{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T17:38:03Z","timestamp":1792604283222,"version":"4.5.0"},"reference-count":40,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T00:00:00Z","timestamp":1792540800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T00:00:00Z","timestamp":1792540800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AG086136"],"award-info":[{"award-number":["R01 AG086136"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Experimental Physiology"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Motor neuron (MN) death and impairment of fast\u2010fatigable motor units is widely recognized in elderly humans and rats. However, the molecular signatures identifying vulnerable MNs remains underexplored. In murine models of amyotrophic lateral sclerosis, matrix metalloproteinase 9 (MMP\u20109) and chondrolectin (Chodl) decline with disease progression and have been considered molecular markers of fast\u2010fatigable MNs. However, their expression in brainstem and lumbar MNs, in accordance with the \u2018size principle\u2019 (in which motor units are recruited in a size\u2010dependent manner, with MNs of lower capacitance activated before those of greater capacitance) and their expression throughout the lifespan remain unclear. Here, we evaluated MMP\u20109 and Chodl in lumbar and hypoglossal MNs in young (6\u00a0months) and old (24\u00a0months) Fischer 344 (F344) rats. Longitudinal lumbar spinal cord transverse brainstem sections (the orientations providing maximal MN somal sizes for each pool) were immunolabelled for choline acetyltransferase, MMP\u20109 and Chodl. Expression was quantified using confocal microscopy in young and old rats (\n                    <jats:italic>n<\/jats:italic>\n                    = 5 females,\n                    <jats:italic>n<\/jats:italic>\n                    = 5 males per age). Overall, MMP\u20109 demonstrated a positive association with lumbar MN somal surface area in young rats. Paired within\u2010animal analysis showed that in larger MNs, MMP\u20109 positivity was \u223c70% greater than smaller MNs. The size\u2010dependence of MMP\u20109 expression was absent in old lumbar MNs, suggesting either selective loss or downregulation of MMP\u20109 MN expression in ageing. No size\u2010dependent change in Chodl was observed in lumbar or hypoglossal MNs, nor was MMP\u20109 associated with MN size in hypoglossal MNs. Collectively, these findings identify MMP\u20109 as a marker enriched within large lumbar MNs in young rats and suggest that age\u2010related alterations in MMP\u20109 expression may reflect the selective vulnerability of the lumbar MNs.\n                  <\/jats:p>","DOI":"10.1113\/ep094279","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T16:44:13Z","timestamp":1792601053000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular signatures of selective motor neuron vulnerability in old age"],"prefix":"10.1113","author":[{"given":"Sang Won","family":"Cheung","sequence":"first","affiliation":[{"name":"Department of Physiology &amp; Biomedical Engineering Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0128-7042","authenticated-orcid":false,"given":"Matthew J.","family":"Fogarty","sequence":"additional","affiliation":[{"name":"Department of Physiology &amp; Biomedical Engineering Mayo Clinic  Rochester Minnesota USA"},{"name":"Department of Neurology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,21]]},"reference":[{"issue":"1","key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"3251","DOI":"10.1038\/s41467-021-23224-7","article-title":"Locomotor deficits in a mouse model of ALS are paralleled by loss of V1\u2010interneuron connections onto fast motor neurons","volume":"12","author":"Allodi I.","year":"2021","journal-title":"Nature Communications"},{"issue":"3","key":"e_1_2_10_3_1","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1002\/cne.903090309","article-title":"Dendritic architecture of nucleus ambiguus motoneurons projecting to the upper alimentary tract in the rat","volume":"309","author":"Altschuler S. M.","year":"1991","journal-title":"Journal of Comparative Neurology"},{"issue":"20","key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"3489","DOI":"10.1242\/dev.053348","article-title":"Retrograde influence of muscle fibers on their innervation revealed by a novel marker for slow motoneurons","volume":"137","author":"Chakkalakal J. V.","year":"2010","journal-title":"Development"},{"issue":"3","key":"e_1_2_10_5_1","doi-asserted-by":"crossref","DOI":"10.1111\/nan.12982","article-title":"Perineuronal nets are phagocytosed by MMP\u20109 expressing microglia and astrocytes in the SOD1(G93A) ALS mouse model","volume":"50","author":"Cheung S. W.","year":"2024","journal-title":"Neuropathology and Applied Neurobiology"},{"issue":"11","key":"e_1_2_10_6_1","doi-asserted-by":"crossref","DOI":"10.14814\/phy2.70967","article-title":"The evidence for old age motor neuron death: A scoping review","volume":"14","author":"Cheung S. W.","year":"2026","journal-title":"Physiological Reports"},{"key":"e_1_2_10_7_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.nbd.2024.106614","article-title":"Phagocytosis of aggrecan\u2010positive perineuronal nets surrounding motor neurons by reactive microglia expressing MMP\u20109 in TDP\u201043(Q331K) ALS model mice","volume":"200","author":"Cheung S. W.","year":"2024","journal-title":"Neurobiology of Disease"},{"issue":"2","key":"e_1_2_10_8_1","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1007\/s11357-025-02075-w","article-title":"Structural and mitochondrial dendritic degenerations in old hypoglossal motor neurons","volume":"48","author":"Christensen T. A.","year":"2026","journal-title":"Geroscience"},{"issue":"9","key":"e_1_2_10_9_1","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1113\/JP275498","article-title":"The vulnerability of spinal motoneurons and soma size plasticity in a mouse model of amyotrophic lateral sclerosis","volume":"596","author":"Dukkipati S. S.","year":"2018","journal-title":"The Journal of Physiology"},{"issue":"12","key":"e_1_2_10_10_1","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.1002\/cne.22332","article-title":"Identification of novel spinal cholinergic genetic subtypes disclose Chodl and Pitx2 as markers for fast motor neurons and partition cells","volume":"518","author":"Enjin A.","year":"2010","journal-title":"Journal of Comparative Neurology"},{"issue":"13","key":"e_1_2_10_11_1","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1113\/JP276312","article-title":"The bigger they are the harder they fall: Size\u2010dependent vulnerability of motor neurons in amyotrophic lateral sclerosis","volume":"596","author":"Fogarty M. J.","year":"2018","journal-title":"The Journal of Physiology"},{"key":"e_1_2_10_12_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.resp.2023.104092","article-title":"Loss of larger hypoglossal motor neurons in aged Fischer 344 rats","volume":"314","author":"Fogarty M. J.","year":"2023","journal-title":"Respiratory Physiology & Neurobiology"},{"issue":"5","key":"e_1_2_10_13_1","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1113\/JP287457","article-title":"Dendritic alterations precede age\u2010related dysphagia and nucleus ambiguus motor neuron death","volume":"603","author":"Fogarty M. J.","year":"2025","journal-title":"The Journal of Physiology"},{"issue":"4","key":"e_1_2_10_14_1","doi-asserted-by":"crossref","first-page":"5211","DOI":"10.1007\/s11357-026-02226-7","article-title":"Inflammaging\u2010associated mitochondrial degeneration occurs in hypoglossal motor neurons prior to tongue muscle","volume":"48","author":"Fogarty M. J.","year":"2026","journal-title":"Geroscience"},{"key":"e_1_2_10_15_1","doi-asserted-by":"crossref","first-page":"153","DOI":"10.3389\/fncir.2013.00153","article-title":"A method for the three\u2010dimensional reconstruction of NeurobiotinTM\u2010filled neurons and the location of their synaptic inputs","volume":"7","author":"Fogarty M. J.","year":"2013","journal-title":"Frontiers in Neural Circuits"},{"issue":"5","key":"e_1_2_10_16_1","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1152\/jn.00868.2017","article-title":"Phrenic motor neuron loss in aged rats","volume":"119","author":"Fogarty M. J.","year":"2018","journal-title":"Journal of Neurophysiology"},{"issue":"6","key":"e_1_2_10_17_1","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1152\/japplphysiol.00021.2023","article-title":"Size\u2010dependent differences in mitochondrial volume density in phrenic motor neurons","volume":"134","author":"Fogarty M. 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J.","year":"2019","journal-title":"Comprehensive Physiology"},{"issue":"3287","key":"e_1_2_10_19_1","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1126\/science.126.3287.1345","article-title":"Relation between size of neurons and their susceptibility to discharge","volume":"126","author":"Henneman E.","year":"1957","journal-title":"Science"},{"issue":"7","key":"e_1_2_10_20_1","doi-asserted-by":"crossref","first-page":"3755","DOI":"10.1007\/s00429-015-1130-8","article-title":"Developmental changes in the morphology of mouse hypoglossal motor neurons","volume":"221","author":"Kanjhan R.","year":"2016","journal-title":"Brain Structure & Function"},{"issue":"2","key":"e_1_2_10_21_1","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.neuron.2013.12.009","article-title":"Neuronal matrix metalloproteinase\u20109 is a determinant of selective neurodegeneration","volume":"81","author":"Kaplan A.","year":"2014","journal-title":"Neuron"},{"issue":"3","key":"e_1_2_10_22_1","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.resp.2010.08.019","article-title":"Redox\u2010control of matrix metalloproteinase\u20101: A critical link between free radicals, matrix remodeling and degenerative disease","volume":"174","author":"Kar S.","year":"2010","journal-title":"Respiratory Physiology & Neurobiology"},{"key":"e_1_2_10_23_1","doi-asserted-by":"crossref","first-page":"191","DOI":"10.3389\/fneur.2016.00191","article-title":"Disparate changes in plasma and brainstem cytokine levels in Adult and Ageing Rats associated with age\u2010related changes in facial motor neuron number, snout muscle morphology, and exploratory behavior","volume":"7","author":"Katharesan V.","year":"2016","journal-title":"Frontiers in Neurology"},{"key":"e_1_2_10_24_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.resp.2026.104545","article-title":"Tongue blade neuromuscular junction defects in old F344 Rats","volume":"341","author":"Kemp J. 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V.","year":"1983","journal-title":"International Journal of Neuroscience"},{"issue":"1","key":"e_1_2_10_29_1","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1152\/physrev.00061.2017","article-title":"Sarcopenia: Aging\u2010related loss of muscle mass and function","volume":"99","author":"Larsson L.","year":"2019","journal-title":"Physiological Reviews"},{"issue":"39","key":"e_1_2_10_30_1","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.adx2369","article-title":"BDNF\u2010driven synaptic plasticity requires autocrine matrix metalloproteinase\u20109 activity","volume":"11","author":"Legutko D.","year":"2025","journal-title":"Science Advances"},{"key":"e_1_2_10_31_1","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.30955","article-title":"Hypoexcitability precedes denervation in the large fast\u2010contracting motor units in two unrelated mouse models of ALS","volume":"7","author":"Mart\u00ednez\u2010Silva M. D. L.","year":"2018","journal-title":"eLife"},{"key":"e_1_2_10_32_1","first-page":"1975","article-title":"Transcriptional modulation unique to vulnerable motor neurons predicts ALS across species and SOD1 mutations","volume":"35","author":"Mei I.","year":"2025","journal-title":"Genome Research"},{"issue":"4","key":"e_1_2_10_33_1","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1093\/brain\/awz360","article-title":"Decoding the relationship between ageing and amyotrophic lateral sclerosis: A cellular perspective","volume":"143","author":"Pandya V. A.","year":"2020","journal-title":"Brain"},{"issue":"1","key":"e_1_2_10_34_1","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.neuron.2013.09.020","article-title":"Hox genes: Choreographers in neural development, architects of circuit organization","volume":"80","author":"Philippidou P.","year":"2013","journal-title":"Neuron"},{"key":"e_1_2_10_35_1","doi-asserted-by":"crossref","DOI":"10.14814\/phy2.71035","article-title":"Fiber type specific tibialis anterior muscle atrophy and oxidative capacity reduction is contemporaneous with death of larger lumbar motor neurons in old rats","volume":"14","author":"Rooker K. D.","year":"2026","journal-title":"Physiological Reports"},{"issue":"4","key":"e_1_2_10_36_1","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1152\/physrev.00031.2010","article-title":"Fiber types in mammalian skeletal muscles","volume":"91","author":"Schiaffino S.","year":"2011","journal-title":"Physiological Reviews"},{"key":"e_1_2_10_37_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.resp.2023.104180","article-title":"Sarcopenia of the longitudinal tongue muscles in rats","volume":"319","author":"Sieck G. C.","year":"2023","journal-title":"Respiratory Physiology & Neurobiology"},{"key":"e_1_2_10_38_1","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/0006-8993(67)90145-X","article-title":"Anatomical organization of the brachial spinal cord of the cat","volume":"4","author":"Sterling P.","year":"1976","journal-title":"Brain Research"},{"issue":"11","key":"e_1_2_10_39_1","doi-asserted-by":"crossref","first-page":"B492","DOI":"10.1093\/gerona\/54.11.B492","article-title":"Growth curves and survival characteristics of the animals used in the Biomarkers of Aging Program","volume":"54","author":"Turturro A.","year":"1999","journal-title":"Journals of Gerontology\u2010Series A, Biological Sciences and Medical Sciences"},{"issue":"1","key":"e_1_2_10_40_1","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1002\/cne.902780107","article-title":"Postnatal development of cat hind limb motoneurons. III: Changes in size of motoneurons supplying the triceps surae muscle","volume":"278","author":"Ulfhake B.","year":"1988","journal-title":"Journal of Comparative Neurology"},{"issue":"5","key":"e_1_2_10_41_1","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1152\/jn.1985.53.5.1303","article-title":"Relationship among recruitment order, axonal conduction velocity, and muscle\u2010unit properties of type\u2010identified motor units in cat plantaris muscle","volume":"53","author":"Zajac F. E.","year":"1985","journal-title":"Journal of Neurophysiology"}],"container-title":["Experimental Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/EP094279","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/EP094279","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/EP094279","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T16:44:18Z","timestamp":1792601058000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/EP094279"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,21]]},"references-count":40,"alternative-id":["10.1113\/EP094279"],"URL":"https:\/\/doi.org\/10.1113\/ep094279","archive":["Portico"],"relation":{},"ISSN":["0958-0670","1469-445X"],"issn-type":[{"value":"0958-0670","type":"print"},{"value":"1469-445X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,21]]},"assertion":[{"value":"2026-07-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-15","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"EP094279"}}