title: Measures of bulbar and spinal motor function, muscle innervation, and mitochondrial function in ALS rats.
abstract: Symptom onset in amyotrophic lateral sclerosis (ALS) may occur in the muscles of the limbs (spinal onset) or those of the head and neck (bulbar onset). Most preclinical studies have focused on spinal symptoms, despite the prevalence of and increased morbidity and mortality associated with bulbar disease. We measured lick rhythm and tongue force to evaluate bulbar disease in the SOD1-G93A rat model of familial ALS. Body weight and grip strength were measured concomitantly. Testing spanned the early (maturation), middle (pre-symptomatic), and late (symptomatic and end-stage) phases of the disease. We measured a persistent tongue motility deficit that became apparent in the early phase of the disease, providing behavioral evidence of bulbar pathology. At end-stage, however, cytochrome oxidase (CO) activity was normal in the hypoglossal nucleus, and in the tongue, neuromuscular innervation, citrate synthase (CS) protein levels and activity, and uncoupling protein 3 (UCP3) protein levels remained unchanged. Interestingly, significant denervation and atrophy were evident in the end-stage sternomastoid muscle, providing peripheral anatomical evidence of bulbar pathology. Changes in body weight and grip strength occurred in the late phase of the disease. Extensive atrophy and denervation were observed in the end-stage gastrocnemius muscle. In contrast to our findings in the tongue, CS protein levels were decreased in the extensor digitorum longus (EDL) and soleus, although CS activity was maintained or increased. UCP3 protein was decreased also in the EDL. These data provide evidence of differential effects in muscles that were more or less affected by disease.
authors.affiliation: Department of Molecular & Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, United States. ssmittkamp@kumc.edu
authors.forename: Susan E
authors.initials: SE
authors.lastname: Smittkamp
authors.forename: Heather N
authors.initials: HN
authors.lastname: Spalding
authors.forename: Jordan W
authors.initials: JW
authors.lastname: Brown
authors.forename: Anisha A
authors.initials: AA
authors.lastname: Gupte
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishimune
authors.forename: Paige C
authors.initials: PC
authors.lastname: Geiger
authors.forename: John A
authors.initials: JA
authors.lastname: Stanford
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D000704:Analysis of Variance; D000818:Animals; D001284:Atrophy; D010244:Bulbar Palsy, Progressive / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002950:Citrate (si)-Synthase / Q000378:metabolism; D003391:Cranial Nerves / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004327:Drinking Behavior; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000294:innervation / Q000378:metabolism / Q000503:physiopathology*; D009134:Muscular Atrophy, Spinal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D014059:Tongue / Q000294:innervation / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D000071247:Uncoupling Protein 3
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604394:Ucp3 protein, rat; D000071247:Uncoupling Protein 3; D003576:Electron Transport Complex IV; D002950:Citrate (si)-Synthase