# Respiratory Control in Old Age

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2020 · $605,695

## Abstract

By 2030, ~70 million people in the USA will be >65 years of age and ~10 million will
be >85 years old. With aging of our population, there will be an increased incidence of
age-related muscle wasting and weakness (sarcopenia), which is a significant predictor
of chronic disease and mortality in the elderly. Previously, we found that sarcopenia
affects the diaphragm muscle (DIAm) with atrophy of more fatigable type IIx and/or IIb
muscle fibers, and a reduction in maximum specific force, making the DIAm considerably
weaker in old age. Important to the proposed studies, we found that in older rats there
are fewer large phrenic motor neurons (PMNs) that comprise more fatigable motor units.
This raises the intriguing possibility that DIAm sarcopenia results from the loss of larger
PMNs, leading to denervation of type IIx and/or IIb muscle fibers and DIAm weakness.
In support, we found that DIAm sarcopenia is associated with impaired performance of
higher force airway clearance behaviors (e.g., coughing, sneezing), which may underlie
the increased risk of airway infections in older adults.
Premise: The underlying cause of age-related PMN loss is unclear. Certainly with
breathing, smaller PMNs are recruited more frequently, and thus their energy demands
are higher. Accordingly, it is not surprising that in preliminary studies, we found that
mitochondria in smaller PMNs are more fused and have a higher volume density. In
diseases such as amyotrophic lateral sclerosis (ALS), mitochondrial fragmentation
appears to precede the loss of motor neurons, which is associated with decreased Mfn2
and increased Drp1 expression. Indeed, experimental interventions that support
mitochondrial fusion or inhibit fission appear to ameliorate motor neuron dysfunction and
degeneration in ALS models. It is also important to note that brain-derived neurotropic
factor (BDNF) signaling through its high affinity receptor (TrkB.Fl) promotes motor
neuron survival, and mitochondrial fusion, suggesting there may be a link. In support,
TrkB.Fl is co-localized to the mitochondrial outer membrane, and in preliminary studies
we found that enhanced BDNF/TrkB signaling promotes mitochondrial fusion in NSC34
cultured motor neurons.
Conceptual Framework: We hypothesize that the age-related loss of larger PMNs is
related to mitochondrial fragmentation, which results from decreased Mfn2 and
increased Drp1 expression, and is mitigated by enhanced BDNF/TrkB signaling.
Specific Aim 1: To test the hypothesis that size-dependent differences in
mitochondrial morphology in PMNs are exacerbated with aging and relate to
differences in Mfn2 and Drp1 expression.
Specific Aim 2: To test the hypothesis that the age-related loss of larger PMNs is
related to mitochondrial fragmentation, which results from decreased Mfn2 and
increased Drp1 expression.
Specific Aim 3: To test the hypothesis that enhanced BDNF/TrkB.Fl signaling in
PMNs mitigates age-related PMN loss, through an effect on Mfn2 and Drp1
expressio...

## Key facts

- **NIH application ID:** 9895586
- **Project number:** 5R01AG044615-08
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Carlos B Mantilla
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $605,695
- **Award type:** 5
- **Project period:** 2013-06-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9895586

## Citation

> US National Institutes of Health, RePORTER application 9895586, Respiratory Control in Old Age (5R01AG044615-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9895586. Licensed CC0.

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