Inflammaging-associated mitochondrial degeneration occurs in hypoglossal motor neurons prior to tongue muscle

Mitochondrial degeneration and dysfunctions are increasingly linked with neurodegenerative diseases, with the greatest risk factor being increased age. Mitochondrial dysfunction is also implicated in sarcopenia, the age-associated weakness and atrophy of striated muscle. Untangling the pathophysiological effects of age-related mitochondrial degeneration and dysfunction is of huge interest in gerontology. In elderly humans and Fischer 344 (F344) rats, motor neuron (MN) death and denervation effects are becoming increasingly implicated in sarcopenia. We have previously demonstrated that MN loss and muscle weakness are prevalent in respiratory MNs and muscles; however, the chronology and mechanism of MN death and muscle weakness are relatively unexplored. We evaluated inflammaging (inflammatory cytokine release via ELISA), the endoplasmic reticulum (ER) stress response (via western blotting), mitochondrial degeneration (via serial block-face scanning electron microscopy), mitochondrial function (via SDH_max cellular assay), MN survival (via Nissl histopathology), and tongue muscle cross-sectional area (muscle H&E) and function (via ex vivo field stimulus) in young (6 months), late-middle-age (18 months) and old age (24 months) female and male F344 rats. Systemic, brainstem, and tongue muscle inflammatory cytokine TNFα was elevated from late-middle-age. The ER stress response (pIRE1α^S724), transcriptional activation of downstream genes (CDK5), subsequent mitochondrial fission (pDRP1^S616), and mitochondrial dysfunction (SDH_max) were elevated earlier at late-middle-age in brainstem and hypoglossal MNs compared to the tongue muscle. In the tongue muscle, resilience to inflammaging-triggered mitochondrial dysfunction was reflected by the maintenance of mitochondrial function and muscle morphology at late-middle-age. These findings are consistent with behavioral dysfunctions of swallow and airway defense in elderly humans and F344 rats. We propose that the vulnerability of MNs and their mitochondria to specific degenerative pathways may be a potent locus of therapeutic intervention.