# Mechanisms of sepsis-associated muscle stem cell dysfunction

> **NIH NIH R35** · MAYO CLINIC ROCHESTER · 2020 · $392,984

## Abstract

ABSTRACT
 Sepsis is a life-threatening condition commonly encountered in intensive care settings. While
advancements in clinical sepsis management have lowered acute sepsis mortality rates, a growing number of
severe sepsis survivors progress to chronic illness states. Indeed, many survivors report persistent muscle
weakness, breathing difficulties, and cognitive decline as debilitating complications in their post-sepsis life. We
hypothesize that a key to managing the long-term effect of sepsis is to understand how sepsis-associated
circulating factors impact the metabolic state of long-lived, tissue specific stem cells. Given the high incidence
of post-sepsis muscle dysfunction, we propose to initially evaluate acute and persistent metabolic defects in
skeletal muscle stem cells. In adult skeletal muscle, satellite cells are the primary resident stem cell population
and are indispensible contributors to skeletal muscle repair and regeneration. Since establishing my
independent laboratory, we have made significant progress towards understanding how wasting-associated
factors impair satellite/muscle stem cell (SC) biology and we are well positioned to explore the mechanistic and
metabolic basis of muscle dysfunction following septic shock. The big picture question proposed in this
MIRA/R35 application is: How do sepsis-associated factors impact SC function? This proposal highlights three
of our developing project areas that address this central question using distinct experimental and conceptual
tactics. First, we will explore how sepsis-associated cytokines modulate SC metabolism. We found that muscle
wasting/cachexia-associated cytokines can augment pathways involved in regulating energetic metabolism
and propose to define the effects of sepsis-associated cytokine exposure on lipid metabolism in SCs. Second,
we will examine the mechanisms by which sepsis-associated metabolites impact SC function. We present
evidence that wasting-associated metabolites can antagonize stem cell differentiation and propose
investigating the hypothesis that some of these sepsis metabolic biomarkers also function as bioactive
signaling molecules capable of augmenting SC activation. Third, we will leverage cutting edge metabolomics
analyses of muscle stem cells isolated from murine sepsis models to define metabolic signatures associated
with sepsis onset and extended recovery. We show that SCs can exhibit sustained metabolic alterations to
acute metabolic disruptions and propose that sepsis-associated metabolic derangements compromise SC
metabolic networks long into the recovery period. These three proposed project areas are supported by
rigorous past training in stem cell biology, a vibrant research and clinical environment at the Mayo Clinic, and
continued professional support and guidance from experienced faculty mentors. Overall, successful completion
of this proposed MIRA/R35 award will: a) facilitate the establishment of a dynamic, independent, and cost-
efficie...

## Key facts

- **NIH application ID:** 9955284
- **Project number:** 5R35GM128594-03
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Jason Doles
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $392,984
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9955284

## Citation

> US National Institutes of Health, RePORTER application 9955284, Mechanisms of sepsis-associated muscle stem cell dysfunction (5R35GM128594-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9955284. Licensed CC0.

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