# Site-1 Protease in the regulation of skeletal muscle metabolism and exercise endurance

> **NIH NIH K01** · WASHINGTON UNIVERSITY · 2021 · $120,786

## Abstract

PROJECT SUMMARY
Obesity is associated with an incidence of cardiometabolic abnormalities and an increased risk for
cardiovascular disease (CVD) and type 2 diabetes. Improvements in the severity of these cardiometabolic
readouts are associated with improved disease outcomes and reduced risk for CVD. Common approaches to
treat obesity include lifestyle interventions such as diet and exercise. Exercise is also a key treatment option
for heart failure patients and for tackling CVD risk factors associated with type 2 diabetes. Although exercise
improves patient outcomes, long-term adherence to an exercise routine is difficult for many patients,
regardless of health status. Diseases like heart failure and obesity are associated with disrupted skeletal
muscle function and metabolism (the mechanisms of which are not yet fully understood) and patients may
experience difficulty exercising. The benefits of regular exercise underscore the need for interventions that
promote exercise tolerance. We have identified the Golgi-resident protein, Site-1 Protease (S1P), as a novel
regulator of skeletal muscle metabolism and exercise endurance. S1P is required for the subsequent activation
of several key transcription factors, including the sterol regulatory element-binding protein family and the ER
stress regulator ATF6. While S1P is known to play important roles in regulating diverse pathways involved in
lipid metabolism, autophagy, and ER stress signaling, to date, the role of S1P in skeletal muscle metabolism
remains unknown. Our proposed studies will undertake the following Aims: (1) elucidate the function of S1P in
skeletal muscle metabolism and function under healthy conditions in our skeletal muscle-specific S1P knockout
mice and (2) define a function for S1P in obesity-associated skeletal muscle dysfunction and cardiometabolic
abnormalities using a diet-induced obesity mouse model. The candidate already has a strong background in
S1P biology and cellular stress pathways, this K01 award will provide her with the necessary training and
expertise in intermediary metabolism, skeletal muscle function, and exercise physiology to successfully
complete the proposed studies. Her proposed career development plan includes: (a) quarterly meetings with
her Mentorship Committee (composed of experts in metabolic, cardiovascular, and exercise research) who
have an excellent track record of mentoring junior faculty into successful independent investigators, (b)
relevant coursework and seminars/conferences, and (c) one-on-one individual mentor meetings. These
activities are crucial for the successful completion of the proposed studies and for achievement of the
candidate's long-term goal of leading a successful independent lab that integrates her strong background in
cellular stress pathways and S1P biology with the proposed Mentoring Goals to discover novel mechanisms in
obesity-associated cardiovascular disease and skeletal muscle dysfunction. Future work in her lab will al...

## Key facts

- **NIH application ID:** 10186796
- **Project number:** 5K01HL145326-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Rita Thomas Brookheart
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $120,786
- **Award type:** 5
- **Project period:** 2019-06-01 → 2023-12-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10186796

## Citation

> US National Institutes of Health, RePORTER application 10186796, Site-1 Protease in the regulation of skeletal muscle metabolism and exercise endurance (5K01HL145326-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10186796. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*