Chronic electromyograms in treadmill running SOD1 mice reveal early changes in muscle activation

The present study demonstrates that electromyograms (EMGs) obtained during locomotor activity in mice were effective for identification of early physiological markers of amyotrophic lateral sclerosis (ALS). These measures could be used to evaluate therapeutic intervention strategies in animal models of ALS. Several parameters of locomotor activity were shifted early in the disease time course in SOD1G93A mice, especially when the treadmill was inclined, including intermuscular phase, burst skew and amplitude of the locomotor bursts. The results of the present study indicate that early compensatory changes may be taking place within the neural network controlling locomotor activity, including spinal interneurons. Locomotor EMGs could have potential use as a clinical diagnostic tool.

[1]  N. Shneider,et al.  Gamma motor neurons survive and exacerbate alpha motor neuron degeneration in ALS , 2016, Proceedings of the National Academy of Sciences.

[2]  M. Swash,et al.  Electrodiagnostic criteria for diagnosis of ALS , 2008, Clinical Neurophysiology.

[3]  D. Zytnicki,et al.  Early intrinsic hyperexcitability does not contribute to motoneuron degeneration in amyotrophic lateral sclerosis , 2014, eLife.

[4]  Victoria Del Gaizo Moore,et al.  Characterization of early pathogenesis in the SOD1G93A mouse model of ALS: part II, results and discussion , 2013, Brain and behavior.

[5]  David Grundy,et al.  Principles and standards for reporting animal experiments in The Journal of Physiology and Experimental Physiology , 2015, The Journal of physiology.

[6]  J. Glass,et al.  β2-Adrenoceptor agonists as novel, safe and potentially effective therapies for Amyotrophic lateral sclerosis (ALS) , 2016, Neurobiology of Disease.

[7]  T. Garland,et al.  Altered fibre types in gastrocnemius muscle of high wheel-running selected mice with mini-muscle phenotypes. , 2008, Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology.

[8]  Victoria Del Gaizo Moore,et al.  Characterization of early pathogenesis in the SOD1G93A mouse model of ALS: part I, background and methods , 2013, Brain and behavior.

[9]  Robert H. Brown,et al.  Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. , 2014, Cell reports.

[10]  J. Rothstein,et al.  Loss of the astrocyte glutamate transporter GLT1 modifies disease in SOD1G93A mice , 2006, Experimental Neurology.

[11]  G. Bishop,et al.  Increased expression of the glial glutamate transporter EAAT2 modulates excitotoxicity and delays the onset but not the outcome of ALS in mice. , 2003, Human molecular genetics.

[12]  Robert H. Brown,et al.  SOD1 mutants linked to amyotrophic lateral sclerosis selectively inactivate a glial glutamate transporter , 1999, Nature Neuroscience.

[13]  P. Caroni,et al.  Neuroprotection through Excitability and mTOR Required in ALS Motoneurons to Delay Disease and Extend Survival , 2013, Neuron.

[14]  J. Jansen,et al.  The extent of sprouting of remaining motor units in partly denervated immature and adult rat soleus muscle , 1977, Neuroscience.

[15]  C. Bories,et al.  Early electrophysiological abnormalities in lumbar motoneurons in a transgenic mouse model of amyotrophic lateral sclerosis , 2007 .

[16]  Philipp Berens,et al.  CircStat: AMATLABToolbox for Circular Statistics , 2009, Journal of Statistical Software.

[17]  Pico Caroni,et al.  Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF , 2006, Nature Neuroscience.

[18]  K. Quinlan.  Links between electrophysiological and molecular pathology of amyotrophic lateral sclerosis. , 2011, Integrative and comparative biology.

[19]  Matthew C Kiernan,et al.  Quantifying Disease Progression in Amyotrophic Lateral Sclerosis , 2014, Annals of neurology.

[20]  M. Kiernan,et al.  Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis. , 2008, Brain : a journal of neurology.

[21]  L. Greensmith,et al.  A mutation in dynein rescues axonal transport defects and extends the life span of ALS mice , 2005, The Journal of cell biology.

[22]  P. Branchereau,et al.  Embryonic alteration of motoneuronal morphology induces hyperexcitability in the mouse model of amyotrophic lateral sclerosis , 2013, Neurobiology of Disease.

[23]  P. Ince,et al.  Calcium‐permeable α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid receptors: A molecular determinant of selective vulnerability in amyotrophic lateral sclerosis , 1997 .

[24]  P. Ince,et al.  Calcium-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors: a molecular determinant of selective vulnerability in amyotrophic lateral sclerosis. , 1997, Annals of neurology.

[25]  L. Martin,et al.  Motor neuron degeneration in amyotrophic lateral sclerosis mutant superoxide dismutase‐1 transgenic mice: Mechanisms of mitochondriopathy and cell death , 2007, The Journal of comparative neurology.

[26]  K. Kullander,et al.  Alterations in the motor neuron–renshaw cell circuit in the Sod1G93A mouse model , 2013, The Journal of comparative neurology.

[27]  Jan Celichowski,et al.  Changes in motor unit properties in SOD1 (G93A) rats , 2014, Muscle & nerve.

[28]  B. Liss,et al.  Selective mitochondrial Ca2+ uptake deficit in disease endstage vulnerable motoneurons of the SOD1G93A mouse model of amyotrophic lateral sclerosis , 2013, The Journal of physiology.

[29]  C. Heckman,et al.  Comparison of dendritic calcium transients in juvenile wild type and SOD1G93A mouse lumbar motoneurons , 2015, Front. Cell. Neurosci..

[30]  R. Harris-Warrick,et al.  In Mice Lacking V2a Interneurons, Gait Depends on Speed of Locomotion , 2009, The Journal of Neuroscience.

[31]  X. Navarro,et al.  Early presymptomatic cholinergic dysfunction in a murine model of amyotrophic lateral sclerosis , 2013, Brain and behavior.

[32]  Turgay Akay,et al.  V3 Spinal Neurons Establish a Robust and Balanced Locomotor Rhythm during Walking , 2008, Neuron.

[33]  C. Heckman,et al.  Adult spinal motoneurones are not hyperexcitable in a mouse model of inherited amyotrophic lateral sclerosis , 2014, The Journal of physiology.

[34]  T. Akay.  Long-term measurement of muscle denervation and locomotor behavior in individual wild-type and ALS model mice. , 2014, Journal of neurophysiology.

[35]  Innervation patterns in the cat tibialis anterior six months after self‐reinnervation , 1993, Muscle & nerve.

[36]  C. Heckman,et al.  Progressive Changes in Synaptic Inputs to Motoneurons in Adult Sacral Spinal Cord of a Mouse Model of Amyotrophic Lateral Sclerosis , 2009, The Journal of Neuroscience.

[37]  G. Sobue,et al.  Amyotrophic lateral sclerosis. Lack of central chromatolytic response of motor neurocytons corresponding to active axonal degeneration. , 1983, Archives of neurology.

[38]  J. Shefner,et al.  The mixed nerve silent period in normal subjects and patients with amyotrophic lateral sclerosis. , 1998, Electromyography and clinical neurophysiology.

[39]  M. Tresch,et al.  Design and evaluation of a chronic EMG multichannel detection system for long-term recordings of hindlimb muscles in behaving mice. , 2013, Journal of electromyography and kinesiology : official journal of the International Society of Electrophysiological Kinesiology.

[40]  Lin Jin,et al.  Aberrant RNA Processing in a Neurodegenerative Disease: the Cause for Absent EAAT2, a Glutamate Transporter, in Amyotrophic Lateral Sclerosis , 1998, Neuron.

[41]  M. Molinari,et al.  Altered Functionality, Morphology, and Vesicular Glutamate Transporter Expression of Cortical Motor Neurons from a Presymptomatic Mouse Model of Amyotrophic Lateral Sclerosis. , 2016, Cerebral cortex.

[42]  P. Wirtz,et al.  Postnatal growth and differentiation of muscle fibres in the mouse. II. A histochemical and morphometrical investigation of dystrophic muscle. , 1983, Journal of anatomy.

[43]  V. Edgerton,et al.  HINDLIMB MUSCLE FIBER POPULATIONS OF FIVE MAMMALS , 1973 .

[44]  J. Amendola,et al.  Morphological differences between wild‐type and transgenic superoxide dismutase 1 lumbar motoneurons in postnatal mice , 2008, The Journal of comparative neurology.

[45]  J. F. Yang,et al.  Recovery potential of muscle after partial denervation: A comparison between rats and humans , 1993, Brain Research Bulletin.

[46]  J. Durand,et al.  Early excitability changes in lumbar motoneurons of transgenic SOD1G85R and SOD1G(93A-Low) mice. , 2009, Journal of neurophysiology.

[47]  S. Arber,et al.  Degradation of mouse locomotor pattern in the absence of proprioceptive sensory feedback , 2014, Proceedings of the National Academy of Sciences.

[48]  C. Heckman,et al.  Increased persistent Na+ current and its effect on excitability in motoneurones cultured from mutant SOD1 mice , 2005, The Journal of physiology.

[49]  N. Mercuri,et al.  Increased persistent sodium current determines cortical hyperexcitability in a genetic model of amyotrophic lateral sclerosis , 2009, Experimental Neurology.

[50]  M. Bellingham,et al.  Motor Cortex Layer V Pyramidal Neurons Exhibit Dendritic Regression, Spine Loss, and Increased Synaptic Excitation in the Presymptomatic hSOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis , 2015, The Journal of Neuroscience.

[51]  M. Kiernan,et al.  Novel threshold tracking techniques suggest that cortical hyperexcitability is an early feature of motor neuron disease. , 2006, Brain : a journal of neurology.

[52]  K. Kullander,et al.  Alterations in the motor neuron-renshaw cell circuit in the Sod1(G93A) mouse model. , 2013, The Journal of comparative neurology.

[53]  M D Binder,et al.  Computer simulations of the effects of different synaptic input systems on motor unit recruitment. , 1993, Journal of neurophysiology.

[54]  A. Filipchuk,et al.  Postnatal dendritic development in lumbar motoneurons in mutant superoxide dismutase 1 mouse model of amyotrophic lateral sclerosis , 2012, Neuroscience.

[55]  N. Mercuri,et al.  Over-expression of N-type calcium channels in cortical neurons from a mouse model of Amyotrophic Lateral Sclerosis , 2013, Experimental Neurology.

[56]  Michael Swash,et al.  Motoneuron firing in amyotrophic lateral sclerosis (ALS) , 2014, Front. Hum. Neurosci..

[57]  W. Robberecht,et al.  GluR2 Deficiency Accelerates Motor Neuron Degeneration in a Mouse Model of Amyotrophic Lateral Sclerosis , 2005, Journal of neuropathology and experimental neurology.

[58]  U. Frandsen,et al.  Skeletal Muscle Remodelling as a Function of Disease Progression in Amyotrophic Lateral Sclerosis , 2016, BioMed research international.

[59]  C. Heckman,et al.  Effect of fluoxetine on disease progression in a mouse model of ALS. , 2014, Journal of neurophysiology.

[60]  Robert B. White,et al.  Dynamics of muscle fibre growth during postnatal mouse development , 2010, BMC Developmental Biology.

[61]  D. Farina,et al.  Accessing the Neural Drive to Muscle and Translation to Neurorehabilitation Technologies , 2012, IEEE Reviews in Biomedical Engineering.

[62]  H. Hultborn,et al.  Intrinsic properties of lumbar motor neurones in the adult G127insTGGG superoxide dismutase‐1 mutant mouse in vivo: evidence for increased persistent inward currents , 2010, Acta physiologica.

[63]  G. Landreth,et al.  Retinoids and motor neuron disease: Potential role in amyotrophic lateral sclerosis , 2016, Journal of the Neurological Sciences.

[64]  T. Gordon,et al.  Time course of preferential motor unit loss in the SOD1G93A mouse model of amyotrophic lateral sclerosis , 2007, Neurobiology of Disease.

[65]  K. Millen,et al.  Proprioceptive Sensory Neuropathy in Mice with a Mutation in the Cytoplasmic Dynein Heavy Chain 1 Gene , 2007, The Journal of Neuroscience.

[66]  J. H. Jara,et al.  AAV2 mediated retrograde transduction of corticospinal motor neurons reveals initial and selective apical dendrite degeneration in ALS , 2012, Neurobiology of Disease.

[67]  M. Gurney,et al.  Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. , 1994, Science.

[68]  L. Martin,et al.  Glycinergic innervation of motoneurons is deficient in amyotrophic lateral sclerosis mice: a quantitative confocal analysis. , 2009, The American journal of pathology.

[69]  M. Ghosh,et al.  The role of the serotonergic system in locomotor recovery after spinal cord injury , 2015, Front. Neural Circuits.

[70]  D. McCrea,et al.  Organization of mammalian locomotor rhythm and pattern generation , 2008, Brain Research Reviews.

[71]  C. Heckman,et al.  Hyperexcitability of cultured spinal motoneurons from presymptomatic ALS mice. , 2004, Journal of neurophysiology.

[72]  M. Tresch,et al.  Flexibility of motor pattern generation across stimulation conditions by the neonatal rat spinal cord. , 2010, Journal of neurophysiology.

[73]  Postnatal growth and differentiation of muscle fibres in the mouse. I. A histochemical and morphometrical investigation of normal muscle. , 1983, Journal of anatomy.

[74]  D. Kernell,et al.  Fibre type regionalisation in lower hindlimb muscles of rabbit, rat and mouse: a comparative study , 2001, Journal of anatomy.

[75]  P. Caroni,et al.  Early and Selective Loss of Neuromuscular Synapse Subtypes with Low Sprouting Competence in Motoneuron Diseases , 2000, The Journal of Neuroscience.

[76]  J. Rothstein,et al.  Advances in treating amyotrophic lateral sclerosis: insights from pathophysiological studies , 2014, Trends in Neurosciences.

[77]  T. Yaksh,et al.  Mutant dynein (Loa) triggers proprioceptive axon loss that extends survival only in the SOD1 ALS model with highest motor neuron death , 2008, Proceedings of the National Academy of Sciences.