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HMGB1 Initiates Inflammasome Mediated Pyroptosis, Atrophy and Adverse Muscle Remodeling
Author(s) -
Narasimhulu Chandrakala Aluganti,
Singla Dinender K.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.04521
Subject(s) - pyroptosis , inflammasome , hmgb1 , medicine , endocrinology , muscle atrophy , fibrosis , diabetic cardiomyopathy , diabetes mellitus , atrophy , caspase 1 , inflammation , skeletal muscle , heart failure , cardiomyopathy
Diabetic cardiomyopathy and associated muscle toxicity is a major concern, therefore it is essential to understand the mechanism and pathophysiology of diabetic skeletal muscle which remains unknown. The current study is undertaken to investigate whether there is an upregulation of High Mobility Group‐B1 (HMGB1) that initiates inflammation induced pyroptosis and involves adverse muscle remodeling. C57BL/6J mice (10±2 weeks) were divided into 2‐groups (n=16/group; 8males and 8females); control (saline) and STZ treated (200mg/kg body weight) via i.p. injection. Diabetes was established by determining the increased levels of glucose in STZ animals. At Day‐42, muscle function was determined using Grip‐strength meter and Rotarod. Mice were euthanized and gastrocnemius (GM) muscle was harvested. Pyroptotic initiator HMGB1, activator TLR4, inflammasome marker (NLRP3), and pyroptotic markers (caspase1, IL1β, IL‐18 and GSDMD) were examined using immunohistochemistry, western blotting and RT‐PCR. Muscle atrophy and fibrosis was examined histologically. IL‐6 inflammatory cytokine levels were analyzed using ELISA. We observed a significant (p<0.05) increase in glucose levels, pyroptotic initiator HMGB1, inflammasome and pyroptotic markers in GM of STZ administered mice as compared to control. A significant (p<0.05) decrease in myofibrillar area was observed in diabetic mice. Atrophy was also confirmed by significant increase (p<0.05) in MuRF1 gene expression. Interstitial and vascular fibrosis was significantly (p<0.05) increased in STZ group versus control. Moreover, a significant decrease (p<0.05) in muscle functions were observed in diabetic animals compared to control. Furthermore, a significant (p<0.05) increase in plasma IL‐6 levels were observed in diabetic mice. In conclusion, our data suggest that diabetes involves a novel form of inflammation induced pyroptosis that leads to muscle dysfunction. Further therapeutic approaches need to be developed to target pyroptosis in diabetes.