# Role of Skeletal Muscle in Pulmonary Vascular Remodeling

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $409,903

## Abstract

Pulmonary hypertension associated with heart failure with preserved ejection fraction (PH-HFpEF) is the most
common cause of PH worldwide, affecting approximately 1.5 million patients with heart failure in the United
States alone. At present, no specific therapy has been identified mainly due to the fact that major pathways
involved in the regulation of PH-HFpEF are still not well understood. We have recently found convincing
evidence that PH-HFpEF-regulating sirtuin-3 (SIRT3) is predominantly decreased in the skeletal muscle. In
fact, our new preliminary data show that the absence of SIRT3 in skeletal muscle leads to a drastic reduction
of the pulmonary vascular tree, accompanied by increased vascular remodeling and higher pulmonary
pressures, indicating a critical role of skeletal muscle SIRT3 in pulmonary vascular remodeling and PH-HFpEF.
Based on a global mass spectrometry-based comparative secretome analysis, our new data indicate that
skeletal muscle SIRT3 deficiency drives the secretion of lysyl oxidase homolog 2 (LOXL2), a matrix enzyme
known to promote cross-linking of collagen, and gremlin-1 (Grem1), a bone morphogenetic protein (BMP)
antagonist known to induce excessive proliferation. We hypothesize that skeletal muscle SIRT3 deficiency
promotes PH-HFpEF by secreting LOXL2 and Grem1, which act as endocrine signaling molecules to induce
pulmonary vascular remodeling. We plan to use a number of cutting-edge approaches, which include the use
of ex vivo precision-cut lung slices and in vivo skeletal muscle-specific KO mice, to address the outstanding
questions.
Specific Aims: 1) To determine whether skeletal muscle SIRT3 deficiency in the metabolic syndrome
contributes to the development of PH-HFpEF. Using wild-type and skeletal muscle-specific Sirt3 KO mice, with
or without high-fat feeding (HFD), which induces a PH-HFpEF phenotype, we will characterize the contribution
of skeletal muscle SIRT3 deficiency to the development of PH-HFpEF. Results may reveal a systemic
pathogenic impact of skeletal muscle SIRT3 deficiency in remote pulmonary vascular remodeling and PH-
HFpEF. 2, 3) To determine whether LOXL2 and Grem1 are endocrine signaling molecules produced by SIRT3-
deficient skeletal muscle cells to induce pulmonary vascular remodeling. Conditioned media from SIRT3-
deficient skeletal muscle cells, with or without LOXL2 and Grem1 inhibition, will be applied to ex vivo precision-
cut lung slices to test if SIRT3 deficiency with subsequent elevated secretion of LOXL2 and Grem1 promotes
vascular remodeling via increased collagen cross-linking and excessive proliferation of pulmonary artery
endothelial and smooth muscle cells. The role of skeletal muscle-secreted LOXL2 and Grem1 in pulmonary
vascular remodeling and PH-HFpEF will be determined in vivo using skeletal muscle-specific Loxl2 and Grem1
KO mice with HFD. LOXL2 and Grem1 targeting therapies will also be evaluated in our recently developed rat
model of PH-HFpEF.
We aim to firmly est...

## Key facts

- **NIH application ID:** 9948733
- **Project number:** 5R01HL142638-03
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Yen Chun Charly Lai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $409,903
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948733

## Citation

> US National Institutes of Health, RePORTER application 9948733, Role of Skeletal Muscle in Pulmonary Vascular Remodeling (5R01HL142638-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9948733. Licensed CC0.

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