Calpain Activation and Organ Failure in Sepsis: Molecular Insights and Therapeutic Perspectives

Abstract

Sepsis is a severe systemic response to infection; its ensuing organ failure commonly portends an unfavorable prognosis. Despite the fact that sepsis has been studied for decades, the molecular mechanisms underlying sepsis-induced organ dysfunction remain elusive and more complex than previously thought, and effective therapies are extremely limited. Calpain is a type of calcium-dependent cysteine protease that includes dozens of isoforms. Calpain, as well as its endogenous-specific inhibitor calpastatin, have been implicated in the pathogenesis of sepsis-induced organ dysfunction. Further, there is an accumulating body of evidence supporting the beneficial effect of calpain inhibition or regulation on multiple organ failure in sepsis. Better understanding of the underlying molecular mechanisms is helpful in the development of calpain/calpastatin-targeted therapeutic strategies to protect against sepsis-induced organ injury. The aim of this review is to summarize the recent literature and evidence surrounding the role of the calpain/calpastatin system in the process of organ dysfunction caused by sepsis-including regulation of cell death, modulation of inflammatory response, and disruption of critical proteins-to provide guidance for future research and therapy development.

Importance of the Innate Immune Response in Skeletal Muscle to Sepsis-Induced Alterations in Protein Balance

“…However, when sustained, the loss of muscle mass impairs muscle contractile function (4) and increases morbidity and mortality (7,8). This reduction in LBM results from an imbalance between the rate of protein synthesis, which is generally observed to be decreased, and the rate of protein degradation (e.g., proteasome activity, calpain activity, and autophagy), which is often elevated (3,65). Although sepsis and inflammatory cytokines are capable of altering basal rates of protein synthesis and degradation, they also antagonize nutrient-, hormone-, and contraction-induced changes in both sides of the protein balance equation resulting in a condition referred to as anabolic resistance (3,4,66).…”

Genome-wide CRISPR screen reveals genetic modifiers of Ca2+-mediated cell death

“…Cyclosporine A) have failed in clinical trials (21,22). Similarly, caspase, calpain, and CaMKII inhibitors have been long sought to prevent cell death in ischemic, septic, and traumatic injury but adverse effects, lack of selectivity, and lack of efficacy have precluded their use in patients (19,(23)(24)(25)(26)(27). These examples highlight that our understanding of Ca 2+ in cell death is incomplete and that identifying other targetable mediators of Ca 2+ toxicity remains as a critical unmet need.…”

What's New in Shock, July 2021?

“…We start the issue with an excellent review from Huang et al (1) which offers an in-depth review of the importance of the calpain protease in sepsis-induced multi-organ failure (MOF). The authors portray calpain as a linchpin molecule with downstream effects on a variety of inflammatory mediators and immune cells.…”