title: Transforming Growth Factor Beta (TGF-β) Is a Muscle Biomarker of Disease Progression in ALS and Correlates with Smad Expression.
abstract: We recently identified Smads1, 5 and 8 as muscle biomarkers in human ALS. In the ALS mouse, these markers are elevated and track disease progression. Smads are signal transducers and become activated upon receptor engagement of ligands from the TGF-β superfamily. Here, we sought to characterize ligands linked to activation of Smads in ALS muscle and their role as biomarkers of disease progression. RNA sequencing data of ALS muscle samples were mined for TGF-β superfamily ligands. Candidate targets were validated by qRT-PCR in a large cohort of human ALS muscle biopsy samples and in the G93A SOD1 mouse. Protein expression was evaluated by Western blot, ELISA and immunohistochemistry. C2C12 muscle cells were used to assess Smad activation and induction. TGF-β1, 2 and 3 mRNAs were increased in ALS muscle samples compared to controls and correlated with muscle strength and Smads1, 2, 5 and 8. In the G93A SOD1 mouse, the temporal pattern of TGF-β expression paralleled the Smads and increased with disease progression. TGF-β1 immunoreactivity was detected in mononuclear cells surrounding muscle fibers in ALS samples. In muscle cells, TGF-β ligands were capable of activating Smads. In conclusion, TGF-β1, 2 and 3 are novel biomarkers of ALS in skeletal muscle. Their correlation with weakness in human ALS and their progressive increase with advancing disease in the ALS mouse suggest that they, as with the Smads, can track disease progression. These ligands are capable of upregulating and activating Smads and thus may contribute to the Smad signaling pathway in ALS muscle.
authors.affiliation: Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Birmingham VA Medical Center, Birmingham, Alabama, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Si
authors.affiliation: Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Soojin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Xiangqin
authors.initials: X
authors.lastname: Cui
authors.affiliation: Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Birmingham VA Medical Center, Birmingham, Alabama, United States of America.
authors.forename: Lei
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Shin J
authors.initials: SJ
authors.lastname: Oh
authors.affiliation: Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Tina
authors.initials: T
authors.lastname: Anderson
authors.affiliation: Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Mohammad
authors.initials: M
authors.lastname: AlSharabati
authors.affiliation: Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Kazamel
authors.affiliation: Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Laura
authors.initials: L
authors.lastname: Volpicelli-Daley
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Marcas M
authors.initials: MM
authors.lastname: Bamman
authors.affiliation: Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Birmingham VA Medical Center, Birmingham, Alabama, United States of America; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Peter H
authors.initials: PH
authors.lastname: King
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000032:analysis*; D015153:Blotting, Western; D002478:Cells, Cultured; D018450:Disease Progression; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000502:physiology*; D000072105:Superoxide Dismutase-1; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger; C000606290:SOD1 protein, human; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1