STAT3 signaling controls satellite cell expansion and skeletal muscle repair

• Published in: Nature medicine Vol. 20; no. 10; pp. 1182 - 1186
• Main Authors: Tierney, Matthew Timothy, Aydogdu, Tufan, Sala, David, Malecova, Barbora, Gatto, Sole, Puri, Pier Lorenzo, Latella, Lucia, Sacco, Alessandra
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2014; Nature Publishing Group
• Subjects: 13/31; 14/19; 38/1; 38/15; 38/77; 42/100; 631/532/2439; 631/80/86/2368; 64/60; Ablation; Age; Aging - genetics; Aging - pathology; Aging - physiology; Analysis; Animals; Biomedicine; Cancer Research; Cell fate; Cell Proliferation; Cell self-renewal; Cells, Cultured; Cellular biology; Cytokines; Depletion; Differentiation; Gene expression; Humans; Infectious Diseases; Inflammation; Interleukin 6; letter; Male; Metabolic Diseases; Mice; Mice, Inbred C57BL; Mice, Inbred mdx; Mice, Knockout; Molecular Medicine; Muscle Development - physiology; Muscles; Musculoskeletal system; Myoblasts; MyoD Protein - genetics; MyoD Protein - metabolism; Neurosciences; PAX7 Transcription Factor - metabolism; Physiological aspects; Regeneration; Regeneration - physiology; Repair; Satellite cells; Satellite Cells, Skeletal Muscle - cytology; Satellite Cells, Skeletal Muscle - physiology; Signal Transduction; Signaling; Skeletal muscle; Stat3 protein; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - physiology; Stem cells
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.3656

In two new reports, STAT3 signaling is shown to be increased in adult muscle satellite cells, and its inhibition improves muscle regeneration. 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 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 . 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 12 , 13 , 14 , 15 . The levels of STAT3, a downstream effector of IL-6, are also elevated with muscle wasting 16 , 17 , and STAT3 has been implicated in the regulation of self-renewal and stem cell fate in several tissues 18 , 19 , 20 , 21 . 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.