically
increased in skeletal muscle (Perm1SkMTransgenic (TG)) or deleted from skeletal muscle (Perm1SkM knockout
(KO)). This hypothesis will be pursued by the following specific aims:
Aim 1. Study the role of Perm1 in metabolic and functional alterations induced by muscle disuse. We will
use Perm1SkMTG and Perm1SkMKO mice to directly evaluate Perm1 function in basal and pathological states
including denervation and cast immobilization.
Aim 2. Study the role of Perm1 in Heart Failure-induced SkM dysfunction. We will study the role of Perm1
in HF-induced SkM dysfunction, comparing WT, to Perm1SkMTG, and Perm1SkMKO mice. We hypothesize
Perm1SkMTG will be protected from HF-induced SkM weakness and exercise intolerance, while Perm1SkMKO
mice wi...

## Key facts

- **NIH application ID:** 10618851
- **Project number:** 5I01BX004897-04
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** Robert Scott Ross
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10618851

## Citation

> US National Institutes of Health, RePORTER application 10618851, Perm1 in skeletal muscle dysfunction induced by disuse and heart failure (5I01BX004897-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10618851. Licensed CC0.

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