# Role of dynamin-related protein 1 in the regulation of metabolism and skeletal muscle mass

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $505,098

## Abstract

ABSTRACT
 Metabolic dysfunction, manifested clinically as the metabolic syndrome (MetSyn), is a significant health
crisis in the US due to its high incidence and strong associations with obesity and type 2 diabetes.
Mitochondrial dysfunction is a robust molecular underpinning contributing to key aspects of the MetSyn. My
laboratory is keenly interested in the role that architecture remodeling plays in regulating mitochondrial
function and cellular insulin action. Mitochondrial remodeling is achieved by fission-fusion dynamics, and
impairment of these processes have been implicated in the pathobiology of metabolic disease and muscle
wasting during aging. However, the molecular links between mitochondrial remodeling muscle metabolism
and muscle mass are inadequately understood. We have previously shown the mitochondrial fission
incompetence mediated by impaired Drp1 signaling underlies derangements in metabolism and insulin
resistance. Herein we show that skeletal muscle-specific knockout of the mitochondrial fission regulator
Dynamin-Related Protein 1 (Drp1) reproduces features of the MetSyn, including glucose intolerance, fat
accumulation, and insulin resistance. We provide evidence that Drp1 colocalizes with succinate
dehydrogenase complex assembly factor 2 (Sdhaf2) to control oxidative metabolism. Moreover, we observed
a unique and dramatic muscle wasting phenotype along with mitochondrial DNA (mtDNA) depletion in the
inducible Drp1 knockout mouse model. I hypothesize that Drp1 is essential for the maintenance of muscle
metabolic function and mtDNA stability in part by its actions on succinate dehydrogenase (SDH)/mitochondrial
complex II. This hypothesis will be tested using both constitutive and conditional muscle-specific Drp1 deletion
mice: mDrp1HET and miDrp1KO. In Aim 1, both cellular and animal studies will be employed to investigate the
effects of Drp1 deletion on mitochondrial function, muscle metabolism, and insulin sensitivity. In Aim 2, we will
determine the role of Drp1 in the regulation of SDH/complex II activity. In Aim 3, we will determine the
mechanisms of Drp1 in regulating skeletal muscle mtDNA copy number and muscle mass. These proposed
studies are of important translational relevance as the research will elucidate the molecular mechanisms
underlying mitochondrial dysfunction in skeletal muscle and link defective mitochondrial dynamics with
features of MetSyn and type 2 diabetes mellitus-associated myopathy.

## Key facts

- **NIH application ID:** 10211540
- **Project number:** 1R01DK125354-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Zhenqi Zhou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $505,098
- **Award type:** 1
- **Project period:** 2021-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10211540

## Citation

> US National Institutes of Health, RePORTER application 10211540, Role of dynamin-related protein 1 in the regulation of metabolism and skeletal muscle mass (1R01DK125354-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10211540. Licensed CC0.

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