# Role of Central Autonomic Relays in Aging Sarcopenia

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2022 · $594,096

## Abstract

Summary:
SNS failure is common in old age and neurodegenerative diseases that impair adaptation to common
physiological stressors. We and others found that sympathetic axons innervate skeletal muscle fibers and
maintain the integrity of skeletal muscle composition and function at the presynaptic and postsynaptic
neuromuscular junction (NMJ) in health and disease. We also demonstrated that (a) SNS impairment leads to
skeletal muscle motor denervation; (b) both the SNS and sympathomimetics regulate motoneuron synaptic
vesicle release and postsynaptic molecular composition; and (c) aging blunts the influence of the SNS on NMJ
transmission. These data support the strong influence of the SNS on motoneuron and myofiber molecular
composition and function.
Probing deeper, we found that the SNS and sympathomimetics regulate motoneuron synaptic vesicle release
via extracellular Ca2+ and such molecular targets, as TRPV1 and P/Q- and N-type voltage-activated Ca2+
channels. Recently, we demonstrated that ?1-adrenoceptor is expressed in motoneurons and declines
significantly with aging. These studies unveil the molecular substrate that accounts for the influence of
peripheral sympathetic neurons on NMJ transmission in young mice and its decline with aging. However, we
do not know whether and how the central autonomic relays (CARs)—particularly the pontine A5 nucleus, which
projects to the spinal cord intermediolateral (IML) column—regulate skeletal muscle mass, strength,
innervation, and NMJ transmission and whether this influence declines over time. Optogenetics combined with
neuron retrograde labeling provides a unique opportunity to determine the precise role of A5 nucleus in living
mice.
Based on our published and preliminary data, we propose that aging impairs A5 nucleus regulation of
the peripheral SNS, increasing skeletal muscle sympathetic and motor denervation and loss of mass
and strength.
The following specific aims are designed to test this hypothesis: Aim 1 define the role of A5 sympathetic
neurons projecting to hindlimb muscles (SNPHLM) in muscle motoneuron denervation, impaired NMJ
transmission, and sarcopenia with aging, and Aim 2 will determine whether sustained expression of the master
sympathetic transcription factor Phox-2b in A5 SNPHLM attenuates skeletal muscle sympathetic and motor
denervation with aging.
This project will be the first to define CARs’ role in NMJ transmission and muscle sympathetic and motor
innervation. It will elucidate upper level control of the motor unit to achieve an integrated, comprehensive
understanding of aging sarcopenia. Successful results will shift the treatment target for sarcopenia from the
skeletal muscle to the central sympathetic neuron.

## Key facts

- **NIH application ID:** 10363160
- **Project number:** 1R01AG071545-01A1
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Osvaldo Delbono
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $594,096
- **Award type:** 1
- **Project period:** 2022-02-15 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10363160

## Citation

> US National Institutes of Health, RePORTER application 10363160, Role of Central Autonomic Relays in Aging Sarcopenia (1R01AG071545-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10363160. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*