AMP-activated Protein Kinase Stimulates Warburg-like Glycolysis and Activation of Satellite Cells during Muscle Regeneration

• Published in: The Journal of biological chemistry 2015-10, Vol.290 (44), p.26445-26456
• Main Authors: Fu, Xing, Zhu, Mei-Jun, Dodson, Mike V., Du, Min
• Format: Article
• Language: English
• Subjects: AMP-activated kinase (AMPK); AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animals; Cell Biology; Glycolysis - physiology; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Mice; Mice, Knockout; Muscle, Skeletal - cytology; Muscle, Skeletal - physiology; myogenesis; regeneration; Regeneration - physiology; satellite cell; Satellite Cells, Skeletal Muscle - cytology; Satellite Cells, Skeletal Muscle - enzymology; skeletal muscle; Sonic Hedgehog (SHH)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.665232

Satellite cells are the major myogenic stem cells residing inside skeletal muscle and are indispensable for muscle regeneration. Satellite cells remain largely quiescent but are rapidly activated in response to muscle injury, and the derived myogenic cells then fuse to repair damaged muscle fibers or form new muscle fibers. However, mechanisms eliciting metabolic activation, an inseparable step for satellite cell activation following muscle injury, have not been defined. We found that a noncanonical Sonic Hedgehog (Shh) pathway is rapidly activated in response to muscle injury, which activates AMPK and induces a Warburg-like glycolysis in satellite cells. AMPKα1 is the dominant AMPKα isoform expressed in satellite cells, and AMPKα1 deficiency in satellite cells impairs their activation and myogenic differentiation during muscle regeneration. Drugs activating noncanonical Shh promote proliferation of satellite cells, which is abolished because of satellite cell-specific AMPKα1 knock-out. Taken together, AMPKα1 is a critical mediator linking noncanonical Shh pathway to Warburg-like glycolysis in satellite cells, which is required for satellite activation and muscle regeneration. Background: The mechanisms eliciting metabolic activation in satellite cells are unclear. Results: Noncanonical Sonic Hedgehog is activated following muscle injury, which activates AMPKα1 to induce Warburg-like glycolysis and promote satellite cell activation and proliferation. Conclusion: AMPKα1 is required for Warburg-like glycolysis in satellite cells, which promotes satellite cell activation and muscle regeneration. Significance: AMPK promotes satellite cell activation during muscle regeneration.