title: Small molecule adiponectin receptor agonist GTDF protects against skeletal muscle atrophy.
abstract: Skeletal muscle atrophy is a debilitating response to several major diseases, muscle disuse and chronic steroid treatment for which currently no therapy is available. Since adiponectin signaling plays key roles in muscle energetics, we assessed if globular adiponectin (gAd) or the small molecule adiponectin mimetic 6-C-β-D-glucopyranosyl-(2S,3S)-(+)-5,7,3',4'-tetrahydroxydihydroflavonol (GTDF) could ameliorate muscle atrophy. Both GTDF and gAd induced C2C12 myoblast differentiation. GTDF and gAd effectively prevented reduction in myotube area and suppressed the expressions of atrophy markers; atrogin-1 and muscle ring finger protein-1 (MuRF1) in models of steroid, cytokine and starvation -induced muscle atrophy. The protective effects of GTDF and gAd were routed through AMPK and AKT activation and thereby stimulation of PPAR gamma coactivator 1α and inhibition of forkhead box O transcription factors. Finally, GTDF and gAd mitigated dexamethasone-induced muscle atrophy in vivo. Together, our results demonstrate that activating adiponectin signaling may be an effective therapeutic strategy against skeletal muscle atrophy.
authors.affiliation: Division of Biochemistry, CSIR-Central Drug Research Institute, 10, Janakipuram Extn, Sitapur Road, Lucknow 226031, India.
authors.forename: Abhishek Kumar
authors.initials: AK
authors.lastname: Singh
authors.affiliation: Division of Molecular and Structural Biology, CSIR-Central Drug Research Institute, 10, Janakipuram Extn, Sitapur Road, Lucknow 226031, India.
authors.forename: Sonal
authors.initials: S
authors.lastname: Shree
authors.affiliation: Division of Biochemistry, CSIR-Central Drug Research Institute, 10, Janakipuram Extn, Sitapur Road, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), CSIR- Central Drug Research Institute Campus, 10, Janakipuram Extn, Sitapur Road, Lucknow 226031, India.
authors.forename: Sourav
authors.initials: S
authors.lastname: Chattopadhyay
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, 10, Janakipuram Extn, Sitapur Road, Lucknow 226031, India.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Division of Biochemistry, CSIR-Central Drug Research Institute, 10, Janakipuram Extn, Sitapur Road, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), CSIR- Central Drug Research Institute Campus, 10, Janakipuram Extn, Sitapur Road, Lucknow 226031, India.
authors.forename: Anagha
authors.initials: A
authors.lastname: Gurjar
authors.affiliation: Division of Biochemistry, CSIR-Central Drug Research Institute, 10, Janakipuram Extn, Sitapur Road, Lucknow 226031, India.
authors.forename: Sapana
authors.initials: S
authors.lastname: Kushwaha
authors.affiliation: Division of Biochemistry, CSIR-Central Drug Research Institute, 10, Janakipuram Extn, Sitapur Road, Lucknow 226031, India.
authors.forename: Harish
authors.initials: H
authors.lastname: Kumar
authors.affiliation: Division of Biochemistry, CSIR-Central Drug Research Institute, 10, Janakipuram Extn, Sitapur Road, Lucknow 226031, India.
authors.forename: Arun Kumar
authors.initials: AK
authors.lastname: Trivedi
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, 10, Janakipuram Extn, Sitapur Road, Lucknow 226031, India.
authors.forename: Naibedya
authors.initials: N
authors.lastname: Chattopadhyay
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, 10, Janakipuram Extn, Sitapur Road, Lucknow 226031, India.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Maurya
authors.affiliation: Division of Molecular and Structural Biology, CSIR-Central Drug Research Institute, 10, Janakipuram Extn, Sitapur Road, Lucknow 226031, India.
authors.forename: Ravishankar
authors.initials: R
authors.lastname: Ramachandran
authors.affiliation: Division of Biochemistry, CSIR-Central Drug Research Institute, 10, Janakipuram Extn, Sitapur Road, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), CSIR- Central Drug Research Institute Campus, 10, Janakipuram Extn, Sitapur Road, Lucknow 226031, India. Electronic address: sanyal@cdri.res.in.
authors.forename: Sabyasachi
authors.initials: S
authors.lastname: Sanyal
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D052242:Adiponectin / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D003907:Dexamethasone; D005260:Female; D044948:Flavonols / Q000494:pharmacology / Q000627:therapeutic use*; D005960:Glucosides / Q000494:pharmacology / Q000627:therapeutic use*; D008070:Lipopolysaccharides; D051379:Mice; D024510:Muscle Development / Q000187:drug effects; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000473:pathology*; D009133:Muscular Atrophy / Q000188:drug therapy* / Q000473:pathology; D032446:Myoblasts / Q000187:drug effects / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D054419:Receptors, Adiponectin / Q000819:agonists* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology / Q000627:therapeutic use*; D000070584:Tripartite Motif Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: C000624537:6-C-glucopyranosyl-5,7,3',4'-tetrahydroxydihydroflavonol; D052242:Adiponectin; D044948:Flavonols; D005960:Glucosides; D008070:Lipopolysaccharides; D009124:Muscle Proteins; D020011:Protective Agents; D054419:Receptors, Adiponectin; D054852:Small Molecule Libraries; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; D000263:Adenylate Kinase; D002118:Calcium
keywords: Adiponectin; Adiponectin receptor; FoxO; GTDF; PGC-1α; Skeletal muscle atrophy