Xbp1 Promotes Skeletal Muscle Regeneration And Growth In A Cell Non-autonomous Manner: 1887 Board #43 May 30 2:00 PM - 3:30 PM

Kyle R. Bohnert1,2 and Ashok Kumar1 1University of Louisville 2St. Ambrose University PURPOSE: Skeletal muscle exhibits a remarkable capacity for regeneration following injury. However, the molecular mechanisms governing skeletal muscle regeneration remain poorly understood. X-box binding protein (XBP1) is a downstream target of the endoplasmic reticulum (ER) stress inducer inositol-requiring enzyme 1 (IRE1). The purpose of this study was to determine the role of XBP1 in regulation of skeletal muscle regeneration and growth. METHODS: To investigate the role of XBP1 in the regulation of skeletal muscle regeneration and growth, we generated muscle-specific knockout (KO) mice of XBP1. Control and KO mice were then injected with 100 μl of 1.2% BaCl2 into the tibialis anterior muscle to induce a necrotic injury. In a separate experiment, control and KO mice were subjected to the synergistic ablation model of overload hypertrophy of the plantaris muscle. Skeletal muscle was collected and analyzed using histological and biochemical techniques. RESULTS: Protein levels of XBP1 are increased in regenerating muscle fibers (1 ± 0.21 vs. 17.66 ± 13.9, p < 0.05). Moreover, genetic deletion of XBP1 inhibits regeneration due to reducing the number 2 or more centrally nucleated fibers (44.2 ± 2.8 vs. 30.7 ± 1.7, p < 0.05) and the number of satellite cells per 100 myofibers (26.5 ± 2.4 vs. 19.3 ± 1.4, p < 0.05). Furthermore, targeted ablation of XBP1 inhibits increases in cross-sectional area of myofibers due to a functional overload in adult mice (2266.3 ± 304.4 μm2 vs. 1779.5 ± 150.9 μm2, p < 0.05). Interestingly, XBP1 does not affect the rate of protein synthesis during muscle growth. Rather, deletion of XBP1 prevents skeletal muscle hypertrophy through reducing the total number of satellite cells per 100 myofibers (9.5 ± 1.1 vs. 5.8 ± 0.8, p < 0.05). CONCLUSIONS: The results of the present study suggest that XBP1 is necessary for skeletal muscle regeneration and adult skeletal muscle hypertrophy. Furthermore, XBP1-mediated signaling in myofibers promotes satellite cell proliferation and fusion in a non-cell autonomous manner. More investigations are needed to further understand the mechanisms, especially gene network that XBP1 regulates during skeletal muscle formation and growth.