Long‐term, induced expression of Hand2 in peripheral sympathetic neurons ameliorates sarcopenia in geriatric mice

Abstract Background The discovery of adrenoceptors, which mediate the effects of the sympathetic nervous system neurotransmitter norepinephrine on specific tissues, sparked the development of sympathomimetics that have profound influence on skeletal muscle mass. However, chronic administration has serious side effects that preclude their use for muscle‐wasting conditions such as sarcopenia, the age‐dependent decline in muscle mass, force, and power. Devising interventions that can adjust neurotransmitter release to changing physiological demands will require understanding how the sympathetic nervous system affects muscle motor innervation and muscle mass, which will prevent sarcopenia‐associated impaired mobility, falls, institutionalization, co‐morbidity, and premature death. Here, we tested the hypothesis that prolonged heart and neural crest derivative 2 (Hand2) expression in peripheral sympathetic neurons (SNs) ameliorates sympathetic muscle denervation, motor denervation, and sarcopenia in geriatric mice. Methods We delivered either a viral vector encoding the transcription factor Hand2 or an empty vector (EV) driven to SNs by the PRSx8 promoter by injecting the saphenous vein in 16‐month‐old C57BL/6 mice that were sacrificed 10–11 months later. Studies relied on sympathetic and muscle immunohistochemistry analysed by confocal microscopy, nerve and muscle protein expression assessed by immunoblots, nerve‐evoked and muscle‐evoked maximal muscle contraction force, extensor digitorum longus (EDL) muscle RNA sequencing, SN real‐time PCR, and tests of physical performance using an inverted‐cling grip test and in an open‐arena setting. Results Examining the mice 10–11 months later, we found that inducing Hand2 expression in peripheral SNs preserved (i) the number of neurons (EV: 0.32 ± 0.03/μm2, n = 6; Hand2: 0.92 ± 0.08/μm2, n = 7; P