title: Molecular targets of androgen signaling that characterize skeletal muscle recovery and regeneration.
abstract: The high regenerative capacity of adult skeletal muscle relies on a self-renewing depot of adult stem cells, termed muscle satellite cells (MSCs). Androgens, known mediators of overall body composition and specifically skeletal muscle mass, have been shown to regulate MSCs. The possible overlapping function of androgen regulation of muscle growth and MSC activation has not been carefully investigated with regards to muscle regeneration.Therefore, the aim of this study was to examine coinciding androgen-mediated genetic changes in an in vitro MSC model and clinically relevant in vivo models. A gene signature was established via microarray analysis for androgen-mediated MSC engagement and highlighted several markers including follistatin (FST), IGF-1, C-X-C chemokine receptor 4 (CXCR4), hepatocyte growth factor (HGF) and glucocorticoid receptor (GR). In an in vivo muscle atrophy model, androgen re-supplementation significantly increased muscle size and expression of IGF-1, FST, and HGF, while significantly decreasing expression of GR. Biphasic gene expression profiles over the 7-day re-supplementation period identified temporal androgen regulation of molecular targets involved in satellite cell engagement into myogenesis. In a muscle injury model, removal of androgens resulted in delayed muscle recovery and regeneration. Modifications in the androgen signaling gene signature, along with reduced Pax7 and MyoD expression, suggested that limited MSC activation and increased inflammation contributed to the delayed regeneration. However, enhanced MSC activation in the androgen-deplete mouse injury model was driven by an androgen receptor (AR) agonist. These results provide novel in vitro and in vivo evidence describing molecular targets of androgen signaling, while also increasing support for translational use of AR agonists in skeletal muscle recovery and regeneration.
authors.affiliation: Musculoskeletal Research (JGM, BCY, HB, PS, HUB, VK), Lead Optimization Biology (KC), Lilly Research Labs, Eli Lilly & Company, Indianapolis, IN, USA .
authors.forename: James G
authors.initials: JG
authors.lastname: MacKrell
authors.affiliation: Musculoskeletal Research (JGM, BCY, HB, PS, HUB, VK), Lead Optimization Biology (KC), Lilly Research Labs, Eli Lilly & Company, Indianapolis, IN, USA .
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Yaden
authors.affiliation: Musculoskeletal Research (JGM, BCY, HB, PS, HUB, VK), Lead Optimization Biology (KC), Lilly Research Labs, Eli Lilly & Company, Indianapolis, IN, USA .
authors.forename: Heather
authors.initials: H
authors.lastname: Bullock
authors.affiliation: Musculoskeletal Research (JGM, BCY, HB, PS, HUB, VK), Lead Optimization Biology (KC), Lilly Research Labs, Eli Lilly & Company, Indianapolis, IN, USA .
authors.forename: Keyue
authors.initials: K
authors.lastname: Chen
authors.affiliation: Musculoskeletal Research (JGM, BCY, HB, PS, HUB, VK), Lead Optimization Biology (KC), Lilly Research Labs, Eli Lilly & Company, Indianapolis, IN, USA .
authors.forename: Pamela
authors.initials: P
authors.lastname: Shetler
authors.affiliation: Musculoskeletal Research (JGM, BCY, HB, PS, HUB, VK), Lead Optimization Biology (KC), Lilly Research Labs, Eli Lilly & Company, Indianapolis, IN, USA .
authors.forename: Henry U
authors.initials: HU
authors.lastname: Bryant
authors.affiliation: Musculoskeletal Research (JGM, BCY, HB, PS, HUB, VK), Lead Optimization Biology (KC), Lilly Research Labs, Eli Lilly & Company, Indianapolis, IN, USA .
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Krishnan
mesh_terms: D000728:Androgens / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D038681:Follistatin / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D008024:Ligands; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology* / Q000187:drug effects / Q000293:injuries / Q000502:physiology*; D051381:Rats; D011944:Receptors, Androgen / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics; D012038:Regeneration / Q000187:drug effects; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000728:Androgens; D015415:Biomarkers; D038681:Follistatin; D008024:Ligands; D011944:Receptors, Androgen; D019718:Receptors, CXCR4; D011965:Receptors, Glucocorticoid
keywords: Androgen; Levator Ani; Regeneration; Satellite Cells; Skeletal Muscle