Neuro-muscular function in the wobbler murine model of primary motor neuronopathy

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Neuro-muscular function in the wobbler murine model of primary motor neuronopathy. / Broch-Lips, Martin; Pedersen, Thomas Holm; Riisager, Anders; Schmitt-John, Thomas; Nielsen, Ole Bækgaard.

In: Experimental Neurology, Vol. 248, 10.2013, p. 406-415.

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@article{e1bfea2d35e041b2856066e02c09b755,
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±2nmol/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.",
keywords = "Neuronopathy, Wobbler mice, Myosin protein, Contractile phenotype, SR Ca2 + ATPase",
author = "Martin Broch-Lips and Pedersen, {Thomas Holm} and Anders Riisager and Thomas Schmitt-John and Nielsen, {Ole B{\ae}kgaard}",
note = "{\circledC} 2013.",
year = "2013",
month = "10",
doi = "10.1016/j.expneurol.2013.07.005",
language = "English",
volume = "248",
pages = "406--415",
journal = "Experimental Neurology",
issn = "0014-4886",
publisher = "Academic Press",

}

RIS

TY - JOUR

T1 - Neuro-muscular function in the wobbler murine model of primary motor neuronopathy

AU - Broch-Lips, Martin

AU - Pedersen, Thomas Holm

AU - Riisager, Anders

AU - Schmitt-John, Thomas

AU - Nielsen, Ole Bækgaard

N1 - © 2013.

PY - 2013/10

Y1 - 2013/10

N2 - 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±2nmol/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.

AB - 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±2nmol/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.

KW - Neuronopathy

KW - Wobbler mice

KW - Myosin protein

KW - Contractile phenotype

KW - SR Ca2 + ATPase

U2 - 10.1016/j.expneurol.2013.07.005

DO - 10.1016/j.expneurol.2013.07.005

M3 - Journal article

C2 - 23872513

VL - 248

SP - 406

EP - 415

JO - Experimental Neurology

JF - Experimental Neurology

SN - 0014-4886

ER -