# Skeletal Muscle as a Target for Cardio-Metabolic Disease in Sarcopenic Obesity

> **NIH NIH K01** · OKLAHOMA STATE UNIVERSITY STILLWATER · 2022 · $128,772

## Abstract

The objective of this application is to examine how augmented muscle mass, a by-product of the exercise
intervention commonly prescribed for treatment of obesity and sarcopenia, can prevent and rescue metabolic
and vascular dysfunction in sarcopenic obesity. The core hypothesis of this application is that targeting skeletal
muscle function in aging can ameliorate metabolic dysfunction and oxidant-induced hypertension in obesity
and lay the groundwork for establishment of an independent research program directed toward determining if
obesity-derived cardiometabolic dysfunction can be rescued through augmented mass with aging and specific
fiber types.
The goals of this application will be accomplished by examining the effect of augmented muscle mass, through
myostatin deletion, on cardiometabolic function in a mouse model of obesity (the db/db mouse). Experimental
methods include in vivo blood pressure using telemetry in conscious mice, vascular function assessments
using pressure myography of isolated vessels, and metabolic function using metabolic chambers, glucose
tolerance tests, whole body quantification of lean mass and adiposity via DXA Piximus, and blood lipid profiles.
Our data indicate that increasing muscle mass in obese mice protects against the loss of muscle mass and
strength, glycemic control and vascular dysfunction, which accompany obesity in the db/db mouse.
Importantly, our preliminary data indicate that these improvements to metabolic and cardiovascular function
prevent hypertension in the db/db mouse. Further, this application will determine the relative contribution to
organ specific oxidant stress, namely vascular NOX1 and renal NOX4 in a model of sarcopenic obesity.
The model currently used (constitutive myostatin deletion) involves lifelong augmented muscle. A key question
remains unanswered; can augmented muscle rescue/reverse obesity-derived cardiovascular dysfunction or is
lifelong fitness essential? The applicant intends to focus his transition to independence on answering these key
questions. I will use a novel inducible knockout of myostatin in a db/db mouse to determine if augmented
muscle mass can rescue metabolic and vascular dysfunction after development of a fully obese phenotype.
This will serve to mimic the patient population and allow for results to translate to the clinic. Additionally,
literature suggests that skeletal muscle fiber type plays a crucial role in outcomes. The myostatin model used
results in predominantly glycolytic skeletal muscle expansion and it would be advantageous to determine if a
mouse model of obesity with predominantly oxidative skeletal muscle expansion (PGC1) would have similar
cardiometabolic improvements.

## Key facts

- **NIH application ID:** 10407603
- **Project number:** 5K01AG064121-03
- **Recipient organization:** OKLAHOMA STATE UNIVERSITY STILLWATER
- **Principal Investigator:** Joshua Thomas Butcher
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $128,772
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10407603

## Citation

> US National Institutes of Health, RePORTER application 10407603, Skeletal Muscle as a Target for Cardio-Metabolic Disease in Sarcopenic Obesity (5K01AG064121-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10407603. Licensed CC0.

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