# Differential changes in energy metabolism in response to mechanical tension give rise to human scaring heterogeneity

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $320,800

## Abstract

PROJECT SUMMARY
Dermal injury leads to fibrosis and scar formation, which can be a significant source of morbidity. Interestingly,
humans respond to identical skin injuries with different degrees of scar formation that range from low to high
scaring phenotypes. Understanding the mechanisms that drive heterogeneous scarring outcomes will allow us
to design strategies to direct wound healing toward regeneration and reduced scarring. Biomechanical forces
are known to influence how the skin heals. Biomechanical tension signals fibroblast proliferation, migration,
inflammatory functions and production of extracellular matrix (ECM). These responses, in conjunction with
oxidative stress in the wound, place a high energy demand on fibroblasts. Typically, metabolic requirements of
cells are met via mitochondrial oxidative phosphorylation (OXPHOS) under homeostatic conditions or via
glycolysis when oxygen is limited. Recent studies have shown that increase in mechanical cues can alter energy
metabolism by promoting glycolysis. Notably, the phenomenon of a metabolic shift towards ‘aerobic glycolysis’
(Warburg effect) was mainly described in progression of fibrotic diseases, but our data showed that fibroblasts
from uninjured skin of healthy patients with high scarring phenotype (HS) have higher OXPHOS and glycolysis
than those from low scarrers, and demonstrated changes in mitochondrial function that suggest a higher energy
state at baseline. Expression of PKM2, a key rate-limiting enzyme of aerobic glycolysis, was also higher in HS
fibroblasts, with increased PKM2 phosphorylation/dimerization shunting metabolites toward increased ATP
production and promoting aerobic glycolysis and pro-fibrotic pathways under TGF-β stimulation. HS fibroblasts
also had an exaggerated response to mechanical tension, with an increase in total and phosphorylated PKM2.
These data support the concept that PKM2-mediated aerobic glycolysis in fibroblasts under tension may
influence the magnitude of fibrosis. Consistently, we also noted an exaggerated increase in phosphorylation of
Hsp27 in HS fibroblast under tension. To our knowledge, this is the first evidence of differential aerobic glycolysis
and biomechanical tension responses being linked to opposing scar outcomes in physiologic wounds, which
could explain wound healing heterogeneity. We hypothesize that patient-specific scarring responses are due to
PKM2/Hsp27-dependent alterations in fibroblast aerobic glycolysis that are influenced by wound biomechanical
forces. In Aim 1, we designed in vitro and in vivo experiments with low and high scar-derived patient fibroblasts
to investigate differences in PKM2 and Hsp27 phosphorylation/activation and their effect on metabolic pathways,
energy metabolism, and ECM production. In Aim 2, we will utilize in vitro and human skin xenotransplant wound
models to examine how biomechanical tension alters PKM2/Hsp27 mediated energy metabolism to drive patient
scarring responses and then develop...

## Key facts

- **NIH application ID:** 10862618
- **Project number:** 5R01GM141366-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Swathi Balaji
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $320,800
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10862618

## Citation

> US National Institutes of Health, RePORTER application 10862618, Differential changes in energy metabolism in response to mechanical tension give rise to human scaring heterogeneity (5R01GM141366-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10862618. Licensed CC0.

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