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image of Intricacies of PKB/Akt Activity after Sciatic Nerve Damage: A Comprehensive Review

Abstract

Sciatic nerve injury represents a prevalent and incapacitating condition characterized by denervation, muscular atrophy, and compromised functionality. The Protein Kinase B (PKB)/Akt signaling cascade serves as a vital modulator of skeletal muscle hypertrophy, metabolic processes, and regenerative capabilities. Subsequent to sciatic nerve injury, the PI3K/Akt signaling pathway exhibits dysregulation, exacerbating muscle atrophy and hindering recovery processes due to feedback inhibition of PKB/Akt phosphorylation by mTORC1, which consequently increases the expression of E3 ubiquitin ligases and causes muscle atrophy. Additionally, a multitude of other variables, encompassing neurotrophic factors, intracellular calcium ion concentrations, carboxyl-terminal modulator proteins, connexins, and tumor necrosis factor-α, either exert regulatory influences on Akt or are subject to regulation by Akt in a multifaceted manner. Hence, this review discusses the complex role of the PI3K/Akt signaling pathway in skeletal muscle dynamics following sciatic nerve injury, emphasizing its regulatory mechanisms and downstream effectors, and highlights strategies to target this pathway to enhance muscle regeneration and restore functional capabilities.

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2026-01-15
2026-01-29
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References

  1. Xu X. Talifu Z. Zhang C.J. Gao F. Ke H. Pan Y.Z. Gong H. Du H.Y. Yu Y. Jing Y.L. Du L.J. Li J.J. Yang D.G. Mechanism of skeletal muscle atrophy after spinal cord injury: A narrative review. Front. Nutr. 2023 10 1099143 10.3389/fnut.2023.1099143 36937344
    [Google Scholar]
  2. Yadav A. Dabur R. Skeletal muscle atrophy after sciatic nerve damage: Mechanistic insights. Eur. J. Pharmacol. 2024 970 176506 10.1016/j.ejphar.2024.176506 38492879
    [Google Scholar]
  3. Yoshida T. Delafontaine P. Mechanisms of IGF-1-mediated regulation of skeletal muscle hypertrophy and atrophy. Cells 2020 9 9 1970 10.3390/cells9091970 32858949
    [Google Scholar]
  4. Wang H. Wu P. Chawla A. Spinner R.J. Yu C. Yaszemski M.J. Windebank A.J. Key changes in denervated muscles and their impact on regeneration and reinnervation. Neural Regen. Res. 2014 9 20 1796 1809 10.4103/1673‑5374.143424 25422641
    [Google Scholar]
  5. Castets P. Rion N. Théodore M. Falcetta D. Lin S. Reischl M. Wild F. Guérard L. Eickhorst C. Brockhoff M. Guridi M. Ibebunjo C. Cruz J. Sinnreich M. Rudolf R. Glass D.J. Rüegg M.A. mTORC1 and PKB/Akt control the muscle response to denervation by regulating autophagy and HDAC4. Nat. Commun. 2019 10 1 3187 10.1038/s41467‑019‑11227‑4 31320633
    [Google Scholar]
  6. Singh A. Yadav A. Phogat J. Dabur R. Dynamics and Interplay between Autophagy and Ubiquitin-proteasome system Coordination in Skeletal Muscle Atrophy. Curr. Mol. Pharmacol. 2022 15 3 475 486 10.2174/1874467214666210806163851 34365963
    [Google Scholar]
  7. Singh A. Phogat J. Yadav A. Dabur R. The dependency of autophagy and ubiquitin proteasome system during skeletal muscle atrophy. Biophys. Rev. 2021 13 2 203 219 10.1007/s12551‑021‑00789‑7 33927785
    [Google Scholar]
  8. Stitt T.N. Drujan D. Clarke B.A. Panaro F. Timofeyva Y. Kline W.O. Gonzalez M. Yancopoulos G.D. Glass D.J. The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol. Cell 2004 14 3 395 403 10.1016/S1097‑2765(04)00211‑4 15125842
    [Google Scholar]
  9. Pallafacchina G. Calabria E. Serrano A.L. Kalhovde J.M. Schiaffino S. A protein kinase B-dependent and rapamycin-sensitive pathway controls skeletal muscle growth but not fiber type specification. Proc. Natl. Acad. Sci. USA 2002 99 14 9213 9218 10.1073/pnas.142166599 12084817
    [Google Scholar]
  10. Deppmann C.D. Ginty D.D. Retrograde control of neural circuit formation. Cell 2006 127 7 1306 1307 10.1016/j.cell.2006.12.013 17190596
    [Google Scholar]
  11. Cisterna B.A. Cardozo C. Sáez J.C. Neuronal involvement in muscular atrophy. Front. Cell. Neurosci. 2014 8 405 10.3389/fncel.2014.00405 25540609
    [Google Scholar]
  12. Yang X. Xue P. Chen H. Yuan M. Kang Y. Duscher D. Machens H.G. Chen Z. Denervation drives skeletal muscle atrophy and induces mitochondrial dysfunction, mitophagy and apoptosis via miR-142a-5p/MFN1 axis. Theranostics 2020 10 3 1415 1432 10.7150/thno.40857 31938072
    [Google Scholar]
  13. Meijboom K.E. Sutton E.R. McCallion E. McFall E. Anthony D. Edwards B. Kubinski S. Tapken I. Bünermann I. Hazell G. Ahlskog N. Claus P. Davies K.E. Kothary R. Wood M.J.A. Bowerman M. Dysregulation of Tweak and Fn14 in skeletal muscle of spinal muscular atrophy mice. Skelet. Muscle 2022 12 1 18 10.1186/s13395‑022‑00301‑z 35902978
    [Google Scholar]
  14. Sekiguchi K. Kanda F. Mitsui S. Kohara N. Chihara K. Fibrillation potentials of denervated rat skeletal muscle are associated with expression of cardiac-type voltage-gated sodium channel isoform Nav1.5. Clin. Neurophysiol. 2012 123 8 1650 1655 10.1016/j.clinph.2012.01.002 22336133
    [Google Scholar]
  15. Bryndina I.G. Shalagina M.N. Protopopov V.A. Sekunov A.V. Zefirov A.L. Zakirjanova G.F. Petrov A.M. Early lipid raft-related changes: Interplay between unilateral denervation and hindlimb suspension. Int. J. Mol. Sci. 2021 22 5 2239 10.3390/ijms22052239 33668129
    [Google Scholar]
  16. Cisterna B.A. Vargas A.A. Puebla C. Sáez J.C. Connexin hemichannels explain the ionic imbalance and lead to atrophy in denervated skeletal muscles. Biochim. Biophys. Acta Mol. Basis Dis. 2016 1862 11 2168 2176 10.1016/j.bbadis.2016.08.020 27580092
    [Google Scholar]
  17. Cea L.A. Cisterna B.A. Puebla C. Frank M. Figueroa X.F. Cardozo C. Willecke K. Latorre R. Sáez J.C. De novo expression of connexin hemichannels in denervated fast skeletal muscles leads to atrophy. Proc. Natl. Acad. Sci. USA 2013 110 40 16229 16234 10.1073/pnas.1312331110 24043768
    [Google Scholar]
  18. Sáez J.C. Cisterna B.A. Vargas A. Cardozo C.P. Regulation of pannexin and connexin channels and their functional role in skeletal muscles. Cell. Mol. Life Sci. 2015 72 15 2929 2935 10.1007/s00018‑015‑1968‑1 26084874
    [Google Scholar]
  19. Alsina F.C. Ledda F. Paratcha G. New insights into the control of neurotrophic growth factor receptor signaling: Implications for nervous system development and repair. J. Neurochem. 2012 123 5 652 661 10.1111/jnc.12021 22994539
    [Google Scholar]
  20. Spahic H. Parmar P. Miller S. Emerson P.C. Lechner C. St Pierre M. Rastogi N. Nugent M. Duck S.A. Kirkwood A. Chavez-Valdez R. Dysregulation of ErbB4 signaling pathway in the dorsal hippocampus after neonatal hypoxia-ischemia and late deficits in PV+ interneurons, synaptic plasticity and working memory. Int. J. Mol. Sci. 2022 24 1 508 10.3390/ijms24010508 36613949
    [Google Scholar]
  21. Watt M.J. Dzamko N. Thomas W.G. Rose-John S. Ernst M. Carling D. Kemp B.E. Febbraio M.A. Steinberg G.R. CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK. Nat. Med. 2006 12 5 541 548 10.1038/nm1383 16604088
    [Google Scholar]
  22. Rentería I. García-Suárez P.C. Fry A.C. Moncada-Jiménez J. Machado-Parra J.P. Antunes B.M. Jiménez-Maldonado A. The Molecular Effects of BDNF Synthesis on Skeletal Muscle: A Mini-Review. Front. Physiol. 2022 13 934714 10.3389/fphys.2022.934714 35874524
    [Google Scholar]
  23. Bentzinger C.F. Lin S. Romanino K. Castets P. Guridi M. Summermatter S. Handschin C. Tintignac L.A. Hall M.N. Rüegg M.A. Differential response of skeletal muscles to mTORC1 signaling during atrophy and hypertrophy. Skelet. Muscle 2013 3 1 6 10.1186/2044‑5040‑3‑6 23497627
    [Google Scholar]
  24. Zhao J. Shen X. Cao X. He H. Han S. Chen Y. Cui C. Wei Y. Wang Y. Li D. Zhu Q. Yin H. HDAC4 regulates the proliferation, differentiation and apoptosis of chicken skeletal muscle satellite cells. Animals (Basel) 2020 10 1 84 10.3390/ani10010084 31947925
    [Google Scholar]
  25. Ma W. Cai Y. Shen Y. Chen X. Zhang L. Ji Y. Chen Z. Zhu J. Yang X. Sun H. HDAC4 Knockdown Alleviates Denervation-Induced Muscle Atrophy by Inhibiting Myogenin-Dependent Atrogene Activation. Front. Cell. Neurosci. 2021 15 663384 10.3389/fncel.2021.663384 34276308
    [Google Scholar]
  26. Yoon M.S. The role of mammalian target of rapamycin (mTOR) in insulin signaling. Nutrients 2017 9 11 1176 10.3390/nu9111176 29077002
    [Google Scholar]
  27. Ham D.J. Börsch A. Lin S. Thürkauf M. Weihrauch M. Reinhard J.R. Delezie J. Battilana F. Wang X. Kaiser M.S. Guridi M. Sinnreich M. Rich M.M. Mittal N. Tintignac L.A. Handschin C. Zavolan M. Rüegg M.A. The neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia. Nat. Commun. 2020 11 1 4510 10.1038/s41467‑020‑18140‑1 32908143
    [Google Scholar]
  28. 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 10.1126/scisignal.2004809 24570486
    [Google Scholar]
  29. Abruzzo P.M. di Tullio S. Marchionni C. Belia S. Fanó G. Zampieri S. Carraro U. Kern H. Sgarbi G. Lenaz G. Marini M. Oxidative stress in the denervated muscle. Free Radic. Res. 2010 44 5 563 576 10.3109/10715761003692487 20298122
    [Google Scholar]
  30. Lahair M.M. Howe C.J. Rodriguez-Mora O. McCubrey J.A. Franklin R.A. Molecular pathways leading to oxidative stress-induced phosphorylation of Akt. Antioxid. Redox Signal. 2006 8 9-10 1749 1756 10.1089/ars.2006.8.1749 16987028
    [Google Scholar]
  31. Zhao Y. Hu X. Liu Y. Dong S. Wen Z. He W. Zhang S. Huang Q. Shi M. ROS signaling under metabolic stress: cross-talk between AMPK and AKT pathway. Mol. Cancer 2017 16 1 79 10.1186/s12943‑017‑0648‑1 28407774
    [Google Scholar]
  32. Chan C.H. Li C.F. Yang W.L. Gao Y. Lee S.W. Feng Z. Huang H.Y. Tsai K.K.C. Flores L.G. Shao Y. Hazle J.D. Yu D. Wei W. Sarbassov D. Hung M.C. Nakayama K.I. Lin H.K. The Skp2-SCF E3 ligase regulates Akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis. Cell 2012 149 5 1098 1111 10.1016/j.cell.2012.02.065 22632973
    [Google Scholar]
  33. Han F. Li C.F. Cai Z. Zhang X. Jin G. Zhang W.N. Xu C. Wang C.Y. Morrow J. Zhang S. Xu D. Wang G. Lin H.K. The critical role of AMPK in driving Akt activation under stress, tumorigenesis and drug resistance. Nat. Commun. 2018 9 1 4728 10.1038/s41467‑018‑07188‑9 30413706
    [Google Scholar]
  34. Kjøbsted R. Hingst J.R. Fentz J. Foretz M. Sanz M.N. Pehmøller C. Shum M. Marette A. Mounier R. Treebak J.T. Wojtaszewski J.F.P. Viollet B. Lantier L. AMPK in skeletal muscle function and metabolism. FASEB J. 2018 32 4 1741 1777 10.1096/fj.201700442R 29242278
    [Google Scholar]
  35. Gliwińska A. Czubilińska-Łada J. Więckiewicz G. Świętochowska E. Badeński A. Dworak M. Szczepańska M. The role of brain-derived neurotrophic factor (BDNF) in diagnosis and treatment of epilepsy, depression, schizophrenia, anorexia nervosa and Alzheimer’s disease as highly drug-resistant diseases: A narrative review. Brain Sci. 2023 13 2 163 10.3390/brainsci13020163 36831706
    [Google Scholar]
  36. Fernyhough P. Maeda K. Tomlinson D.R. Brain-derived neurotrophic factor mRNA levels are up-regulated in hindlimb skeletal muscle of diabetic rats: effect of denervation. Exp. Neurol. 1996 141 2 297 303 10.1006/exnr.1996.0164 8812163
    [Google Scholar]
  37. Rozanska O. Uruska A. Zozulinska-Ziolkiewicz D. Brain-derived neurotrophic factor and diabetes. Int. J. Mol. Sci. 2020 21 3 841 10.3390/ijms21030841 32012942
    [Google Scholar]
  38. Pradhan J. Noakes P.G. Bellingham M.C. The role of altered BDNF/TrkB signaling in amyotrophic lateral sclerosis. Front Cell Neurosci 2019 13 368 10.3389/fncel.2019.00368 31456666
    [Google Scholar]
  39. Matthews V.B. Åström M.B. Chan M.H.S. Bruce C.R. Krabbe K.S. Prelovsek O. Åkerström T. Yfanti C. Broholm C. Mortensen O.H. Penkowa M. Hojman P. Zankari A. Watt M.J. Bruunsgaard H. Pedersen B.K. Febbraio M.A. Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase. Diabetologia 2009 52 7 1409 1418 10.1007/s00125‑009‑1364‑1 19387610
    [Google Scholar]
  40. Wang J. Fry C.M.E. Walker C.L. Carboxyl-terminal modulator protein regulates Akt signaling during skeletal muscle atrophy in vitro and a mouse model of amyotrophic lateral sclerosis. Sci. Rep. 2019 9 1 3920 10.1038/s41598‑019‑40553‑2 30850672
    [Google Scholar]
  41. Ono H. Sakoda H. Fujishiro M. Anai M. Kushiyama A. Fukushima Y. Katagiri H. Ogihara T. Oka Y. Kamata H. Horike N. Uchijima Y. Kurihara H. Asano T. Carboxy-terminal modulator protein induces Akt phosphorylation and activation, thereby enhancing antiapoptotic, glycogen synthetic, and glucose uptake pathways. Am. J. Physiol. Cell Physiol. 2007 293 5 C1576 C1585 10.1152/ajpcell.00570.2006 17615157
    [Google Scholar]
  42. Zhu M. Zheng R. Guo Y. Zhang Y. Zuo B. NDRG4 promotes myogenesis via Akt/CREB activation. Oncotarget 2017 8 60 101720 101734 10.18632/oncotarget.21591 29254199
    [Google Scholar]
  43. Hervé J.C. Derangeon M. Gap-junction-mediated cell-to-cell communication. Cell Tissue Res. 2013 352 1 21 31 10.1007/s00441‑012‑1485‑6 22940728
    [Google Scholar]
  44. Merrifield P.A. Laird D.W. Connexins in skeletal muscle development and disease. Semin. Cell Dev. Biol. 2016 50 67 73 10.1016/j.semcdb.2015.12.001 26688333
    [Google Scholar]
  45. Xie X. Lan T. Chang X. Huang K. Huang J. Wang S. Chen C. Shen X. Liu P. Huang H. Connexin43 mediates NF-κB signalling activation induced by high glucose in GMCs: involvement of c-Src. Cell Commun. Signal. 2013 11 1 38 10.1186/1478‑811X‑11‑38 23718910
    [Google Scholar]
  46. Nidai Ozes O. Mayo L.D. Gustin J.A. Pfeffer S.R. Pfeffer L.M. Donner D.B. NF-κB activation by tumour necrosis factor requires the Akt serine–threonine kinase. Nature 1999 401 6748 82 85 10.1038/43466 10485710
    [Google Scholar]
  47. Dan H.C. Cooper M.J. Cogswell P.C. Duncan J.A. Ting J.P.Y. Baldwin A.S. Akt-dependent regulation of NF-κB is controlled by mTOR and Raptor in association with IKK. Genes Dev. 2008 22 11 1490 1500 10.1101/gad.1662308 18519641
    [Google Scholar]
  48. Meng F. Liu L. Chin P.C. D’Mello S.R. Akt is a downstream target of NF-kappa B. J. Biol. Chem. 2002 277 33 29674 29680 10.1074/jbc.M112464200 12052823
    [Google Scholar]
  49. Meng F. D’Mello S.R. NF-κB stimulates Akt phosphorylation and gene expression by distinct signaling mechanisms. Biochim. Biophys. Acta Gene Struct. Expr. 2003 1630 1 35 40 10.1016/j.bbaexp.2003.09.001 14580677
    [Google Scholar]
  50. Wu D.P. Zhou Y. Hou L.X. Zhu X.X. Yi W. Yang S.M. Lin T.Y. Huang J.L. Zhang B. Yin X.X. Cx43 deficiency confers EMT-mediated tamoxifen resistance to breast cancer via c-Src/PI3K/Akt pathway. Int. J. Biol. Sci. 2021 17 10 2380 2398 10.7150/ijbs.55453 34326682
    [Google Scholar]
  51. Solan J.L. Márquez-Rosado L. Lampe P.D. Cx43 phosphorylation–mediated effects on ERK and Akt protect against ischemia reperfusion injury and alter the stability of the stress-inducible protein NDRG1. J. Biol. Chem. 2019 294 31 11762 11771 10.1074/jbc.RA119.009162 31189653
    [Google Scholar]
  52. Calderón J.F. Retamal M.A. Regulation of connexins expression levels by MicroRNAs, an update. Front. Physiol. 2016 7 558 10.3389/fphys.2016.00558 27932990
    [Google Scholar]
  53. Nakamura T. Iwamoto T. Nakamura H.M. Shindo Y. Saito K. Yamada A. Yamada Y. Fukumoto S. Nakamura T. Regulation of miR-1-mediated connexin 43 expression and cell proliferation in dental epithelial cells. Front. Cell Dev. Biol. 2020 8 156 10.3389/fcell.2020.00156 32258035
    [Google Scholar]
  54. Zhou M. Zheng M. Zhou X. Tian S. Yang X. Ning Y. Li Y. Zhang S. The roles of connexins and gap junctions in the progression of cancer. Cell Commun. Signal. 2023 21 1 8 10.1186/s12964‑022‑01009‑9 36639804
    [Google Scholar]
  55. Lo Buglio A. Bellanti F. Vendemiale G. The aging muscle: Sarcopenia, mitochondrial function, and redox biology. J. Gerontol. Geriatr. 2024 72 1 1 10.36150/2499‑6564‑N695
    [Google Scholar]
  56. You J.S. Kim K. Steinert N.D. Chen J. Hornberger T.A. mTORC1 mediates fiber type-specific regulation of protein synthesis and muscle size during denervation. Cell Death Discov. 2021 7 1 74 10.1038/s41420‑021‑00460‑w 33846288
    [Google Scholar]
  57. Gao H. Li Y.F. Distinct signal transductions in fast- and slow- twitch muscles upon denervation. Physiol. Rep. 2018 6 4 13606 10.14814/phy2.13606 29464929
    [Google Scholar]
  58. Delezie J. Weihrauch M. Maier G. Tejero R. Ham D.J. Gill J.F. Karrer-Cardel B. Rüegg M.A. Tabares L. Handschin C. BDNF is a mediator of glycolytic fiber-type specification in mouse skeletal muscle. Proc. Natl. Acad. Sci. USA 2019 116 32 16111 16120 10.1073/pnas.1900544116 31320589
    [Google Scholar]
  59. Afroze D. Kumar A. ER stress in skeletal muscle remodeling and myopathies. FEBS J. 2019 286 2 379 398 10.1111/febs.14358 29239106
    [Google Scholar]
  60. Yung H.W. Charnock-Jones D.S. Burton G.J. Regulation of AKT phosphorylation at Ser473 and Thr308 by endoplasmic reticulum stress modulates substrate specificity in a severity dependent manner. PLoS One 2011 6 3 17894 10.1371/journal.pone.0017894 21445305
    [Google Scholar]
  61. D. A. B. S., K. J., Alterations in sarco/endoplasmic reticulum proteins in human skeletal muscle in ALS and other neuropathic conditions. Amyotroph. Lateral Scler. Frontotemporal Degener. 2014 15 154 155
    [Google Scholar]
  62. Boncompagni S. Pozzer D. Viscomi C. Ferreiro A. Zito E. Physical and functional cross talk between endo-sarcoplasmic reticulum and mitochondria in skeletal muscle. Antioxid. Redox Signal. 2020 32 12 873 883 10.1089/ars.2019.7934 31825235
    [Google Scholar]
  63. Turinsky J. Bayly B.P. O’Sullivan D.M. 1,2-Diacylglycerol and ceramide levels in rat skeletal muscle and liver in vivo. Studies with insulin, exercise, muscle denervation, and vasopressin. J. Biol. Chem. 1990 265 14 7933 7938 10.1016/S0021‑9258(19)39021‑0 2186032
    [Google Scholar]
  64. Turinsky J. Bayly B.P. O’Sullivan D.M. 1,2-Diacylglycerol and ceramide levels in rat liver and skeletal muscle in vivo. Am. J. Physiol. Endocrinol. Metab. 1991 261 5 E620 E627 10.1152/ajpendo.1991.261.5.E620 1951687
    [Google Scholar]
  65. Morissette M.R. Cook S.A. Buranasombati C. Rosenberg M.A. Rosenzweig A. Myostatin inhibits IGF-I-induced myotube hypertrophy through Akt. Am. J. Physiol. Cell Physiol. 2009 297 5 1124 1132 10.1152/ajpcell.00043.2009 19759331
    [Google Scholar]
  66. Horak M. Novak J. Bienertova-Vasku J. Muscle-specific microRNAs in skeletal muscle development. Dev. Biol. 2016 410 1 1 13 10.1016/j.ydbio.2015.12.013 26708096
    [Google Scholar]
  67. Luo W. Nie Q. Zhang X. MicroRNAs involved in skeletal muscle differentiation. J. Genet. Genomics 2013 40 3 107 116 10.1016/j.jgg.2013.02.002 23522383
    [Google Scholar]
  68. Wang Y. Ma J. Qiu W. Zhang J. Feng S. Zhou X. Wang X. Jin L. Long K. Liu L. Xiao W. Tang Q. Zhu L. Jiang Y. Li X. Li M. Guanidinoacetic acid regulates myogenic differentiation and muscle growth through miR-133a-3p and miR-1a-3p Co-mediated Akt/mTOR/S6K signaling pathway. Int. J. Mol. Sci. 2018 19 9 2837 10.3390/ijms19092837 30235878
    [Google Scholar]
  69. Ma G. Wang Y. Li Y. Cui L. Zhao Y. Zhao B. Li K. MiR-206, a key modulator of skeletal muscle development and disease. Int. J. Biol. Sci. 2015 11 3 345 352 10.7150/ijbs.10921 25678853
    [Google Scholar]
  70. Winbanks C.E. Beyer C. Hagg A. Qian H. Sepulveda P.V. Gregorevic P. miR-206 represses hypertrophy of myogenic cells but not muscle fibers via inhibition of HDAC4. PLoS One 2013 8 9 73589 10.1371/journal.pone.0073589 24023888
    [Google Scholar]
  71. Motohashi N. Alexander M.S. Shimizu-Motohashi Y. Myers J.A. Kawahara G. Kunkel L.M. Regulation of IRS1/Akt insulin signaling by microRNA-128a during myogenesis. J. Cell Sci. 2013 126 Pt 12 jcs.119966 10.1242/jcs.119966 23606743
    [Google Scholar]
  72. Hitachi K. Nakatani M. Tsuchida K. Myostatin signaling regulates Akt activity via the regulation of miR-486 expression. Int. J. Biochem. Cell Biol. 2014 47 93 103 10.1016/j.biocel.2013.12.003 24342526
    [Google Scholar]
  73. Fochi S. Giuriato G. De Simone T. Gomez-Lira M. Tamburin S. Del Piccolo L. Schena F. Venturelli M. Romanelli M.G. Regulation of micrornas in satellite cell renewal, muscle function, sarcopenia and the role of exercise. Int. J. Mol. Sci. 2020 21 18 6732 10.3390/ijms21186732 32937893
    [Google Scholar]
  74. Small E.M. O’Rourke J.R. Moresi V. Sutherland L.B. McAnally J. Gerard R.D. Richardson J.A. Olson E.N. Regulation of PI3-kinase/Akt signaling by muscle-enriched microRNA-486. Proc. Natl. Acad. Sci. USA 2010 107 9 4218 4223 10.1073/pnas.1000300107 20142475
    [Google Scholar]
  75. Gintoni I. Vassiliou S. Chrousos G.P. Yapijakis C. Review of disease-specific microRNAs by strategically bridging genetics and epigenetics in oral squamous cell carcinoma. Genes (Basel) 2023 14 8 1578 10.3390/genes14081578 37628629
    [Google Scholar]
  76. Marinho R. Alcântara P.S.M. Ottoch J.P. Seelaender M. Role of exosomal MicroRNAs and myomiRs in the development of cancer cachexia-associated muscle wasting. Front. Nutr. 2018 4 69 10.3389/fnut.2017.00069 29376055
    [Google Scholar]
  77. Wu S. Lin S. Zhang X. Alizada M. Wang L. Zheng Y. Ke Q. Xu J. Recent advances in cell-based and cell-free therapeutic approaches for sarcopenia. FASEB J. 2022 36 11 22614 10.1096/fj.202200675R 36250337
    [Google Scholar]
  78. Gordon R.A. Zumbro E.L. Guerin G.D. Sokoloski M.L. Ben-Ezra V. Brower C.S. Rigby R.B. Duplanty A.A. Both acute and consecutive days of formoterol stimulation influence myogenic, mitochondrial, and myomiR gene expression in human skeletal muscle cells. Muscles 2023 2 1 86 96 10.3390/muscles2010008
    [Google Scholar]
  79. Spiller H.A. James K.J. Scholzen S. Borys D.J. A descriptive study of adverse events from clenbuterol misuse and abuse for weight loss and bodybuilding. Subst. Abus. 2013 34 3 306 312 10.1080/08897077.2013.772083 23844963
    [Google Scholar]
  80. Stewart Coats A.J. Ho G.F. Prabhash K. von Haehling S. Tilson J. Brown R. Beadle J. Anker S.D. for and on behalf of the ACT-ONE study group Espindolol for the treatment and prevention of cachexia in patients with stage III/IV non-small cell lung cancer or colorectal cancer: A randomized, double-blind, placebo-controlled, international multicentre phase II study (the ACT-ONE trial). J. Cachexia Sarcopenia Muscle 2016 7 3 355 365 10.1002/jcsm.12126 27386169
    [Google Scholar]
  81. Stacchini C. Botrè F. Comunità F. de la Torre X. Dima A.P. Ricci M. Mazzarino M. Simultaneous detection of different chemical classes of selective androgen receptor modulators in urine by liquid chromatography-mass spectrometry-based techniques. J. Pharm. Biomed. Anal. 2021 195 113849 10.1016/j.jpba.2020.113849 33383501
    [Google Scholar]
  82. Wagener F. Guddat S. Görgens C. Angelis Y.S. Petrou M. Lagojda A. Kühne D. Thevis M. Investigations into the elimination profiles and metabolite ratios of micro-dosed selective androgen receptor modulator LGD-4033 for doping control purposes. Anal. Bioanal. Chem. 2022 414 2 1151 1162 10.1007/s00216‑021‑03740‑7 34734312
    [Google Scholar]
  83. Yuan Y. Lee J.S. Yost S.E. Frankel P.H. Ruel C. Egelston C.A. Guo W. Gillece J.D. Folkerts M. Reining L. Highlander S.K. Robinson K. Padam S. Martinez N. Tang A. Schmolze D. Waisman J. Sedrak M. Lee P.P. Mortimer J. A phase II clinical trial of pembrolizumab and enobosarm in patients with androgen receptor-positive metastatic triple-negative breast cancer. Oncologist 2021 26 2 99 e217 10.1002/onco.13583 33141975
    [Google Scholar]
  84. Hanada K. Fukasawa K. Hinata H. Imai S. Takayama K. Hirai H. Ohfusa R. Hayashi Y. Itoh F. Combination therapy with anamorelin and a myostatin inhibitor is advantageous for cancer cachexia in a mouse model. Cancer Sci. 2022 113 10 3547 3557 10.1111/cas.15491 35849084
    [Google Scholar]
  85. Miyake M. Hori S. Itami Y. Oda Y. Owari T. Fujii T. Ohnishi S. Morizawa Y. Gotoh D. Nakai Y. Anai S. Torimoto K. Tanaka N. Fujimoto K. Supplementary oral anamorelin mitigates anorexia and skeletal muscle atrophy induced by gemcitabine plus cisplatin systemic chemotherapy in a mouse model. Cancers (Basel) 2020 12 7 1942 10.3390/cancers12071942 32709007
    [Google Scholar]
  86. Porporato P.E. Filigheddu N. Reano S. Ferrara M. Angelino E. Gnocchi V.F. Prodam F. Ronchi G. Fagoonee S. Fornaro M. Chianale F. Baldanzi G. Surico N. Sinigaglia F. Perroteau I. Smith R.G. Sun Y. Geuna S. Graziani A. Acylated and unacylated ghrelin impair skeletal muscle atrophy in mice. J. Clin. Invest. 2013 123 2 611 622 10.1172/JCI39920 23281394
    [Google Scholar]
  87. Busquets S. Serpe R. Sirisi S. Toledo M. Coutinho J. Martínez R. Orpí M. López-Soriano F.J. Argilés J.M. Megestrol acetate: Its impact on muscle protein metabolism supports its use in cancer cachexia. Clin. Nutr. 2010 29 6 733 737 10.1016/j.clnu.2010.06.003 20621398
    [Google Scholar]
  88. Zhang L. Li M. Wang W. Yu W. Liu H. Wang K. Chang M. Deng C. Ji Y. Shen Y. Qi L. Sun H. Celecoxib alleviates denervation-induced muscle atrophy by suppressing inflammation and oxidative stress and improving microcirculation. Biochem. Pharmacol. 2022 203 115186 10.1016/j.bcp.2022.115186 35882305
    [Google Scholar]
  89. Okyayuz-Baklouti I. The effects of torbafylline on blood flow, pO2 and function of rat ischaemic skeletal muscle. Eur. J. Pharmacol. 1989 166 1 75 86 10.1016/0014‑2999(89)90685‑7 2530093
    [Google Scholar]
  90. Joshi R. Kadeer N. Sheriff S. Friend L.A. James J.H. Balasubramaniam A. Phosphodiesterase (PDE) inhibitor torbafylline (HWA 448) attenuates burn-induced rat skeletal muscle proteolysis through the PDE4/cAMP/EPAC/PI3K/Akt pathway. Mol. Cell. Endocrinol. 2014 393 1-2 152 163 10.1016/j.mce.2014.06.012 24973766
    [Google Scholar]
  91. Hinkle R.T. Dolan E. Cody D.B. Bauer M.B. Isfort R.J. Phosphodiesterase 4 inhibition reduces skeletal muscle atrophy. Muscle Nerve 2005 32 6 775 781 10.1002/mus.20416 16116651
    [Google Scholar]
  92. Rooks D. Swan T. Goswami B. Filosa L.A. Bunte O. Panchaud N. Coleman L.A. Miller R.R. Garcia Garayoa E. Praestgaard J. Perry R.G. Recknor C. Fogarty C.M. Arai H. Chen L.K. Hashimoto J. Chung Y.S. Vissing J. Laurent D. Petricoul O. Hemsley S. Lach-Trifilieff E. Papanicolaou D.A. Roubenoff R. Bimagrumab vs. optimized standard of care for treatment of sarcopenia in community-dwelling older adults. JAMA Netw. Open 2020 3 10 2020836 10.1001/jamanetworkopen.2020.20836 33074327
    [Google Scholar]
  93. Zhu J. Li Y. Lu A. Gharaibeh B. Ma J. Kobayashi T. Quintero A.J. Huard J. Follistatin improves skeletal muscle healing after injury and disease through an interaction with muscle regeneration, angiogenesis, and fibrosis. Am. J. Pathol. 2011 179 2 915 930 10.1016/j.ajpath.2011.04.008 21689628
    [Google Scholar]
  94. Winbanks C.E. Weeks K.L. Thomson R.E. Sepulveda P.V. Beyer C. Qian H. Chen J.L. Allen J.M. Lancaster G.I. Febbraio M.A. Harrison C.A. McMullen J.R. Chamberlain J.S. Gregorevic P. Follistatin-mediated skeletal muscle hypertrophy is regulated by Smad3 and mTOR independently of myostatin. J. Cell Biol. 2012 197 7 997 1008 10.1083/jcb.201109091 22711699
    [Google Scholar]
  95. Nakatani M. Takehara Y. Sugino H. Matsumoto M. Hashimoto O. Hasegawa Y. Murakami T. Uezumi A. Takeda S. Noji S. Sunada Y. Tsuchida K. Transgenic expression of a myostatin inhibitor derived from follistatin increases skeletal muscle mass and ameliorates dystrophic pathology in mdx mice. FASEB J. 2008 22 2 477 487 10.1096/fj.07‑8673com 17893249
    [Google Scholar]
  96. Liu S. Duan R. Wu Y. Du F. Zhang J. Li X. Guo S. Wang M. Zhang Q. Li Y. Li N. Effects of vaspin on insulin resistance in rats and underlying mechanisms. Sci. Rep. 2018 8 1 13542 10.1038/s41598‑018‑31923‑3 30202052
    [Google Scholar]
  97. Nicholson T. Church C. Tsintzas K. Jones R. Breen L. Davis E.T. Baker D.J. Jones S.W. Vaspin promotes insulin sensitivity in elderly muscle and is upregulated in obesity. J. Endocrinol. 2019 241 1 31 43 10.1530/JOE‑18‑0528 30721136
    [Google Scholar]
  98. Yadav A. Yadav S.S. Singh S. Dabur R. Natural products: Potential therapeutic agents to prevent skeletal muscle atrophy. Eur. J. Pharmacol. 2022 925 174995 10.1016/j.ejphar.2022.174995 35523319
    [Google Scholar]
  99. Bakhtiari N. Hosseinkhani S. Soleimani M. Hemmati R. Noori-Zadeh A. Javan M. Tashakor A. Short-term ursolic acid promotes skeletal muscle rejuvenation through enhancing of SIRT1 expression and satellite cells proliferation. Biomed. Pharmacother. 2016 78 185 196 10.1016/j.biopha.2016.01.010 26898441
    [Google Scholar]
  100. Bang H.S. Seo D.Y. Chung Y.M. Kim D.H. Lee S.J. Lee S.R. Kwak H.B. Kim T.N. Kim M. Oh K.M. Son Y.J. Kim S. Han J. Ursolic acid supplementation decreases markers of skeletal muscle damage during resistance training in resistance-trained men: a pilot study. Korean J. Physiol. Pharmacol. 2017 21 6 651 656 10.4196/kjpp.2017.21.6.651 29200908
    [Google Scholar]
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