# Tissue-specific role of aberrant mitochondrial Ca2+ uptake in respiratory and limb muscle dysfunction in ALS

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2023 · $62,011

## Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset neurodegenerative disease characterized by
progressive motor neuron (MN) loss, muscle denervation, and eventually, paralysis. Currently, no effective
treatments are available to stop or reverse ALS disease progression and the precise molecular mechanisms
underlie ALS pathogenesis remain elusive. Prior studies revealed mitochondrial dysfunction as an early global
pathology in both MN and skeletal muscle in ALS patients and mouse models. The first sign of ALS pathology
occurs at the neuromuscular junction (NMJ), where presynaptic MN axons connect with postsynaptic skeletal
muscle end plates. To date, whether signals resulting in the initial NMJ damage are from MN or skeletal muscle
remain unclear. Respiratory failure is the leading cause of death in ALS patients. However, limited research has
been focused on mechanisms of respiratory MN loss, and even less on mechanisms of respiratory muscle
weakness. In this project, we aim to determine the tissue-specific causative role of mitochondrial Ca2+ uptake in
MN loss and muscle dysfunction in both limb and respiratory muscles and the therapeutic efficacy of reducing
mitochondrial Ca2+ uptake on disease progression and respiratory function in ALS mice. We hypothesize that
aberrant mitochondrial Ca2+ uptake in both skeletal muscle and MN synergistically contribute to limb and
respiratory muscle weakness and that tissue-specific attenuation of mitochondrial Ca2+ uptake will mitigate Ca2+-
induced mitochondrial dysfunction, promote MN survival and preserve limb and diaphragm muscle function. To
test this hypothesis, we will use transgenic mice with inducible, skeletal muscle or MN-specific expression of a
dominant negative form of the mitochondrial Ca2+ uniporter to specifically and selectively reduce mitochondrial
Ca2+ uptake in skeletal muscle and MN in hSOD1G93A mice. The central hypothesis will be tested in two Specific
Aims. Aim 1 will test the hypothesis that tissue-specific attenuation of mitochondrial Ca2+ uptake in skeletal
muscle or MN prolongs mouse survival, improves motor and breathing function, preserves NMJ transmission
and overall muscle performance in ALS mice. Aim 2 will test the hypothesis that tissue-specific inhibition of
mitochondrial Ca2+ uptake in skeletal muscle or MN promotes MN survival, preserves NMJ structure, muscle
contractile and Ca2+ signaling properties and mitochondrial function in both limb and respiratory muscles in ALS
mice. This project will: 1) provide a systematic, longitudinal characterization of limb and respiratory muscle and
NMJ function from a cellular level to whole animal level at different stages of disease progression in hSOD1G93A
mice; 2) provide the first detailed dissection on the relative role of mitochondrial Ca2+ uptake in skeletal muscle
and MN in ALS phenotype using the same genetic model and determine the origin of the signals that result in
NMJ destruction (from muscle or MN or both); 3) pr...

## Key facts

- **NIH application ID:** 10841776
- **Project number:** 3R01NS127858-01A1S1
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Lan Wei-LaPierre
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $62,011
- **Award type:** 3
- **Project period:** 2023-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841776

## Citation

> US National Institutes of Health, RePORTER application 10841776, Tissue-specific role of aberrant mitochondrial Ca2+ uptake in respiratory and limb muscle dysfunction in ALS (3R01NS127858-01A1S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10841776. Licensed CC0.

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