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Role of Sympathetic Nervous System in Aging Sarcopenia

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abstract
Sarcopenia, or age-dependent decline in muscle force and power, impairs mobility, increasing the risk of falls, institutionalization, comorbidity, and premature death. Despite the relevance for the onset and outcome of sarcopenia, the etiology of age-related skeletal muscle denervation remains unknown. Symptoms of autonomic failure are frequently the presentation of advanced age and neurodegenerative diseases that impair adaptation to common physiologic stressors. Here, we reported that the SNS regulates neuromuscular junction transmission, maintains optimal Gαi2 expression and prevents any increase in Hdac4, myogenin, MuRF1, and miR-206. Ablation of SNS leads to upregulation of MuRF1, muscle atrophy, and downregulation of postsynaptic AChR. We elucidated the mechanism of action of sympathomimetic drugs, clenbuterol and salbutamol, which allowed us to conclude that the SNS influences skeletal muscle physiology by acting, not only at the NMJ postterminal, but the motor neuron terminal, in P/Q-Ca2+ channels and TRPV1 channels, and the sympathetic axon, in N-type Ca2+ channels. Our research also showed that prolonged NMJ activation depends on their effect on the balance between sympathetic and motor axon terminal activity. Next, we unveiled the molecular substrate accounting for the influence of endogenous sympathetic neurons on motoneuron-muscle transmission in young mice and its decline with aging. Finally, we showed that selective expression of Hand2 in the mouse sympathetic neurons from middle- through old-age increases muscle mass and force by (a) regulating skeletal muscle sympathetic and motor innervation; (b) improving AChR stability and NMJ transmission; (c) preventing inflammation and myofibrillar protein degradation; (d) increasing autophagy; and (e) probably enhancing protein synthesis. Our findings are relevant to clinical conditions characterized by progressive decline of sympathetic innervation, such as neurodegenerative diseases and aging.
subject
Motor System
Sarcopenia
Sympathetic Nervous System
contributor
Zaia Rodrigues, Anna Carolina (author)
Delbono, Osvaldo (committee chair)
Milligan, Carol (committee member)
Oppenheim, Ron (committee member)
Ma, Tao (committee member)
Zhang, Tan (committee member)
date
2020-08-28T08:35:20Z (accessioned)
2020 (issued)
degree
Neuroscience (discipline)
2021-08-27 (liftdate)
embargo
2021-08-27 (terms)
identifier
http://hdl.handle.net/10339/96936 (uri)
language
en (iso)
publisher
Wake Forest University
title
Role of Sympathetic Nervous System in Aging Sarcopenia
type
Dissertation

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