# Elevated mitochondrial fusion and function in Down syndrome  - Revision - 2

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $164,899

## Abstract

Individuals with Down syndrome (DS) contend with deficits in skeletal muscle and motor function, the
underlying causes of which are unknown and much less well studied than those of the central nervous system.
Hypotonia is a universal feature of DS at birth. Later in life, adults with DS experience premature aging of the
neuromuscular junction (NMJ) with reduced skeletal muscle function (sarcopenia). The mechanisms mediating
sarcopenia in the DS population are not known but have a major impact on well-being of individuals with DS
across their lifespan. Furthermore, there is a growing appreciation for the critical connection between physical
fitness and preservation of cognitive function during aging in the general population at large, thus, we posit that
maintaining and improving the integrity of the NMJ in individuals with DS will benefit both their physical and
neurological trajectories. The work proposed under this Administrative Supplement will provide insights into
the molecular mechanisms that contribute to altered development and aging of the NMJ in DS and pave the
way for new knowledge-based therapies designed to improve and preserve muscle function. The Parent
award, R01-HD101544, is an active INCLUDE (Investigation of Co-occurring conditions across the Lifespan to
Understand Down syndromE) project that is funded through the end of June 2024. The proposed studies are
completely in line with the underlying goals of the parent award but add an important new objective focused
specifically on the NMJ. Induced pluripotent stem cells (iPSCs) derived from individuals with DS and isogenic
control iPSCs will be differentiated to motor neurons and cocultured with skeletal muscle myotubes (derived
either from iPSCs or primary mouse myoblasts) to establish functional NMJs (following established protocols).
The cytological and electrophysiological features of the iPSC-derived NMJ (hiNMJs) will be assessed to
compare the developmental, functional, and degenerative trajectories of DS hiNMJs with controls. An
important strength of the hiNMJ model is that it allows us to study a well-defined synapse that requires the
contribution of two very different cell types (motor neurons and muscle fibers) thereby allowing us to separate
the impact of trisomy on pre-synaptic processes from its impact on those in the post-synapse. These studies
enhance the goals of the parent award by developing a tractable model of DS NMJs in which we can test our
underlying hypothesis that elevated metabolic activity and ROS production, coupled with a decreased capacity
to remove damaged mitochondria, increases cumulative, oxidative damage over time in individuals with DS.

## Key facts

- **NIH application ID:** 10645484
- **Project number:** 3R01HD101006-01S1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Beverly A Rothermel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $164,899
- **Award type:** 3
- **Project period:** 2022-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10645484

## Citation

> US National Institutes of Health, RePORTER application 10645484, Elevated mitochondrial fusion and function in Down syndrome  - Revision - 2 (3R01HD101006-01S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10645484. Licensed CC0.

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