Spinal Muscular Atrophy Treatment: The MTOR Regulatory
Intervention

Naser-Aldin      Lashgari; Nazanin   Momeni   Roudsari; Maryam      Shayan; Sadaf      Eshraghi; Saeideh      Momtaz; Tannaz      Jamialahmadi; Amir   Hossein   Abdolghaffari; Amirhossein      Sahebkar
Abstract

Spinal muscular atrophy (SMA) is a hereditary disorder affecting neurons and muscles, resulting in muscle weakness and atrophy. Most SMA cases are diagnosed during infancy or early childhood, the most common inherited cause of infant mortality without treatment. Still, SMA might appear at older ages with milder symptoms. SMA patients demonstrate progressive muscle waste, movement problems, tremors, dysphagia, bone and joint deformations, and breathing difficulties. The mammalian target of rapamycin (mTOR), the mechanistic target of rapamycin, is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases encoded by the mTOR gene in humans. The mTOR phosphorylation, deregulation, and autophagy have shown dissimilarity amongst SMA cell types. Therefore, exploring the underlying molecular process in SMA therapy could provide novel insights and pave the way for finding new treatment options. This paper provides new insight into the possible modulatory effect of mTOR/ autophagy in SMA management.
[1]
Verhaart, I.E.C.; Robertson, A.; Wilson, I.J.; Aartsma-Rus, A.; Cameron, S.; Jones, C.C.; Cook, S.F.; Lochmüller, H. Prevalence, incidence and carrier frequency of 5q–linked spinal muscular atrophy – a literature review. Orphanet J. Rare Dis.,  2017, 12(1), 124.
 [http://dx.doi.org/10.1186/s13023-017-0671-8] [PMID: 28676062]

[2]
Markowitz, J.A.; Singh, P.; Darras, B.T. Spinal muscular atrophy: A clinical and research update. Pediatr. Neurol.,  2012, 46(1), 1-12.
 [http://dx.doi.org/10.1016/j.pediatrneurol.2011.09.001] [PMID: 22196485]

[3]
Ramdas, S.; Servais, L. New treatments in spinal muscular atrophy: An overview of currently available data. Expert Opin. Pharmacother.,  2020, 21(3), 307-315.
 [http://dx.doi.org/10.1080/14656566.2019.1704732] [PMID: 31973611]

[4]
Schorling, D.C.; Pechmann, A.; Kirschner, J. Advances in treatment of spinal muscular atrophy–new phenotypes, new challenges, new implications for care. J. Neuromuscul. Dis.,  2020, 7(1), 1-13.
 [http://dx.doi.org/10.3233/JND-190424] [PMID: 31707373]

[5]
Wang, T.; Long, K.; Zhou, Y.; Jiang, X.; Liu, J.; Fong, J.H.C.; Wong, A.S.L.; Ng, W.L.; Wang, W. Optochemical control of mTOR signaling and mTOR-dependent autophagy. ACS Pharmacol. Transl. Sci.,  2022, 5(3), 149-155.
 [http://dx.doi.org/10.1021/acsptsci.1c00230] [PMID: 35311017]

[6]
Magri, F.; Vanoli, F.; Corti, S. miRNA in spinal muscular atrophy pathogenesis and therapy. J. Cell. Mol. Med.,  2018, 22(2), 755-767.
 [PMID: 29160009]

[7]
Rodriguez-Muela, N.; Parkhitko, A.; Grass, T.; Gibbs, R.M.; Norabuena, E.M.; Perrimon, N.; Singh, R.; Rubin, L.L. Blocking p62-dependent SMN degradation ameliorates spinal muscular atrophy disease phenotypes. J. Clin. Invest.,  2018, 128(7), 3008-3023.
 [http://dx.doi.org/10.1172/JCI95231] [PMID: 29672276]

[8]
Wang, Y.; Shao, Y.; Gao, Y.; Wan, G.; Wan, D.; Zhu, H.; Qiu, Y.; Ye, X. Catalpol prevents denervated muscular atrophy related to the inhibition of autophagy and reduces BAX/BCL2 ratio via mTOR pathway. Drug Des. Devel. Ther.,  2018, 13, 243-253.
 [http://dx.doi.org/10.2147/DDDT.S188968] [PMID: 30643390]

[9]
Wirth, B.; Mendoza-Ferreira, N.; Torres-Benito, L. Spinal muscular atrophy disease modifiers. Spinal muscular atrophy; Elsevier, 2017, pp. 191-210.
 [http://dx.doi.org/10.1016/B978-0-12-803685-3.00012-4]

[10]
Laplante, M; Sabatini, DM mTOR signaling at a glance. J. Cell Sci.,  2009, 122(20), 3589-3594.

[11]
Weichhart, T; Hengstschläger, M; Linke, M Regulation of innate immune cell function by mTOR. Nature Reviews Immunology,  2015, 15(10), 599-614.
 [http://dx.doi.org/10.1038/nri3901]

[12]
Lashgari, N.A.; Roudsari, N.M.; Momtaz, S.; Abdolghaffari, A.H. Mammalian target of rapamycin; novel insight for management of inflammatory bowel diseases. World J. Pharmacol.,  2022, 11(1), 1-5.
 [http://dx.doi.org/10.5497/wjp.v11.i1.1]

[13]
Lashgari, N.A.; Roudsari, N.M.; Momtaz, S.; Ghanaatian, N.; Kohansal, P.; Farzaei, M.H.; Afshari, K.; Sahebkar, A.; Abdolghaffari, A.H. Targeting mammalian target of rapamycin: Prospects for the treatment of inflammatory bowel diseases. Curr. Med. Chem.,  2021, 28(8), 1605-1624.
 [http://dx.doi.org/10.2174/1875533XMTA2jMzE32] [PMID: 32364064]

[14]
Yip, CK; Murata, K; Walz, T; Sabatini, DM; Kang, SA Structure of the human mTOR complex I and its implications for rapamycin inhibition. Molecular Cell,  2010, 38(5), 768-774.

[15]
Scaiola, A.; Mangia, F.; Imseng, S.; Boehringer, D.; Berneiser, K.; Shimobayashi, M The 3.2-Å resolution structure of human mTORC2. Science Advances,  2020, 6(45)

[16]
Rehorst, WA; Thelen, MP; Nolte, H; Türk, C; Cirak, S; Peterson, JM Muscle regulates mTOR dependent axonal local translation in motor neurons via CTRP3 secretion: Implications for a neuromuscular disorder, spinal muscular atrophy. Acta Neuropathol. Commun.,  2019, 7(1)

[17]
Distinct signaling mechanisms of mTORC1 and mTORC2 in glioblastoma multiforme: A. D - 101572336 2015, 57

[18]
Ferri, N.; Siegl, P.; Corsini, A.; Herrmann, J.; Lerman, A.; Benghozi, R. Drug attrition during pre-clinical and clinical development: Understanding and managing drug-induced cardiotoxicity. Pharmacol. Ther.,  2013, 138(3), 470-484.
 [http://dx.doi.org/10.1016/j.pharmthera.2013.03.005] [PMID: 23507039]

[19]
Granato, M.; Rizzello, C.; Gilardini Montani, M.S.; Cuomo, L.; Vitillo, M.; Santarelli, R.; Gonnella, R.; D’Orazi, G.; Faggioni, A.; Cirone, M. Quercetin induces apoptosis and autophagy in primary effusion lymphoma cells by inhibiting PI3K/AKT/mTOR and STAT3 signaling pathways. J. Nutr. Biochem.,  2017, 41, 124-136.
 [http://dx.doi.org/10.1016/j.jnutbio.2016.12.011] [PMID: 28092744]

[20]
Säemann, M.D.; Haidinger, M.; Hecking, M.; Hörl, W.H.; Weichhart, T. The multifunctional role of mTOR in innate immunity: Implications for transplant immunity. Am. J. Transplant.,  2009, 9(12), 2655-2661.
 [http://dx.doi.org/10.1111/j.1600-6143.2009.02832.x] [PMID: 19788500]

[21]
Allan, S. Seeing mTOR in a new light. Nature Reviews Immunology,  2008, 8(12), 904.
 [http://dx.doi.org/10.1038/nri2457]

[22]
Arumugam, S. A study on the role of nf-kb signaling pathway members in regulating survival motor neuron protein level and in the pathogenesis of spinal muscular atrophy: Universitat de lleida 2017.

[23]
Ji, Y.; Li, M.; Chang, M.; Liu, R.; Qiu, J.; Wang, K.; Deng, C.; Shen, Y.; Zhu, J.; Wang, W.; Xu, L.; Sun, H. Inflammation: Roles in skeletal muscle atrophy. Antioxidants,  2022, 11(9), 1686.
 [http://dx.doi.org/10.3390/antiox11091686] [PMID: 36139760]

[24]
Weichhart, T.; Costantino, G.; Poglitsch, M.; Rosner, M.; Zeyda, M.; Stuhlmeier, K.M. The TSC-mTOR signaling pathway regulates the innate inflammatory response. Immunity,  2008, 29(4), 565-577.

[25]
Lefebvre, S.; Sarret, C. Pathogenesis and therapeutic targets in spinal muscular atrophy (SMA). Archives de Pédiatrie,  2020, 27(7), 7S3-7S8.

[26]
Kolb, S.J.; Kissel, J.T. Spinal muscular atrophy: A timely review. Arch Neurol.,  2011, 68(8), 979-984.
 [http://dx.doi.org/10.1001/archneurol.2011.74]

[27]
Hensel, N.; Kubinski, S.; Claus, P. The need for SMN-independent treatments of spinal muscular atrophy (SMA) to complement SMN-enhancing drugs. Front. Neurol.,  2020, 11, 45.
 [http://dx.doi.org/10.3389/fneur.2020.00045] [PMID: 32117013]

[28]
Deguise, M.-O.; Kothary, R. New insights into SMA pathogenesis: Immune dysfunction and neuroinflammation. Ann. Clin. Transl. Neurol.,  2017, 4(7), 522-530.
 [http://dx.doi.org/10.1002/acn3.423]

[29]
Mena, T. Spinal Muscular Atrophy (SMA) Nemours KidsHealth 2018. Available From: https://kidshealth.org/en/parents/sma.html#:~:text=Type%20I%2C%20sometimes%20called%20infantile,7%20and%2018%20months%20old

[30]
Bowerman, M.; Becker, C.G.; Yáñez-Muñoz, R.J.; Ning, K.; Wood, M.J.A.; Gillingwater, T.H.; Talbot, K. Therapeutic strategies for spinal muscular atrophy: SMN and beyond. Dis. Model. Mech.,  2017, 10(8), 943-954.
 [http://dx.doi.org/10.1242/dmm.030148] [PMID: 28768735]

[31]
Soler-Botija, C.; Cuscó, I.; Caselles, L.; López, E.; Baiget, M.; Tizzano, E.F. Implication of fetal SMN2 expression in type I SMA pathogenesis: Protection or pathological gain of function? J. Neuropathol. Exp. Neurol.,  2005, 64(3), 215-223.

[32]
Aslesh, T.; Yokota, T. Restoring SMN expression: An overview of the therapeutic developments for the treatment of spinal muscular atrophy. Cells,  2022, 11(3), 417.
 [http://dx.doi.org/10.3390/cells11030417] [PMID: 35159227]

[33]
Yeo, C.J.J.; Simmons, Z.; De Vivo, D.C.; Darras, B.T. Ethical perspectives on treatment options with spinal muscular atrophy patients. Ann. Neurol.,  2022, 91(3), 305-316.
 [http://dx.doi.org/10.1002/ana.26299] [PMID: 34981567]

[34]
López-Cortés, A.; Echeverría-Garcés, G.; Ramos-Medina, M.J. Molecular pathogenesis and new therapeutic dimensions for spinal muscular atrophy. Biology (Basel),  2022, 11(6), 894.
 [http://dx.doi.org/10.3390/biology11060894] [PMID: 35741415]

[35]
Reilly, A.; Chehade, L.; Kothary, R. Curing SMA: Are we there yet? Gene Ther.,  2022, 1-10.
 [PMID: 35614235]

[36]
Zettler, B.; Estrella, E.; Liaquat, K.; Lichten, L. Evolving approaches to prenatal genetic counseling for Spinal Muscular Atrophy in the new treatment era. J. Genet. Couns.,  2022, 31(3), 803-814.
 [http://dx.doi.org/10.1002/jgc4.1549] [PMID: 35037741]

[37]
Brakemeier, S; Stolte, B; Kleinschnitz, C; Hagenacker, T. Treatment of adult spinal muscular atrophy: Overview and recent developments. Curr. Pharma. Design, 2022.

[38]
Guo, B.; Zhuang, T.; Xu, F.; Lin, X.; Li, F.; Shan, S.K.; Wu, F.; Zhong, J.Y.; Wang, Y.; Zheng, M.H.; Xu, Q.S.; Ehsan, U.M.H.; Yuan, L.Q. New insights into implications of CTRP3 in obesity, metabolic dysfunction, and cardiovascular diseases: Potential of therapeutic interventions. Front. Physiol.,  2020, 11, 570270.
 [http://dx.doi.org/10.3389/fphys.2020.570270] [PMID: 33343381]

[39]
Rehorst, WA Muscle-secreted factors in spinal muscular atrophy: CTRP3 at the interface of muscle and neuron. 2019.

[40]
Singh, N.N.; Hoffman, S.; Reddi, P.P.; Singh, R.N. Spinal muscular atrophy: Broad disease spectrum and sex-specific phenotypes. Biochim. Biophys. Acta Mol. Basis Dis.,  2021, 1867(4), 166063.
 [http://dx.doi.org/10.1016/j.bbadis.2020.166063] [PMID: 33412266]

[41]
Custer, S.K.; Androphy, E.J. Autophagy dysregulation in cell culture and animals models of spinal muscular atrophy. Mol. Cell. Neurosci.,  2014, 61, 133-140.
 [http://dx.doi.org/10.1016/j.mcn.2014.06.006] [PMID: 24983518]

[42]
Piras, A.; Schiaffino, L.; Boido, M.; Valsecchi, V.; Guglielmotto, M.; De Amicis, E.; Puyal, J.; Garcera, A.; Tamagno, E.; Soler, R.M.; Vercelli, A. Inhibition of autophagy delays motoneuron degeneration and extends lifespan in a mouse model of spinal muscular atrophy. Cell Death Dis.,  2017, 8(12), 3223.
 [http://dx.doi.org/10.1038/s41419-017-0086-4] [PMID: 29259166]

[43]
Sansa, A.; Hidalgo, I.; Miralles, M.P.; de la Fuente, S.; Perez-Garcia, M.J.; Munell, F. Spinal Muscular Atrophy autophagy profile is tissue-dependent: Differential regulation between muscle and motoneurons. Acta Neuropathol. Commun.,  2021, 9(1)

[44]
Zhang, Q. Role of mTOR kinase activity in skeletal muscle integrity and physiology: Ecole normale supérieure de lyon-ENS LYON. East China Normal University, 2015.

[45]
Tang, H.; Inoki, K.; Lee, M.; Wright, E.; Khuong, A.; Khuong, A.; Sugiarto, S.; Garner, M.; Paik, J.; DePinho, R.A.; Goldman, D.; Guan, K.L.; Shrager, J.B. mTORC1 promotes denervation-induced muscle atrophy through a mechanism involving the activation of FoxO and E3 ubiquitin ligases. Sci. Signal.,  2014, 7(314), ra18.
 [http://dx.doi.org/10.1126/scisignal.2004809] [PMID: 24570486]

[46]
Wang, P.; Kang, S.Y.; Kim, S.J.; Park, Y.K.; Jung, H.W. Monotropein improves dexamethasone-induced muscle atrophy via the AKT/mTOR/FOXO3a signaling pathways. Nutrients,  2022, 14(9), 1859.
 [http://dx.doi.org/10.3390/nu14091859] [PMID: 35565825]

[47]
Millino, C.; Fanin, M.; Vettori, A.; Laveder, P.; Mostacciuolo, M.L.; Angelini, C. Different atrophy-hypertrophy transcription pathways in muscles affected by severe and mild spinal muscular atrophy. BMC Med.,  2009, 7(1)

[48]
Yin, D.; Lin, D.; Xie, Y.; Gong, A.; Jiang, P.; Wu, J. Neuregulin-1β alleviates sepsis-induced skeletal muscle atrophy by inhibiting autophagy via akt/mtor signaling pathway in rats. Shock: Injury, Inflammation, and Sepsis. Shock,  2022, 57(3), 397-407.
 [http://dx.doi.org/10.1097/SHK.0000000000001860] [PMID: 34559744]

[49]
Valionyte, E.; Yang, Y.; Griffiths, S.A.; Bone, A.T.; Barrow, E.R.; Sharma, V.; Lu, B.; Luo, S. The caspase-6–p62 axis modulates p62 droplets based autophagy in a dominant-negative manner. Cell Death Differ.,  2022, 29(6), 1211-1227.
 [http://dx.doi.org/10.1038/s41418-021-00912-x] [PMID: 34862482]

[50]
Darbar, I.A.; Plaggert, P.G.; Resende, M.B.D.; Zanoteli, E.; Reed, U.C. Evaluation of muscle strength and motor abilities in children with type II and III spinal muscle atrophy treated with valproic acid. BMC Neurol.,  2011, 11(1), 36.
 [http://dx.doi.org/10.1186/1471-2377-11-36] [PMID: 21435220]

[51]
Jablonka, S.; Sendtner, M. Developmental regulation of SMN expression: Pathophysiological implications and perspectives for therapy development in spinal muscular atrophy. Gene Ther.,  2017, 24(9), 506-513.
 [http://dx.doi.org/10.1038/gt.2017.46] [PMID: 28556834]

[52]
Rocchi, A.; Milioto, C.; Parodi, S.; Armirotti, A.; Borgia, D.; Pellegrini, M.; Urciuolo, A.; Molon, S.; Morbidoni, V.; Marabita, M.; Romanello, V.; Gatto, P.; Blaauw, B.; Bonaldo, P.; Sambataro, F.; Robins, D.M.; Lieberman, A.P.; Sorarù, G.; Vergani, L.; Sandri, M.; Pennuto, M. Glycolytic-to-oxidative fiber-type switch and mTOR signaling activation are early-onset features of SBMA muscle modified by high-fat diet. Acta Neuropathol.,  2016, 132(1), 127-144.
 [http://dx.doi.org/10.1007/s00401-016-1550-4] [PMID: 26971100]

[53]
Walter, L.M.; Deguise, M.O.; Meijboom, K.E.; Betts, C.A.; Ahlskog, N.; van Westering, T.L.E.; Hazell, G.; McFall, E.; Kordala, A.; Hammond, S.M.; Abendroth, F.; Murray, L.M.; Shorrock, H.K.; Prosdocimo, D.A.; Haldar, S.M.; Jain, M.K.; Gillingwater, T.H.; Claus, P.; Kothary, R.; Wood, M.J.A.; Bowerman, M. Interventions targeting glucocorticoid-krüppel-like factor 15-branched-chain amino acid signaling improve disease phenotypes in spinal muscular atrophy mice. EBioMedicine,  2018, 31, 226-242.
 [http://dx.doi.org/10.1016/j.ebiom.2018.04.024] [PMID: 29735415]

[54]
Tseng, Y.T.; Chen, C.S.; Jong, Y.J.; Chang, F.R.; Lo, Y.C. Loganin possesses neuroprotective properties, restores SMN protein and activates protein synthesis positive regulator Akt/mTOR in experimental models of spinal muscular atrophy. Pharmacol. Res.,  2016, 111, 58-75.
 [http://dx.doi.org/10.1016/j.phrs.2016.05.023] [PMID: 27241020]

[55]
Kye, M.J.; Niederst, E.D.; Wertz, M.H.; Gonçalves, I.C.G.; Akten, B.; Dover, K.Z.; Peters, M.; Riessland, M.; Neveu, P.; Wirth, B.; Kosik, K.S.; Sardi, S.P.; Monani, U.R.; Passini, M.A.; Sahin, M. SMN regulates axonal local translation via miR-183/mTOR pathway. Hum. Mol. Genet.,  2014, 23(23), 6318-6331.
 [http://dx.doi.org/10.1093/hmg/ddu350] [PMID: 25055867]

[56]
Ning, K.; Drepper, C.; Valori, C.F.; Ahsan, M.; Wyles, M.; Higginbottom, A.; Herrmann, T.; Shaw, P.; Azzouz, M.; Sendtner, M. PTEN depletion rescues axonal growth defect and improves survival in SMN-deficient motor neurons. Hum. Mol. Genet.,  2010, 19(16), 3159-3168.
 [http://dx.doi.org/10.1093/hmg/ddq226] [PMID: 20525971]

[57]
Gabanella, F.; Barbato, C.; Fiore, M.; Petrella, C.; de Vincentiis, M.; Greco, A.; Minni, A.; Corbi, N.; Passananti, C.; Di Certo, M.G. Fine-tuning of mTOR mRNA and nucleolin complexes by SMN. Cells,  2021, 10(11), 3015.
 [http://dx.doi.org/10.3390/cells10113015] [PMID: 34831238]

[58]
Liu, X.; Joshi, S.K.; Samagh, S.P.; Dang, Y.X.; Laron, D.; Lovett, D.H.; Bodine, S.C.; Kim, H.T.; Feeley, B.T. Evaluation of Akt/mTOR activity in muscle atrophy after rotator cuff tears in a rat model. J. Orthop. Res.,  2012, 30(9), 1440-1446.
 [http://dx.doi.org/10.1002/jor.22096] [PMID: 22378614]
Cite As
Current Medicinal Chemistry

Spinal Muscular Atrophy Treatment: The MTOR Regulatory Intervention

Abstract
