title: Evidence for the involvement of the CXCL12 system in the adaptation of skeletal muscles to physical exercise.
abstract: The chemokine CXCL12 and its primary receptor, CXCR4, not only promote developmental myogenesis, but also muscle regeneration. CXCL12 chemoattracts CXCR4-positive satellite cells/blood-borne progenitors to the injured muscle, promotes myoblast fusion, partially with existing myofibers, and induces angiogenesis in regenerating muscles. Interestingly, the mechanisms underlying muscle regeneration are in part identical to those involved in muscular adaptation to intensive physical exercise. These similarities now prompted us to determine whether physical exercise would impact the CXCL12 system in skeletal muscle. We found that CXCL12 and CXCR4 are upregulated in the gastrocnemius muscle of rats that underwent a four-week period of constrained daily running exercise on a treadmill. Double-staining experiments confirmed that CXCL12 and CXCR4 are predominantly expressed in MyHC-positive muscle fibers. Moreover, these training-dependent increases in CXCL12 and CXCR4 expression also occurred in rats with surgical coronary artery occlusion, implying that the muscular CXCL12 system is still active in skeletal myopathy resulting from chronic heart failure. Expression of the second CXCL12 receptor, CXCR7, which presumably acts as a scavenger receptor in muscle, was not affected by training. Attempts to dissect the molecular events underlying the training-dependent effects of CXCL12 revealed that the CXCL12-CXCR4 axis activates anabolic mTOR-p70S6K signaling and prevents upregulation of the catabolic ubiquitin ligase MurF-1 in C2C12 myotubes, eventually increasing myotube diameters. Together, these findings point to a pivotal role of the CXCL12-CXCR4 axis in exercise-induced muscle maintenance and/or growth.
authors.affiliation: Institute of Anatomy, Medical Faculty, University of Leipzig, Liebigstr. 13, 04103 Leipzig, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Puchert
authors.affiliation: Department of Internal Medicine/Cardiology, University of Leipzig, Heart Center, Strümpelstraβe 39, 04289 Leipzig, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Adams
authors.affiliation: Department of Internal Medicine/Cardiology, University of Leipzig, Heart Center, Strümpelstraβe 39, 04289 Leipzig, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Linke
authors.affiliation: Institute of Anatomy, Medical Faculty, University of Leipzig, Liebigstr. 13, 04103 Leipzig, Germany. Electronic address: engj@medizin.uni-leipzig.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Engele
mesh_terms: D000199:Actins / Q000378:metabolism; D000222:Adaptation, Physiological; D000818:Animals; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000378:metabolism*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000502:physiology*; D051763:PAX7 Transcription Factor / Q000378:metabolism; D010805:Physical Conditioning, Animal; D011921:Rats, Inbred WKY; D019718:Receptors, CXCR4 / Q000378:metabolism; D012508:Sarcolemma / Q000378:metabolism; D015398:Signal Transduction; D000070584:Tripartite Motif Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D000199:Actins; D054377:Chemokine CXCL12; D009124:Muscle Proteins; D051763:PAX7 Transcription Factor; D019718:Receptors, CXCR4; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; C498862:Acta2 protein, rat; C499084:Trim63 protein, mouse
keywords: Anabolic pathways; C2C12 myotubes; CXCL12; CXCR4; Catabolic pathways; Muscle fibers