# Role of ULK2 in selective protein degradation and protection against sarcopenia

> **NIH NIH R56** · UNIVERSITY OF IOWA · 2024 · $381,507

## Abstract

PROJECT SUMMARY/ABSTRACT
The US population continues to age, and millions of people will likely be affected by age-related muscle atrophy
and weakness (also referred to as sarcopenia) at some point in life. This represents an enormous unmet medical
need because sarcopenia lacks effective therapy, compromises independence, and increases all-cause
mortality. Skeletal muscle fibers are long-living cells that are particularly susceptible to proteotoxic stress and,
therefore, rely on efficient selective protein degradation (i.e., degradation of damaged/misfolded proteins) to
remain functional. However, the selective degradation of toxic protein aggregates becomes defective with aging
contributing to muscle dysfunction. Protein aggregates are degraded primarily by autophagy, and yet
impairments in autophagic rates (i.e., flux) are not commonly observed in aging muscle. Collectively, these
observations point to an age-dependent impairment in the autophagic sequestration of protein aggregates in
muscle. The research proposed here would address this issue by studying the protein kinase ULK2 and its
binding partner FIP200. We have recently demonstrated that skeletal muscle ULK2, but not its better-known
paralog ULK1, is required for the autophagic sequestration and degradation of protein aggregates. Hence,
defective ULK2 activity could contribute to sarcopenia. ULK2 is activated primarily via phosphorylation. We have
identified two sites at ULK2 that are phosphorylated in adult muscle but not in aged muscle suggesting these
are functionally important. Further, FIP200, a protein that is phosphorylated by ULK2, is hypo-phosphorylated in
aged and ULK2 deficient muscles. This is relevant because FIP200 interacts with toxic protein aggregates
marked for autophagy degradation and is required for autophagosomal formation at these aggregates. Our
proposed studies will build upon these initial findings and use adult and aging mouse models to address the
central hypothesis that ULK2 is required for efficient selective degradation of protein aggregates thereby
preserving skeletal muscle quality (i.e., force and mass) across the lifespan. We propose two specific aims to
address this hypothesis. In Aim 1, we will establish ULK2 role in the development and treatment of sarcopenia.
Here, we will use inducible skeletal muscle-specific mouse models to determine the impact of ULK2 loss and
gain-of-function on the degradation of protein aggregates and muscle quality in adult and aged mice. In Aim 2,
we will define critical mechanisms by which ULK2 regulates the degradation of protein aggregates in adult and
aged muscle. Here, we will establish how phosphorylation modulates ULK2 using rescue-of-function experiments
with phospho-blocking and phospho-mimicking ULK2 mutations in ULK2 deficient and aged muscles. Next, we
will use phospho-blocking and phospho-mimicking FIP200 mutations to test whether FIP200 is required for
ULK2-mediated degradation of protein aggregates and suffi...

## Key facts

- **NIH application ID:** 11170823
- **Project number:** 1R56AG080101-01A1
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Vitor A Lira
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $381,507
- **Award type:** 1
- **Project period:** 2024-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11170823

## Citation

> US National Institutes of Health, RePORTER application 11170823, Role of ULK2 in selective protein degradation and protection against sarcopenia (1R56AG080101-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11170823. Licensed CC0.

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