5-HT_2C agonism as a neurotherapeutic for sarcopenia: preclinical proof of concept

Sarcopenia, the pathological age-related loss of muscle mass and strength, contributes to physical decline, frailty, and diminished healthspan. The impact of sarcopenia is expected to rise as the aging population grows, and treatments remain limited. Therefore, novel approaches for enhancing physical function and strength in older adults are desperately needed. Recent evidence suggests that deficits in motor neuron excitability contribute significantly to age-related weakness. Accordingly, we hypothesized that enhancing motor neuron excitability could be a novel strategy for mitigating age-related declines in physical function and strength. To test this hypothesis, we targeted the 5-HT_2C receptor with an agonist, as this receptor is known to enhance intrinsic excitability and amplify persistent inward currents of motor neurons. We found that a single oral gavage dose of 1.5, 3, and 6 mg/kg lorcaserin, a selective 5-HT_2C agonist, significantly increased indices of motor neuron excitability (e.g., cervical motor evoked potential (cMEP) amplitude by 53-64% and reduced attenuation in cMEP amplitude during repetitive stimulation), along with improvements in motor coordination (22-24% enhancement in rotarod performance) and functional strength (~ 17% increase in max weighted cart pull and 12% increase in grip strength) in aged mice. In contrast, antagonism of 5-HT₂ receptors resulted in the opposite effect, reducing cMEP amplitude by ~ 26%, increasing attenuation of cMEP amplitude during repetitive stimulation, and decreasing grip strength by ~ 10% in aged mice. Overall, our findings indicate that enhancing motor neuron excitability via 5-HT_2C agonism holds promise as a neurotherapeutic approach to treat age-related motor decline and sarcopenia.