# Myokine musclin and exercise induced cardiac conditioning

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2022 · —

## Abstract

Perioperative morbidity and mortality due to heart disease are important complications of non-cardiac
surgery. In the United States approximately 27 million patients undergo non-cardiac surgery annually, with 50
thousand suffering a post- or intra-operative myocardial infarction (MI). The problem is also highly prevalent
among our nation’s veterans. Specifically, the Veterans Health Administration performs about 400,000 surgical
procedures per year, and data derived from the Veterans Affairs Surgical Quality Improvement Program
(VASQIP) indicate that major adverse cardiovascular events (MACE) after non-cardiac surgeries occur in
approximately 5%, while another study indicates that myocardial injury indicated by asymptomatic post-
operative troponin elevation, a major risk factor for post-operative mortality, occurs in 13.9% of veterans
undergoing non-cardiac surgery.
 On the other hand physical activity is one of the most powerful modifiers of cardiovascular risk, with
proven benefits both for those with healthy hearts and for those with diseased hearts. Skeletal muscles are
critical for mobility, but there is also an emerging understanding that they produce and secrete cytokines,
termed “myokines”, which mediate local and systemic changes in order to promote exercise tolerance and
overall health. We recently demonstrated that the myokine musclin is upregulated in response to physical
activity and augments physical endurance. Our preliminary data also indicate that musclin production drives
the myocardial energetic adaptation necessary to increase cardiac stress resistance. Based on these findings
we propose that musclin upregulation is critical for exercise-induced cardiac conditioning and that this effect
utilizes molecular pathways that, once defined, may be harnessed for therapeutic benefit.
 Musclin, also known as osteocrin, has high homology to the cardiac natriuretic peptides (NP) with
comparable affinity for the clearance receptor, NPRC, but low affinity for the guanylyl cyclase-coupled
receptors, NPRA and NPRB. Through competitive interference for elimination at NPRC, musclin increases the
local concentration of NPs and augments their effect on synthesis of cyclic guanosine monophosphate (cGMP)
- a critical intracellular messenger. This project will use unique genetic mouse models and specially developed
bioassays to determine the molecular mechanisms by which musclin integrates skeletal muscle and
myocardial adaptive exercise responses to promote the energetic remodeling necessary for enhanced cardiac
performance and stress resistance. Further, the proposal will assess the ability of synthetic musclin infusion to
mimic some of the benefits triggered by exercise and thereby reduce vulnerability of the heart to injury.
Findings from this study are expected to provide a foundation for development of novel cardioprotective
strategies for high-risk patients, such as those for whom exercise is not possible or well-tolerated due to
illnesses o...

## Key facts

- **NIH application ID:** 10438530
- **Project number:** 5I01BX004840-03
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** Leonid Zingman
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10438530

## Citation

> US National Institutes of Health, RePORTER application 10438530, Myokine musclin and exercise induced cardiac conditioning (5I01BX004840-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10438530. Licensed CC0.

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