Spinal Noradrenergic Overdrive Promotes Reversible Motor Unit Aging and Sarcopenia

Background Sarcopenia is characterized by progressive loss of skeletal muscle mass, strength, and physical function with aging. Motor unit degeneration is a major contributor, but the mechanisms driving age-related deterioration of motor neurons, neuromuscular junctions (NMJs), and muscle fibers remain incompletely understood. Norepinephrine (NE) regulates spinal motor neuron excitability, but its role in motor unit aging has not been established. Methods Whole-cell patch-clamp electrophysiology, optogenetics, fast-scan cyclic voltammetry, microdialysis, high-performance liquid chromatography, western blotting, and chemogenetics were used in mice aged 1-25 months. Motor neuron intrinsic properties were examined in 135 lumbar motor neurons from 81 mice. NE release dynamics, tissue content, and expression of the NE transporter (NET) and α2A-adrenergic autoreceptor were assessed in adult and aged mice. Descending spinally projecting noradrenergic neurons were selectively inhibited in aged mice using a retrograde chemogenetic approach. Results Aging produced progressive motor neuron hyperexcitability characterized by membrane depolarization, increased input resistance, elevated firing frequency, and altered action potential threshold (all P < 0.005). Optogenetically evoked endogenous NE increased motor neuron excitability by reducing action potential latency (P = 0.0001) and decreasing rheobase (P = 0.0028); these effects were prevented by α1-adrenergic receptor blockade (P = 0.0313). Aging enhanced stimulus-evoked spinal NE release, with greater responses at 20 Hz (P = 0.0223), 30 Hz (P = 0.0022), and 40 Hz (P < 0.0001). NE release elicited by stimulation of locus coeruleus and A5 noradrenergic inputs was also increased in aged mice (P = 0.0349 and P = 0.0016, respectively). Basal extracellular NE concentrations were unchanged, whereas spinal cord NE content increased (P = 0.0403). Aging reduced α2A-adrenergic receptor (P = 0.0009) and NET expression (P = 0.0046). Chemogenetic suppression of descending noradrenergic neurons in aged mice increased hindlimb muscle mass (P = 0.0111-0.0344), muscle fiber cross-sectional area (P = 0.0078-0.0467), NMJ innervation (P = 0.0210), and motor neuron soma size (P = 0.0353). Conclusions Aging promotes spinal noradrenergic overdrive characterized by increased NE storage, enhanced activity-dependent NE release, and impaired autoregulatory control. Excessive noradrenergic signaling contributes to motor neuron hyperexcitability and motor unit deterioration. Suppression of descending noradrenergic activity reverses structural features of motor neuron, NMJ, and skeletal muscle aging, identifying spinal noradrenergic signaling as a potential therapeutic target for sarcopenia.