title: Neuro-muscular function in the wobbler murine model of primary motor neuronopathy.
abstract: The wobbler mouse represents a model for neurodegenerative disease affecting motor neurons. This study explored the importance of fiber type specific changes for the contractile dysfunction of soleus and extensor digitorum longus (EDL) muscles from wobbler mice using a specific inhibitor of force generation by the type II myosin protein. Generally, wobbler condition was associated with ~50% reductions in muscle mass and contractile capacity in both muscles. In soleus, an increase in the relative abundance of type I myosin protein was observed. Since, however, only ~40% of the fibers containing type I myosin had functional innervation whereas almost all fibers containing type II myosin were innervated, the shift toward type I myosin was without significance for the in vivo contractile phenotype. Soleus muscles from wobbler mice were further characterized by a 2-fold increase in the width of the twitches, which was associated with a reduction in the excitation frequency necessary to elicit tetanic contractions. Since the SR Ca(2+) ATPase in wobbler soleus was reduced from 22 ± 5 to 10 ± 2 nmol/g muscle tissue (P=0.0006), the increase in twitch width was most likely caused by delayed recovery of cytosolic Ca(2+). Such changes were not observed in EDL. It is concluded that the shift in myosin protein from type II to type I previously reported in both innervated and denervated wobbler muscles primarily takes place in the population of denervated muscle fibers. Since these muscles do not contribute to force generation, the transition is, therefore, of limited relevance for the contractile phenotype of the muscles. Instead, the slow contractile phenotype of wobbler soleus muscles seemed to be a consequence of reduced SR content of Ca(2+) ATPase.
authors.affiliation: Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Broch-Lips
authors.forename: Thomas Holm
authors.initials: TH
authors.lastname: Pedersen
authors.forename: Anders
authors.initials: A
authors.lastname: Riisager
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmitt-John
authors.forename: Ole Bækgaard
authors.initials: OB
authors.lastname: Nielsen
mesh_terms: D000818:Animals; D051379:Mice; D008818:Mice, Neurologic Mutants; D016472:Motor Neuron Disease / Q000378:metabolism / Q000503:physiopathology*; D009119:Muscle Contraction / Q000502:physiology; D018482:Muscle, Skeletal / Q000294:innervation / Q000378:metabolism / Q000503:physiopathology*; D024461:Myosin Type I / Q000378:metabolism; D009469:Neuromuscular Junction / Q000378:metabolism / Q000503:physiopathology*; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism
chemical_list: D024461:Myosin Type I; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
keywords: ALS; BTS; Contractile phenotype; EDL; Excitation frequency necessary to elicit 50% of the increase in muscle force with tetanic stimulation; Hz(50); Myosin protein; N-benzyl-p-toluenesulfonamide; Neuronopathy; SOD1; SR; SR Ca(2+) ATPase; WT; Wild type; Wobbler mice; amyotrophic lateral sclerosis; extensor digitorum longus; sarcoplasmic reticulum; superoxide dismutase 1