{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T16:31:52Z","timestamp":1770913912249,"version":"3.50.1"},"reference-count":40,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T00:00:00Z","timestamp":1632182400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008478","name":"Wake Forest School of Medicine","doi-asserted-by":"publisher","award":["P30\u2010AG21332"],"award-info":[{"award-number":["P30\u2010AG21332"]}],"id":[{"id":"10.13039\/100008478","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG057013\u201002S1"],"award-info":[{"award-number":["R01AG057013\u201002S1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG057013"],"award-info":[{"award-number":["R01AG057013"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012860","name":"Comprehensive Cancer Center at Wake Forest Baptist Medical Center","doi-asserted-by":"publisher","award":["P30CA012197"],"award-info":[{"award-number":["P30CA012197"]}],"id":[{"id":"10.13039\/100012860","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>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\u2010wasting conditions such as sarcopenia, the age\u2010dependent 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\u2010associated impaired mobility, falls, institutionalization, co\u2010morbidity, and premature death. Here, we tested the hypothesis that prolonged<jats:italic>heart and neural crest derivative 2<\/jats:italic>(Hand2) expression in peripheral sympathetic neurons (SNs) ameliorates sympathetic muscle denervation, motor denervation, and sarcopenia in geriatric mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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\u2010month\u2010old C57BL\/6 mice that were sacrificed 10\u201311\u00a0months later. Studies relied on sympathetic and muscle immunohistochemistry analysed by confocal microscopy, nerve and muscle protein expression assessed by immunoblots, nerve\u2010evoked and muscle\u2010evoked maximal muscle contraction force, extensor digitorum longus (EDL) muscle RNA sequencing, SN real\u2010time PCR, and tests of physical performance using an inverted\u2010cling grip test and in an open\u2010arena setting.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Examining the mice 10\u201311\u00a0months later, we found that inducing Hand2 expression in peripheral SNs preserved (i) the number of neurons (EV: 0.32\u00a0\u00b1\u00a00.03\/\u03bcm<jats:sup>2<\/jats:sup>,<jats:italic>n<\/jats:italic>\u00a0=\u00a06; Hand2: 0.92\u00a0\u00b1\u00a00.08\/\u03bcm<jats:sup>2<\/jats:sup>,<jats:italic>n<\/jats:italic>\u00a0=\u00a07;<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001) and size (EV: 279\u00a0\u00b1\u00a018\u00a0\u03bcm<jats:sup>2<\/jats:sup>,<jats:italic>n<\/jats:italic>\u00a0=\u00a06; Hand2: 396\u00a0\u00b1\u00a018\u00a0\u03bcm<jats:sup>2<\/jats:sup>,<jats:italic>n<\/jats:italic>\u00a0=\u00a07;<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001); (ii) lumbricalis muscle sympathetic innervation (EV: 1.4\u00a0\u00b1\u00a01.5\u00a0\u03bcm\/\u03bcm<jats:sup>2<\/jats:sup>,<jats:italic>n<\/jats:italic>\u00a0=\u00a05; Hand2: 12\u00a0\u00b1\u00a01.8\u00a0\u03bcm\/\u03bcm<jats:sup>2<\/jats:sup>,<jats:italic>n<\/jats:italic>\u00a0=\u00a05;<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001); (iii) tibialis anterior, gastrocnemius, EDL, and soleus muscles weight and whole\u2010body strength (EV: 48\u00a0\u00b1\u00a06.4\u00a0s,<jats:italic>n<\/jats:italic>\u00a0=\u00a06; Hand2: 102\u00a0\u00b1\u00a06.8\u00a0s,<jats:italic>n<\/jats:italic>\u00a0=\u00a06;<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001); (iv) EDL type IIb, IIx, and II\/IIx and soleus type I, IIa, IIx, IIa\/IIx, and IIb\/IIx myofibre cross\u2010sectional area; (v) nerve\u2010evoked (EV: 16\u00a0\u00b1\u00a02.7\u00a0mN; Hand2: 30\u00a0\u00b1\u00a04.4\u00a0mN;<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and muscle\u2010evoked (EV: 24\u00a0\u00b1\u00a03.8\u00a0mN,<jats:italic>n<\/jats:italic>\u00a0=\u00a05; Hand2: 38\u00a0\u00b1\u00a03.0\u00a0mN,<jats:italic>n<\/jats:italic>\u00a0=\u00a08;<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) muscle force by 150\u00a0Hz\u20133\u00a0s pulses; and (vi) motor innervation assessed by measuring presynaptic\/postsynaptic neuromuscular junction area overlay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Preserving Hand2 expression in SNs from middle\u2010aged to very old mice attenuates decreases in muscle mass and force by (i) maintaining skeletal muscle sympathetic and motor innervation, (ii) improving membrane and total acetylcholine receptor stability and nerve\u2010evoked and muscle\u2010evoked muscle contraction, (iii) preventing the elevation of inflammation and myofibrillar protein degradation markers, and (iv) increasing muscle autophagy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12790","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T15:39:05Z","timestamp":1632238745000},"page":"1908-1924","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Long\u2010term, induced expression of Hand2 in peripheral sympathetic neurons ameliorates sarcopenia in geriatric mice"],"prefix":"10.1002","volume":"12","author":[{"given":"Anna Carolina Zaia","family":"Rodrigues","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Section on Gerontology and Geriatric Medicine Wake Forest School of Medicine Winston\u2010Salem NC USA"},{"name":"The Neuroscience Program Wake Forest School of Medicine Winston\u2010Salem NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda Laura","family":"Messi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Section on Gerontology and Geriatric Medicine Wake Forest School of Medicine Winston\u2010Salem NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhong\u2010Min","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Section on Gerontology and Geriatric Medicine Wake Forest School of Medicine Winston\u2010Salem NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henry Jacob","family":"Bonilla","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Section on Gerontology and Geriatric Medicine Wake Forest School of Medicine Winston\u2010Salem NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Willard M.","family":"Freeman","sequence":"additional","affiliation":[{"name":"Oklahoma Medical Research Foundation Oklahoma City OK USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1613-8202","authenticated-orcid":false,"given":"Osvaldo","family":"Delbono","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Section on Gerontology and Geriatric Medicine Wake Forest School of Medicine Winston\u2010Salem NC USA"},{"name":"The Neuroscience Program Wake Forest School of Medicine Winston\u2010Salem NC USA"},{"name":"The Sticht Center for Healthy Aging and Alzheimer's Prevention Wake Forest School of Medicine Winston\u2010Salem NC 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