HMGB1 in Septic Muscle Atrophy: Roles and Therapeutic Potential for Muscle Atrophy and Regeneration

Abstract

Currently, the treatment of septic myopathy presents significant challenges with implications for increased mortality rates and prolonged hospitalizations. Effective therapeutic strategies for septic myopathy remain elusive, highlighting an urgent need for novel therapeutic approaches. High-mobility group box 1 (HMGB1) is a conserved nonhistone nuclear protein that is released passively from deceased cells or actively secreted by activated immune cells, influencing both infectious and noninfectious inflammatory responses. Studies have indicated that HMGB1 likely plays a pivotal role in the pathogenesis of septic myopathy by crucial pathways associated with muscle atrophy and contributing to muscle regeneration under certain conditions. This review aims to summarize the possible mechanisms of HMGB1 in muscle atrophy and its potential in muscle regeneration, providing a theoretical basis for HMGB1 treatment of septic myopathy. Research shows that the dual role of HMGB1 is related to its specific forms, which are influenced to varying degrees by environmental factors. HMGB1 is a key participant in septic muscle atrophy, whereas HMGB1 shows therapeutic potential in muscle regeneration. One key mechanism by which HMGB1 contributes to septic muscle atrophy is through the exacerbation of inflammation. HMGB1 can amplify the inflammatory response by promoting the release of pro-inflammatory cytokines, which further damages muscle tissue. HMGB1 is also involved in promoting cell death in sepsis, which contributes to muscle degradation. Another important mechanism is the regulation of protein degradation systems. HMGB1 can activate the ubiquitin–proteasome system and autophagy–lysosome pathway, both of which are crucial for the breakdown of muscle proteins during atrophy. Conversely, targeting HMGB1 has shown the potential to ameliorate muscle atrophy in various diseases. For instance, HMGB1 has been shown to promote muscle vascular regeneration, modify stem cell status and enhance stem cell migration and differentiation, all of which are beneficial for muscle repair and recovery. Pharmacological inhibition of HMGB1 has been explored, with several drugs demonstrating efficacy in reducing inflammation and muscle degradation in sepsis models. These findings suggest that HMGB1 inhibition could be a viable therapeutic approach for septic myopathy. However, the function of promoting muscle regeneration in septic myopathy needs further research. HMGB1 emerges as a promising therapeutic target for the treatment of muscle atrophy in sepsis. This review focuses on identifying the correlation between HMGB1 and septic myopathy, analysing the possible role of HMGB1 in disease development and examining the feasibility of HMGB1 as a therapeutic target.