Fogarty, Matthew

Effective neuromotor function may be considered the combination of activating motor units of a type, matching the desired force and fatigue requirements of a behaviour; and the timing of these activations in concert with motor units of other motor pools and/or with contextual/sensory cues. Although the former is well-established as being impaired with age (i.e., sarcopenia), the latter timing issues remain poorly defined in terms of aging. Indeed, sarcopenia may be considered the apotheosis of a degenerative process that first affects the timing and effective activation of motor units prior to overt weakness. We hypothesized that mild motor impairment (i.e., timing deficiencies and motor neuron synaptic pathology) would precede overt striated muscle weakness and motor neuron death. To test this hypothesis, we evaluated the neuromotor system for swallow, where striated muscle activities do not create torque across a joint (a confounder in aging studies) but pressure in the oropharynx and coordination with ventilation. We used female and male Fischer 344 rats (F344) at 6- (young), 18- (late middle-age) and 24-months-old (old) rats. Behavioral evaluations consisted of pharyngeal and thoracic pressures during naturalistic (0.5 ml oral water bolus) swallow. Synapse evaluations consisted of golgi-cox evaluation of nucleus ambiguus and hypoglossal motor neurons, and serial blockface electron microscopy evaluation of hypoglossal motor neurons. We assessed longitudinal (intrinsic) and genioglossus (extrinsic) muscle function and histopathology using platinum plate electrodes and immunohistochemistry for myosin heavy chain (MyHC) expression, respectively. Overall, we show that swallow timing abnormalities occur at late middle-age, contemporaneous with dendritic synaptic and mitochondrial deficits. Notably, motor neuron survival and muscle function and cross-sectional areas were unchanged in late middle- age, with sarcopenia and nucleus ambiguus and hypoglossal motor neuron death only apparent from old age. These results are consistent with the concept of “mild motor impairment” being a harbinger of striated muscle sarcopenia and frailty. There is every reason to suggest that these early motor timing deficits occur in spinal motor neurons. These results illustrate the importance motor neuron health has on maintenance of motor function into old age. Funding: This study was supported by R56 HL166204 & R01 AG086136 (MJF) This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Brain derived neurotrophic factor (BDNF) signals through its high-affinity full-length tropomyosin receptor kinase-B (TrkB.FL) and plays role in maintaining the survival and function of phrenic motor neurons (PhMNs), neuromuscular transmission and synaptic activity. Disruption of this pathway is a hallmark of several neurodegenerative diseases associated with dysfunction and death of PhMNs with impaired mitochondrial function. BDNF/TrkB.FL signaling phosphorylates CREB at serine 133 (pCREBS133) and promotes its nuclear localization in cervical ventral horn of rats, however its downstream molecular pathway has not yet been established. Recently, we demonstrated that in human airway smooth muscle cells, pCREBS133, as a transcription factor, binds to the CRE sequence in the PGC1a promoter and activates its expression. PGC1a co-transcriptionally activates mitochondrial transcription factor A (TFAM) expression promoting mitochondrial DNA (mtDNA) replication and mitochondrial biogenesis. In the present study, we hypothesized that BDNF/TrkB.FL signaling promotes pCREBS133 phosphorylation and transcriptional activation of PGC1a and downstream expression of TFAM, leading to mitochondrial biogenesis. In this study, we employed a loss of function approach using a novel chemogenetic rat model (TrkBF616A) with a knock-in allele sensitive to the selective kinase inhibitor 1NMPP1 to inhibit TrkB.FL kinase activity. One group of female and male rats were treated intrathecally at C4 with either artificial cerebrospinal fluid (aCSF) or BDNF (450 ng/ 300 g b.w.; diluted in aCSF) for 40 mins, followed by collection of C3-C6 cervical ventral horn. In a second group, female and male rats were treated with 1NMPP1 (25 uM; i.p.) or the vehicle DMSO for 2 h. After 2 h, both groups were treated intrathecally with BDNF for 40 min and the C3-C6 cervical ventral horn collected. Intrathecal BDNF increased the pTrkB.FLY817 autophosphorylation and downstream phosphorylation of pCREBS133. Bioinformatic analysis identified a putative binding site of pCREBS133 on PGC1a promoter, which was confirmed by Chromatin immunoprecipitation (ChIP) assay. Consistent with this, BDNF treatment increased the expression of PGC1a and downstream TFAM, with an increase in mtDNA copy number. 1NMPP1 inhibition of TrkB.FL kinase (blunted BDNF-induced pTrkB.FLY817 phosphorylation) inhibited downstream activation of the pCREBS133/PGC1a/TFAM signaling cascade. Additionally, 1NMPP1 treatment blunted the BDNF-induced increase in mtDNA copy number. We conclude that BDNF/TrKB.FL signaling mediates mitochondrial biogenesis in the cervical ventral horn suggesting that interventions targeting this pathway could be a therapeutic strategy for neurodegenerative diseases. This research was funded by NIH Grants HL146114 & AG44615. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.