Chronic Treatment with the AMPK Agonist AICAR Prevents Skeletal Muscle Pathology but Fails to Improve Clinical Outcome in a Mouse Model of Severe Spinal Muscular Atrophy

详细信息    查看全文

• 作者：Clàudia Cerveró ; Neus Montull ; Olga Tarabal ; Lídia Piedrafita…
• 关键词：AICAR ; Spinal muscular atrophy ; SMNΔ7 mouse ; Skeletal muscle ; Neuromuscular junction ; Spinal cord
• 刊名：Neurotherapeutics
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：13
• 期：1
• 页码：198-216
• 全文大小：2,850 KB
• 参考文献：1.Emery AE. Population frequencies of inherited neuromuscular diseases—a world survey. Neuromuscul Disord 1991;1:19-29.PubMed CrossRef
  2.Crawford TO, Pardo CA. The neurobiology of childhood spinal muscular atrophy. Neurobiol Dis 1996;3:97-110.PubMed CrossRef
  3.Lefebvre S, Burglen L, Reboullet S, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 1995;80:155-165.PubMed CrossRef
  4.Pellizzoni L, Kataoka N, Charroux B, Dreyfuss G. A novel function for SMN, the spinal muscular atrophy disease gene product, in pre-mRNA splicing. Cell 1998;95:615-624.PubMed CrossRef
  5.Kolb SJ, Battle DJ, Dreyfuss G. Molecular functions of the SMN complex. J Child Neurol 2007;22:990-994.PubMed CrossRef
  6.Lorson CL, Hahnen E, Androphy EJ, Wirth B. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci U S A 1999;96:6307-6011.PubMedCentral PubMed CrossRef
  7.Lefebvre S, Burlet P, Liu Q, et al. Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet 1997;16:265-269.PubMed CrossRef
  8.Coovert DD, Le TT, McAndrew PE, et al. The survival motor neuron protein in spinal muscular atrophy. Hum Mol Gen 1997;6:1205-1214.PubMed CrossRef
  9.Burghes AH, Beattie CE. Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick? Nat Rev Neurosci 2009;10:597-609.PubMedCentral PubMed CrossRef
  10.Dombert B, Sivadasan R, Simon CM, Jablonka S, Sendtner M. Presynaptic localization of Smn and hnRNP R in axon terminals of embryonic and postnatal mouse motoneurons. PLoS One 2014;9:e110846.PubMedCentral PubMed CrossRef
  11.Cifuentes-Diaz C, Frugier T, Tiziano FD, et al. Deletion of murine SMN exon 7 directed to skeletal muscle leads to severe muscular dystrophy. J Cell Biol 2001;152:1107-1114.PubMedCentral PubMed CrossRef
  12.Arnold AS, Gueye M, Guettier-Sigrist S, et al. Reduced expression of nicotinic AChRs in myotubes from spinal muscular atrophy I patients. Lab Invest 2004;84:1271-1278.PubMed CrossRef
  13.Dachs E, Hereu M, Piedrafita L, Casanovas A, Calderó J, Esquerda JE. Defective neuromuscular junction organization and postnatal myogenesis in mice with severe spinal muscular atrophy. J Neuropathol Exp Neurol 2011;70:444-461.PubMed CrossRef
  14.Boyer JG, Deguise MO, Murray LM, et al. Myogenic program dysregulation is contributory to disease pathogenesis in spinal muscular atrophy. Hum Mol Gen 2014;23:4249-4259.PubMedCentral PubMed CrossRef
  15.Bricceno KV, Martinez T, Leikina E, et al. Survival motor neuron protein deficiency impairs myotube formation by altering myogenic gene expression and focal adhesion dynamics. Hum Mol Gen 2014;23:4745-4757.PubMedCentral PubMed CrossRef
  16.Fayzullina S, Martin LJ. Skeletal muscle DNA damage precedes spinal motor neuron DNA damage in a mouse model of Spinal Muscular Atrophy (SMA). PLoS One 2014;9:e93329.PubMedCentral PubMed CrossRef
  17.Boyer JG, Ferrier A, Kothary R. More than a bystander: the contributions of intrinsic skeletal muscle defects in motor neuron diseases. Front Physiol 2013;4:356.PubMedCentral PubMed CrossRef
  18.Pruss RM, Giraudon-Paoli M, Morozova S, Berna P, Abitbol JL, Bordet T. Drug discovery and development for spinal muscular atrophy: lessons from screening approaches and future challenges for clinical development. Future Med Chem 2010;2:1429-1440.PubMed CrossRef
  19.Tsai LK. Therapy development for spinal muscular atrophy in SMN independent targets. Neural Plast 2012;2012:456478.PubMedCentral PubMed
  20.Seo J, Howell MD, Singh NN, Singh RN. Spinal muscular atrophy: an update on therapeutic progress. Biochim Biophys Acta 2013;1832:2180-2190.
  21.d'Ydewalle C, Sumner CJ. Spinal muscular atrophy therapeutics: where do we stand? Neurotherapeutics 2015;12:303-316.PubMedCentral PubMed CrossRef
  22.Makhortova NR, Hayhurst M, Cerqueira A, et al. A screen for regulators of survival of motor neuron protein levels. Nat Chem Biol 2011;7:544-552.PubMedCentral PubMed CrossRef
  23.Chen PC, Gaisina IN, El-Khodor BF, et al. Identification of a maleimide-mased glycogen synthase kinase-3 (GSK-3) inhibitor, BIP-135, that prolongs the median survival time of delta7 SMA KO mouse model of spinal muscular atrophy. ACS Chem Neurosci 2012;3:5-11.PubMedCentral PubMed CrossRef
  24.Markowitz JA, Singh P, Darras BT. Spinal muscular atrophy: a clinical and research update. Pediatr Neurol 2012;46:1-12.PubMed CrossRef
  25.Cherry JJ, Kobayashi DT, Lynes MM, et al. Assays for the identification and prioritization of drug candidates for spinal muscular atrophy. Assay Drug Dev Technol 2014;12:315-341.PubMedCentral PubMed CrossRef
  26.Iascone DM, Henderson CE, Lee JC. Spinal muscular atrophy: from tissue specificity to therapeutic strategies. F1000Prime Rep 2015;7:04.
  27.Monani UR, De Vivo DC. Neurodegeneration in spinal muscular atrophy: from disease phenotype and animal models to therapeutic strategies and beyond. Future Neurol 2014;9:49-65.PubMedCentral PubMed CrossRef
  28.Burghes AH, McGovern VL. Antisense oligonucleotides and spinal muscular atrophy: skipping along. Genes Dev 2010;24:1574-1579.PubMedCentral PubMed CrossRef
  29.Passini MA, Bu J, Richards AM, et al. Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy. Sci Transl Med 2011;3:72ra18.
  30.Rigo F, Hua Y, Krainer AR, Bennett CF. Antisense-based therapy for the treatment of spinal muscular atrophy. J Cell Biol 2012;199:21-25.PubMedCentral PubMed CrossRef
  31.Douglas AG, Wood MJ. Splicing therapy for neuromuscular disease. Mol Cell Neurosci 2013;56:169-185.PubMedCentral PubMed CrossRef
  32.Sivanesan S, Howell MD, Didonato CJ, Singh RN. Antisense oligonucleotide mediated therapy of spinal muscular atrophy. Transl Neurosci 2013;4.
  33.Wyatt TJ, Keirstead HS. Stem cell-derived neurotrophic support for the neuromuscular junction in spinal muscular atrophy. Expert Opin Biol Ther 2010;10:1587-1594.PubMed CrossRef
  34.Gowing G, Svendsen CN. Stem cell transplantation for motor neuron disease: current approaches and future perspectives. Neurother 2011;8:591-606.CrossRef
  35.Kirkinezos IG, Hernandez D, Bradley WG, Moraes CT. Regular exercise is beneficial to a mouse model of amyotrophic lateral sclerosis. Ann of Neurol 2003;53:804-807.CrossRef
  36.Liebetanz D HK, von Lewinski F, Kahler E, Paulus W. Extensive exercise is not harmful in amyotrophic lateral sclerosis. Eur J Neurosci 2004;20:3115-3120.
  37.Mahoney DJ, Rodriguez C, Devries M, Yasuda N, Tarnopolsky MA. Effects of high-intensity endurance exercise training in the G93A mouse model of amyotrophic lateral sclerosis. Muscle Nerve 2004;29:656-662.PubMed CrossRef
  38.Grondard C, Biondi O, Armand AS, et al. Regular exercise prolongs survival in a type 2 spinal muscular atrophy model mouse. J Neurosci 2005;25:7615-7622.PubMed CrossRef
  39.Biondi O, Grondard C, Lecolle S, et al. Exercise-induced activation of NMDA receptor promotes motor unit development and survival in a type 2 spinal muscular atrophy model mouse. J Neurosci 2008;28:953-962.PubMed CrossRef
  40.Andreassi C, Patrizi AL, Monani UR, Burghes AH, Brahe C, Eboli ML. Expression of the survival of motor neuron (SMN) gene in primary neurons and increase in SMN levels by activation of the N-methyl-D-aspartate glutamate receptor. Neurogenetics 2002;4:29-36.PubMed CrossRef
  41.Fujii N, Hayashi T, Hirshman MF, et al. Exercise induces isoform-specific increase in 5'AMP-activated protein kinase activity in human skeletal muscle. Biochem Biophys Res Commun 2000;273:1150-1155.PubMed CrossRef
  42.Chen ZP, Stephens TJ, Murthy S, et al. Effect of exercise intensity on skeletal muscle AMPK signaling in humans. Diabetes 2003;52:2205-2212.PubMed CrossRef
  43.Mu J, Brozinick JT, Jr., Valladares O, Bucan M, Birnbaum MJ. A role for AMP-activated protein kinase in contraction- and hypoxia-regulated glucose transport in skeletal muscle. Mol Cell 2001;7:1085-1094.PubMed CrossRef
  44.Ljubicic V, Burt M, Jasmin BJ. The therapeutic potential of skeletal muscle plasticity in Duchenne muscular dystrophy: phenotypic modifiers as pharmacologic targets. FASEB J 2014;28:548-568.PubMed CrossRef
  45.Jorgensen SB, Richter EA, Wojtaszewski JF. Role of AMPK in skeletal muscle metabolic regulation and adaptation in relation to exercise. J Physiol 2006;574:17-31.PubMedCentral PubMed CrossRef
  46.Merrill GF, Kurth EJ, Hardie DG, Winder WW. AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol 1997;273:E1107-E1112.PubMed
  47.Holmes BF, Kurth-Kraczek EJ, Winder WW. Chronic activation of 5'-AMP-activated protein kinase increases GLUT-4, hexokinase, and glycogen in muscle. J Appl Physiol 1999;87:1990-1995.PubMed
  48.Winder WW, Holmes BF, Rubink DS, Jensen EB, Chen M, Holloszy JO. Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle. J Appl Physiol 2000;88:2219-2226.PubMed
  49.Yan Z, Okutsu M, Akhtar YN, Lira VA. Regulation of exercise-induced fiber type transformation, mitochondrial biogenesis, and angiogenesis in skeletal muscle. J Appl Physiol 2011;110:264-274.PubMedCentral PubMed CrossRef
  50.Narkar VA, Downes M, Yu RT, et al. AMPK and PPARdelta agonists are exercise mimetics. Cell 2008;134:405-415.PubMedCentral PubMed CrossRef
  51.Ljubicic V, Miura P, Burt M, et al. Chronic AMPK activation evokes the slow, oxidative myogenic program and triggers beneficial adaptations in mdx mouse skeletal muscle. Hum Mol Gen 2011;20:3478-3493.PubMed CrossRef
  52.Bueno Junior CR, Pantaleao LC, Voltarelli VA, Bozi LH, Brum PC, Zatz M. Combined effect of AMPK/PPAR agonists and exercise training in mdx mice functional performance. PLoS One 2012;7:e45699.PubMedCentral PubMed CrossRef
  53.Jahnke VE, Van Der Meulen JH, Johnston HK, et al. Metabolic remodeling agents show beneficial effects in the dystrophin-deficient mdx mouse model. Skelet Muscle 2012;2:16.PubMedCentral PubMed CrossRef
  54.Pauly M, Daussin F, Burelle Y, et al. AMPK activation stimulates autophagy and ameliorates muscular dystrophy in the mdx mouse diaphragm. Am J Pathol 2012;181:583-592.PubMed CrossRef
  55.Le TT, Pham LT, Butchbach ME, et al. SMNDelta7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN. Hum Mol Gen 2005;14:845-857.PubMed CrossRef
  56.Sleigh JN, Gillingwater TH, Talbot K. The contribution of mouse models to understanding the pathogenesis of spinal muscular atrophy. Dis Model Mech 2011;4:457-467.PubMedCentral PubMed CrossRef
  57.Tarabal O, Caraballo-Miralles V, Cardona-Rossinyol A, et al. Mechanisms involved in spinal cord central synapse loss in a mouse model of spinal muscular atrophy. J Neuropathol Exp Neurol 2014;73:519-535.PubMed CrossRef
  58.El-Khodor BF, Edgar N, Chen A, et al. Identification of a battery of tests for drug candidate evaluation in the SMNDelta7 neonate model of spinal muscular atrophy. Exp Neurol 2008;212:29-43.PubMed CrossRef
  59.Clarke PGH, Oppenheim RW. Neuron death in vertebrate development—in-vivo methods. Methods Cell Biol 1995;46:277-321.PubMed CrossRef
  60.Calderó J, Ciutat D, Lladó J, Castán E, Oppenheim RW, Esquerda JE. Effects of excitatory amino acids on neuromuscular development in the chick embryo. J Comp Neurol 1997;387:73-95.PubMed CrossRef
  61.Gogliotti RG, Quinlan KA, Barlow CB, Heier CR, Heckman CJ, Didonato CJ. Motor neuron rescue in spinal muscular atrophy mice demonstrates that sensory-motor defects are a consequence, not a cause, of motor neuron dysfunction. J Neurosci 2012;32:3818-3829.PubMedCentral PubMed CrossRef
  62.Ljubicic V, Khogali S, Renaud JM, Jasmin BJ. Chronic AMPK stimulation attenuates adaptive signaling in dystrophic skeletal muscle. Am J Physiol Cell Physiol 2012;302:C110-C121.PubMed CrossRef
  63.Scarpulla RC. Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta 2011;1813:1269-1278.
  64.Schiaffino S, Reggiani C. Fiber types in mammalian skeletal muscles. Physiol Rev 2011;91:1447-1531.PubMed CrossRef
  65.Baar K, Wende AR, Jones TE, Marison M, Nolte LA, Chen M. Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. FASEB J 2002; 16:1879-1886.PubMed CrossRef
  66.Russell AP, Feilchenfeldt J, Schreiber S, et al. Endurance training in humans leads to fiber type-specific increases in levels of peroxisome proliferator-activated receptor-gamma coactivator-1 and peroxisome proliferator-activated receptor-alpha in skeletal muscle. Diabetes 2003;52:2874-2881.PubMed CrossRef
  67.Terada S, Goto M, Kato M, Kawanaka K, Shimokawa T, Tabata I. Effects of low-intensity prolonged exercise on PGC-1 mRNA expression in rat epitrochlearis muscle. Biochem Biophys Res Commun 2002;296:350-354.PubMed CrossRef
  68.Jager S, Handschin C, St-Pierre J, Spiegelman B. M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci U S A 2007;104:12017-12022.PubMedCentral PubMed CrossRef
  69.Lee YI, Mikesh M, Smith I, Rimer M, Thompson W. Muscles in a mouse model of spinal muscular atrophy show profound defects in neuromuscular development even in the absence of failure in neuromuscular transmission or loss of motor neurons. Dev Biol 2011;356:432-444.PubMedCentral PubMed CrossRef
  70.Kong L, Wang X, Choe DW, et al. Impaired synaptic vesicle release and immaturity of neuromuscular junctions in spinal muscular atrophy mice. J Neurosci 2009;29:842-851.PubMedCentral PubMed CrossRef
  71.Pette D, Staron RS. Myosin isoforms, muscle fiber types, and transitions. Microsc Res Tech 2000;50:500-509.PubMed CrossRef
  72.Hamalainen N, Pette D. The histochemical profiles of fast fiber types IIB, IID, and IIA in skeletal muscles of mouse, rat, and rabbit. J Histochem Cytochem 1993;41:733-743.PubMed CrossRef
  73.Ling KK, Gibbs RM, Feng Z, Ko CP. Severe neuromuscular denervation of clinically relevant muscles in a mouse model of spinal muscular atrophy. Hum Mol Gen 2012;21:185-195.PubMedCentral PubMed CrossRef
  74.Ling KK, Lin MY, Zingg B, Feng Z, Ko CP. Synaptic defects in the spinal and neuromuscular circuitry in a mouse model of spinal muscular atrophy. PLoS One 2010;5:e15457.PubMedCentral PubMed CrossRef
  75.Murray LM, Comley LH, Thomson D, Parkinson N, Talbot K, Gillingwater TH. Selective vulnerability of motor neurons and dissociation of pre- and post-synaptic pathology at the neuromuscular junction in mouse models of spinal muscular atrophy. Hum Mol Gen 2008;17:949-962.PubMed CrossRef
  76.Murray LM, Beauvais A, Bhanot K, Kothary R. Defects in neuromuscular junction remodelling in the Smn(2B/–) mouse model of spinal muscular atrophy. Neurobiol Dis 2013;49:57-67.PubMed CrossRef
  77.Matteoli M, Balbi S, Sala C, et al. Developmentally regulated expression of calcitonin gene-related peptide at mammalian neuromuscular-junction. J Mol Neurosci 1990;2:175-184.PubMed CrossRef
  78.Sala C, Andreose JS, Fumagalli G, Lomo T. Calcitonin gene-related peptide: possible role in formation and maintenance of neuromuscular junctions. J Neurosci 1995;15:520-528.PubMed
  79.Tarabal O, Calderó J, Esquerda JE. Intramuscular nerve sprouting induced by CNTF is associated with increases in CGRP content in mouse motor nerve terminals. Neurosci Lett 1996;219:60-64.PubMed CrossRef
  80.Tarabal O, Calderó J, Ribera J, et al. Regulation of motoneuronal calcitonin gene-related peptide (CGRP) during axonal growth and neuromuscular synaptic plasticity induced by botulinum toxin in rats. Eur J Neurosci 1996;8:829-836.PubMed CrossRef
  81.Dachs E, Piedrafita L, Hereu M, Esquerda JE, Calderó J. Chronic treatment with lithium does not improve neuromuscular phenotype in a mouse model of severe spinal muscular atrophy. Neuroscience 2013;250:417-433.PubMed CrossRef
  82.Park GH, Maeno-Hikichi Y, Awano T, Landmesser LT, Monani UR. Reduced survival of motor neuron (SMN) protein in motor neuronal progenitors functions cell autonomously to cause spinal muscular atrophy in model mice expressing the human centromeric (SMN2) gene. J Neurosci 2010;30:12005-12019.PubMedCentral PubMed CrossRef
  83.Mentis GZ, Blivis D, Liu W, et al. Early functional impairment of sensory-motor connectivity in a mouse model of spinal muscular atrophy. Neuron 2011;69:453-467.PubMedCentral PubMed CrossRef
  84.McCartney N, Moroz D, Garner SH, McComas AJ. The effects of strength training in patients with selected neuromuscular disorders. Med Sci Sports Exerc 1988;20:362-368.PubMed CrossRef
  85.Lewelt A, Krosschell KJ, Stoddard GJ, et al. Resistance Strength Training Exercise in Children with Spinal Muscular Atrophy. Muscle Nerve 2015;52:559-567.PubMed CrossRef
  86.Madsen KL, Hansen RS, Preisler N, Thogersen F, Berthelsen MP, Vissing J. Training improves oxidative capacity, but not function in Spinal Muscular Atrophy Type III. Muscle Nerve 2015;52:240-244.PubMed CrossRef
  87.Pette D, Staron RS. Mammalian skeletal muscle fiber type transitions. Int Rev Cytol 1997;170:143-223.PubMed CrossRef
  88.Ljubicic V, Jasmin BJ. AMP-activated protein kinase at the nexus of therapeutic skeletal muscle plasticity in Duchenne muscular dystrophy. Trends Mol Med 2013;19:614-624.PubMed CrossRef
  89.Witczak CA, Sharoff CG, Goodyear LJ. AMP-activated protein kinase in skeletal muscle: From structure and localization to its role as a master regulator of cellular metabolism. Cell Mol Life Sci 2008;65:3737-3755.PubMed CrossRef
  90.Mylabathula DB, Rice KM, Wang Z, Uddemarri S, Kinnard RS, Blough ER. Age-associated changes in MAPK activation in fast- and slow-twitch skeletal muscle of the F344/NNiaHSD X Brown Norway/BiNia rat model. Exp Gerontol 2006;41:205-214.PubMed CrossRef
  91.Singh R, Millman G, Turin E, et al. Increases in nuclear p65 activation in dystrophic skeletal muscle are secondary to increases in the cellular expression of p65 and are not solely produced by increases in IkappaB-alpha kinase activity. J Neurol Sci 2009;285:159-171.PubMed CrossRef
  92.Thomson DM, Brown JD, Fillmore N, et al. AMP-activated protein kinase response to contractions and treatment with the AMPK activator AICAR in young adult and old skeletal muscle. Journal Physiol 2009;587:2077-2086.CrossRef
  93.Dubowitz V, Sewry CA. Muscle biopsy: a practical approach. 3rd ed. Saunders Elsevier, Philadelphia, PA, 2007.
  94.Minnaard R, Drost MR, Wagenmakers AJ, van Kranenburg GP, Kuipers H, Hesselink MK. Skeletal muscle wasting and contractile performance in septic rats. Muscle Nerve 2005;31:339-348.PubMed CrossRef
  95.Le TT, McGovern VL, Alwine IE, et al. Temporal requirement for high SMN expression in SMA mice. Hum Mol Gen 2011;20:3578-3591.PubMedCentral PubMed CrossRef
  96.Lutz CM, Kariya S, Patruni S, et al. Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy. J Clin Invest 2011;121:3029-3041.PubMedCentral PubMed CrossRef
  97.Kariya S, Obis T, Garone C, et al. Requirement of enhanced Survival Motoneuron protein imposed during neuromuscular junction maturation. J Clin Invest 2014;124:785-800.PubMedCentral PubMed CrossRef
  98.Handschin C, Kobayashi YM, Chin S, Seale P, Campbell KP, Spiegelman BM. PGC-1alpha regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy. Genes Dev 2007;21:770-783.PubMedCentral PubMed CrossRef
  99.Goto M, Terada S, Kato M, et al. cDNA Cloning and mRNA analysis of PGC-1 in epitrochlearis muscle in swimming-exercised rats. Biochem Biophys Res Commun 2000;274:350-354.PubMed CrossRef
  100.Nishimune H, Stanford JA, Mori Y. Role of exercise in maintaining the integrity of the neuromuscular junction. Muscle Nerve 2014;49:315-324.PubMedCentral PubMed CrossRef
  101.Martinez TL, Kong L, Wang X, et al. Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy. J Neurosci 2012;32:8703-8715.PubMedCentral PubMed CrossRef
  102.Thirumalai V, Behrend RM, Birineni S, Liu W, Blivis D, O'Donovan MJ. Preservation of VGLUT1 synapses on ventral calbindin-immunoreactive interneurons and normal locomotor function in a mouse model of spinal muscular atrophy. J Neurophysiol 2013;109:702-710.PubMedCentral PubMed CrossRef
  103.Liu H, Lu J, Chen H, Du Z, Li XJ, Zhang S. Spinal muscular atrophy patient-derived motor neurons exhibit hyperexcitability. Sci Rep 2015;5:12189.PubMedCentral PubMed CrossRef
  104.McGovern VL, Iyer CC, Arnold WD, et al. SMN expression is required in motor neurons to rescue electrophysiological deficits in the SMNDelta7 mouse model of SMA. Hum Mol Genet 2015;24:5524-5541.PubMed CrossRef
  105.Alvarez FJ, Titus-Mitchell HE, Bullinger KL, Kraszpulski M, Nardelli P, Cope TC. Permanent central synaptic disconnection of proprioceptors after nerve injury and regeneration. I. Loss of VGLUT1/IA synapses on motoneurons. J Neurophysiol 2011;106:2450-2470.PubMedCentral PubMed CrossRef
  106.Schreml J, Riessland M, Paterno M, et al. Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585. Eur J Hum Gen 2013;21:643-652.CrossRef
  107.Hamilton G, Gillingwater TH. Spinal muscular atrophy: going beyond the motor neuron. Trends Mol Med 2013;19:40-50.PubMed CrossRef
  108.Lee AJ, Awano T, Park GH, Monani UR. Limited phenotypic effects of selectively augmenting the SMN protein in the neurons of a mouse model of severe spinal muscular atrophy. PLoS One 2012;7:e46353.PubMedCentral PubMed CrossRef
  109.Paez-Colasante X, Seaberg B, Martinez TL, Kong L, Sumner CJ, Rimer, M. Improvement of neuromuscular synaptic phenotypes without enhanced survival and motor function in severe spinal muscular atrophy mice selectively rescued in motor neurons. PLoS One 2013;8:e75866.PubMed
  110.Iyer CC, McGovern VL, Murray JD, et al. Low levels of Survival Motor Neuron protein are sufficient for normal muscle function in the SMNDelta7 mouse model of SMA. Hum Mol Genet 2015;24:6160-6173.PubMed CrossRef
  111.Bowerman M, Murray LM, Beauvais A, Pinheiro B, Kothary R. A critical smn threshold in mice dictates onset of an intermediate spinal muscular atrophy phenotype associated with a distinct neuromuscular junction pathology. Neuromuscul Disord 2012;22:263-276.PubMed CrossRef
  
• 作者单位：Clàudia Cerveró (1)
  Neus Montull (1)
  Olga Tarabal (1)
  Lídia Piedrafita (1)
  Josep E. Esquerda (1)
  Jordi Calderó (1)
  
  1. Unitat de Neurobiologia Cel·lular, Departament de Medicina Experimental, Facultat de Medicina, Universitat de Lleida and Institut de Recerca Biomèdica de Lleida (IRBLLEIDA), Av. Rovira Roure 80, 25198, Lleida, Catalonia, Spain
  
• 刊物主题：Neurosciences; Neurology; Neurosurgery; Neurobiology;
• 出版者：Springer US
• ISSN：1878-7479

文摘

Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder characterized by spinal and brainstem motor neuron (MN) loss and skeletal muscle paralysis. Currently, there is no effective treatment other than supportive care to ameliorate the quality of life of patients with SMA. Some studies have reported that physical exercise, by improving muscle strength and motor function, is potentially beneficial in SMA. The adenosine monophosphate-activated protein kinase agonist 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) has been reported to be an exercise mimetic agent that is able to regulate muscle metabolism and increase endurance both at rest and during exercise. Chronic AICAR administration has been shown to ameliorate the dystrophic muscle phenotype and motor behavior in the mdx mouse, a model of Duchenne muscular dystrophy. Here, we investigated whether chronic AICAR treatment was able to elicit beneficial effects on motor abilities and neuromuscular histopathology in a mouse model of severe SMA (the SMNΔ7 mouse). We report that AICAR improved skeletal muscle atrophy and structural changes found in neuromuscular junctions of SMNΔ7 animals. However, although AICAR prevented the loss of glutamatergic excitatory synapses on MNs, this compound was not able to mitigate MN loss or the microglial and astroglial reaction occurring in the spinal cord of diseased mice. Moreover, no improvement in survival or motor performance was seen in SMNΔ7 animals treated with AICAR. The beneficial effects of AICAR in SMA found in our study are SMN-independent, as no changes in the expression of this protein were seen in the spinal cord and skeletal muscle of diseased animals treated with this compound. Keywords AICAR Spinal muscular atrophy SMNΔ7 mouse Skeletal muscle Neuromuscular junction Spinal cord