Pyroptosis and Sarcopenia: Frontier Perspective of Disease Mechanism

Abstract

With global ageing, sarcopenia, as an age-related disease, has brought a heavy burden to individuals and society. Increasing attention has been given to further exploring the morbidity mechanism and intervention measures for sarcopenia. Pyroptosis, also known as cellular inflammatory necrosis, is a kind of regulated cell death that plays a role in the ageing progress at the cellular level. It is closely related to age-related diseases such as cardiovascular diseases, Alzheimer's disease, osteoarthritis, and sarcopenia. In the process of ageing, aggravated oxidative stress and poor skeletal muscle perfusion in ageing muscle tissues can activate the nod-like receptor (NLRP) family to trigger pyroptosis. Chronic inflammation is a representative characteristic of ageing. The levels of inflammatory factors such as TNF-α may activate the signaling pathways of pyroptosis by the NF-κB-GSDMD axis, which remains to be further studied. Autophagy is a protective mechanism in maintaining the integrity of intracellular organelles and the survival of cells in adverse conditions. The autophagy of skeletal muscle cells can inhibit the activation of the pyroptosis pathway to some extent. A profound understanding of the mechanism of pyroptosis in sarcopenia may help to identify new therapeutic targets in the future. This review article focuses on the role of pyroptosis in the development and progression of sarcopenia.

Keywords: NLRP; aging; gasdermin; pyroptosis; sarcopenia.

Figure 1

The autophagy of skeletal muscle cells in normal conditions can inhibit the activation of the pyroptosis to some extent. Autophagy can inhibit the activation of the nod-like receptor 3 (NLRP3) inflammasome by removing the damaged mitochondria, inhibiting the production of oxidizing agents, and promoting the degradation of inflammation components, such as pro-Interleukin-1β (pro-IL-1β), NLRP3, caspase-1, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC).

Figure 2

An increase in the level of oxidative stress caused by aging may trigger pyroptosis in skeletal muscle cells by the nuclear factor—kappaB (NF-κB)—gasdermin D (GSDMD) Axis. NF-κB is a transcription factor of GSDMD. When NLRP3 inflammasomes are activated by multiple activation mechanisms, the GSDMD will be subsequently cleaved, causing the release of the N-terminus of the GSDMD, which can form nanoscale pores in the cell membrane leading to the pyroptosis of skeletal muscle cells.

Figure 3

Possible interventions may focus on interfering with the signaling pathway of pyroptosis. a. Melatonin can reduce the expression of pyroptosis-related genes in the influence of endothelial cells. b. Treatment with bone morphogenetic protein 7 (BMP-7) reduces caspase-1, Interleukin-1β (IL-1β), and Interleukin-18 (IL-18), markers of pyroptosis cascade. c. Carbenoxolone can attenuate intracellular lipid accumulation and inflammation aggravation in the liver and skeletal muscle in obese mice induced by the high-fat diet by regulating the IkappaB-alpha (IκB-α)/ nuclear factor—kappaB (NF-κB) pathway and the nod-like receptor 3 (NLRP3) inflammasome. d. Treatment of trimetazidine can reverse the pyroptosis of muscle in C2C12 mouses induced by dexamethasone.