Preclinical characterization of the JAK/STAT inhibitor SGI-1252 on skeletal muscle function, morphology, and satellite cell content

• Published in: PloS one 2018-06, Vol.13 (6), p.e0198611-e0198611
• Main Authors: Sorensen, Jacob R, Fuqua, Jordan D, Deyhle, Michael R, Parmley, Jacob, Skousen, Caitlin, Hancock, Chad, Parcell, Allen C, Hyldahl, Robert D
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Biology and Life Sciences; Cell Differentiation - drug effects; Cell Proliferation - drug effects; Cells (biology); Contraction; Cytology; Dextrose; Diamines - pharmacology; Drug Administration Schedule; Drug Evaluation, Preclinical; Fatigue; Fuel consumption; Gastrocnemius muscle; Glucose; Health aspects; Humans; Inhibitors; Janus Kinases - antagonists & inhibitors; Janus Kinases - metabolism; Medicine and Health Sciences; Metabolism; Mice; Mice, Inbred C57BL; Morphology; Muscle function; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscles; Musculoskeletal system; Myoblasts; Myoblasts - cytology; Myoblasts - drug effects; Myoblasts - metabolism; MyoD protein; MyoD Protein - metabolism; Myogenin; Myogenin - metabolism; PAX7 Transcription Factor - metabolism; Phosphorylation; Phosphorylation - drug effects; Physiological aspects; Physiology; Protein Kinase Inhibitors - pharmacology; Proteins; Pyrimidines - pharmacology; Satellite cells; Satellite Cells, Skeletal Muscle - cytology; Satellite Cells, Skeletal Muscle - drug effects; Satellite Cells, Skeletal Muscle - metabolism; Satellites; Signal transduction; Skeletal muscle; STAT Transcription Factors - antagonists & inhibitors; STAT Transcription Factors - metabolism; Stat3 protein; Strength training; Ventilation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0198611

Recent studies have highlighted the JAK/STAT signaling pathway in the regulation of muscle satellite cell behavior. Herein we report preclinical studies designed to characterize the effects of a novel JAK/STAT inhibitor on plantar flexor skeletal muscle function, morphology, and satellite cell content. The compound, SGI-1252, was administered orally (400mg/kg) in a 10% dextrose solution to wild type mice (n = 6) 3 times per week for 8 weeks. A control group (n = 6) received only the dextrose solution. SGI-1252 was well tolerated, as animals displayed similar weight gain over the 8-week treatment period. Following treatment, fatigue in the gastrocnemius-soleus-plantaris complex was greater in the SGI-1252 mice during a 300 second tetanic contraction bout (p = 0.035), though both the rate of fatigue and maximal force production were similar. SGI-1252 treated mice had increased type II myofiber cross-sectional area (1434.8 ± 225.4 vs 1754.7 ± 138.5 μm2), along with an increase in wet muscle mass (125.45 ± 5.46 vs 139.6 ± 12.34 mg, p = 0.032) of the gastrocnemius relative to vehicle treated mice. SGI-1252 treatment reduced gastrocnemius STAT3 phosphorylation 53% (94.79 ± 45.9 vs 44.5 ± 6.1 MFI) and significantly increased the concentration of Pax7+ satellite cells (2589.2 ± 105.5 vs 2859.4 ± 177.5 SC/mm3) in the gastrocnemius. SGI-1252 treatment suppressed MyoD (p = 0.013) and Myogenin (p