title: STAT3 signaling controls satellite cell expansion and skeletal muscle repair.
abstract: The progressive loss of muscle regenerative capacity with age or disease results in part from a decline in the number and function of satellite cells, the direct cellular contributors to muscle repair. However, little is known about the molecular effectors underlying satellite cell impairment and depletion. Elevated levels of inflammatory cytokines, including interleukin-6 (IL-6), are associated with both age-related and muscle-wasting conditions. The levels of STAT3, a downstream effector of IL-6, are also elevated with muscle wasting, and STAT3 has been implicated in the regulation of self-renewal and stem cell fate in several tissues. Here we show that IL-6-activated Stat3 signaling regulates satellite cell behavior, promoting myogenic lineage progression through myogenic differentiation 1 (Myod1) regulation. Conditional ablation of Stat3 in Pax7-expressing satellite cells resulted in their increased expansion during regeneration, but compromised myogenic differentiation prevented the contribution of these cells to regenerating myofibers. In contrast, transient Stat3 inhibition promoted satellite cell expansion and enhanced tissue repair in both aged and dystrophic muscle. The effects of STAT3 inhibition on cell fate and proliferation were conserved in human myoblasts. The results of this study indicate that pharmacological manipulation of STAT3 activity can be used to counteract the functional exhaustion of satellite cells in pathological conditions, thereby maintaining the endogenous regenerative response and ameliorating muscle-wasting diseases.
authors.affiliation: 1] Graduate School of Biomedical Sciences, Sanford-Burnham Medical Research Institute, La Jolla, California, USA. [2].
authors.forename: Matthew Timothy
authors.initials: MT
authors.lastname: Tierney
authors.affiliation: 1] Development, Aging and Regeneration Program (DARe), Sanford-Burnham Medical Research Institute, La Jolla, California, USA. [2] Life Sciences Solutions, Thermo Fisher Scientific, Carlsbad, California, USA. [3].
authors.forename: Tufan
authors.initials: T
authors.lastname: Aydogdu
authors.affiliation: Development, Aging and Regeneration Program (DARe), Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Sala
authors.affiliation: Development, Aging and Regeneration Program (DARe), Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Barbora
authors.initials: B
authors.lastname: Malecova
authors.affiliation: Development, Aging and Regeneration Program (DARe), Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Sole
authors.initials: S
authors.lastname: Gatto
authors.affiliation: 1] Development, Aging and Regeneration Program (DARe), Sanford-Burnham Medical Research Institute, La Jolla, California, USA. [2] Epigenetics and Regenerative Medicine, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy.
authors.forename: Pier Lorenzo
authors.initials: PL
authors.lastname: Puri
authors.affiliation: 1] Epigenetics and Regenerative Medicine, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy. [2] Institute of Translational Pharmacology, National Research Council of Italy, Rome, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Latella
authors.affiliation: Development, Aging and Regeneration Program (DARe), Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Sacco
mesh_terms: D000375:Aging / Q000235:genetics / Q000473:pathology / Q000502:physiology; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D024510:Muscle Development / Q000502:physiology; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D051763:PAX7 Transcription Factor / Q000378:metabolism; D012038:Regeneration / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D051763:PAX7 Transcription Factor; C497322:Pax7 protein, mouse; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse