The new mechanism of iron death leading to skeletal muscle aging

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The new mechanism of iron death leading to skeletal muscle aging

Researchese found that the new mechanism of iron death leading to skeletal muscle aging, providing new ideas for prevention and treatment, providing new ideas for the prevention and treatment of skeletal muscle aging. 

Exercise can effectively reduce and improve the risk of a variety of chronic diseases including type 2 diabetes, obesity, and muscular dystrophy. Although skeletal muscle is the largest and most important component of the human motion system, it plays a vital role in the regulation of body motion and glucose and lipid metabolism, but how to promote the repair of skeletal muscle damage and reduce muscle loss in elderly individuals is still It is an open question.

herefore, studying the molecular mechanism of muscle atrophy in elderly individuals and the development of effective drugs to prevent muscle loss will help improve the exercise performance of elderly individuals and accelerate the realization of “healthy aging”.

Recently, the research team of Xie Liwei from the Institute of Microbiology of Guangdong Academy of Sciences and the State Key Laboratory of Applied Microbiology in South China published a titled “Transferrin receptor 1 ablation in satellite cells impedes skeletal muscle regeneration through activation of” in the Journal of Cachexia, Sarcopenia and Muscle. “ferroptosis” research paper.

This study reported for the first time that the functional transformation of aging skeletal muscle Tfr1-Slc39a14 can promote the absorption and accumulation of skeletal muscle iron and induce the occurrence of skeletal muscle iron death. The findings of this study can provide new targets and intervention programs for the early prevention and intervention of skeletal muscle aging.

Pattern of iron accumulation and iron death in aging skeletal muscle

Programmed cell death (PCD) is a ubiquitous behavior in the development of organisms in which cells in multicellular organisms commit collective suicide according to a predetermined procedure. It includes two types of apoptosis and autophagy. It is an important process to eliminate unnecessary or senescent cells and dead cells during the development/regeneration of the body and organs.

In addition to being the main organ of exercise, skeletal muscle is also involved in regulating the metabolism of the whole body. Muscle cell death occurs in many forms, such as apoptosis, necrosis, and autophagy. Under regenerative conditions, cell death, clearance and regeneration are precisely regulated, and abnormal regulation of these processes can lead to muscular dystrophy and muscle loss. Skeletal muscle necrosis can occur under various non-pathogenic conditions, such as malnutrition and local blood circulation disorders. Specifically, acute or physiological injury can activate apoptosis, and apoptosis is affected by several key molecules (such as anti-apoptotic oncoprotein Bcl2, Caspase 3 and death receptor Fas/Apo1/Cd953)
adjust.

This process is accompanied by the infiltration of inflammatory cells, especially macrophages. In the initial stage of regeneration, M1 macrophages participate in the secretion of cytokines, the removal of fibrous fragments, and the iron cycle of the microenvironment in the process of skeletal muscle regeneration. Important. After the removal of fiber debris is completed, M1 is transformed into M2 macrophages, which help to secrete anti-inflammatory cytokines and promote regeneration.

The growth and regeneration of skeletal muscle depend on the adult stem cells formed from the mesoderm-satellite cells
(Satellite cells, SCs). The resting satellite cells are located between the basal layer of muscle fibers and the plasma membrane, maintaining self-renewal and high regeneration potential. When the body receives external stimulation or muscle damage, resting satellite cells can be activated, enter the cell cycle, proliferate and differentiate, form new myotubes, and then participate in muscle repair.

Ferroptosis is a newly established and unique pathway of cell death, which is involved in the occurrence and development of many diseases, such as cancer, cardiomyopathy caused by ischemia-reperfusion, degenerative diseases and stroke. Iron death is dependent on iron ions and reactive oxygen species (ROS)
, The death mode of cell damage caused by the accumulation of lipid peroxides.

Recent studies have shown that during the occurrence and development of cardiomyopathy, the up-regulation of Hmox1 mediated by Nrf2 contributes to heme degradation and release of iron, leading to lipid peroxidation on the mitochondrial lipid bilayer, which is the heart damage caused by iron death The main mechanism. Other diseases, such as liver fibrosis or cirrhosis, are also associated with iron-dependent cell death. Patients with liver cirrhosis are diagnosed with higher iron content and lipid peroxidation, but lower transferrin (Trf) content. Under a high-iron diet, liver-specific Trf-deficient mice are susceptible to liver fibrosis caused by iron death. In addition, no iron death has been reported in other organs such as skeletal muscle.

The growth and regeneration of skeletal muscle is accompanied by the precise regulation of various nutrients, such as amino acids and minerals. As nutrients, trace minerals play an important role in the physiological function and energy metabolism of skeletal muscle. Iron is an essential trace mineral that maintains the normal physiological functions of skeletal muscles
(Such as muscle cell differentiation, skeletal muscle growth and myoglobin biosynthesis, etc.) necessary. Generally speaking, iron is absorbed by the epithelial cells of the small intestine, enters the blood circulation, binds to the transferrin receptor 1 (Tfr1) on the membrane surface in the form of transferrin-bound iron (TBI), and is then endocytosed and absorbed. Tfr1 protein is commonly found in tissues such as liver, fat and skeletal muscle.

In this study, transcriptome sequencing (RNAseq) was used to compare and analyze the skeletal muscle gene expression profiles of C57 mice at different ages (2, 8, 40, 60 and 80 weeks old). Data analysis showed that the expression of Tfr1 and Slc39a14 were compared with those of mice Negative and positive correlations between age growth. And Tfr1 protein expression is down-regulated in skeletal muscle and muscle satellite cells of aging mice (~80 weeks old), and iron ions accumulate in aging skeletal muscle, increase synthesis of unsaturated fatty acids, and glutathione metabolism disorder, which further induces aging Mouse skeletal muscle iron death (down-regulation of Gpx4 and Fth1 expression); intraperitoneal injection of iron death inhibitor (Ferrostatin-1) can significantly inhibit skeletal muscle iron death in aging mice, and significantly improve the motor function of aging mice (movement distance and time) ).

In addition, this study also reported for the first time that with skeletal muscle aging, the expression of Tfr1 decreased and the expression of Slc39a14 increased, and it was enriched on the surface of the skeletal muscle cell membrane of aging mice, increasing the absorption of non-transferrin-bound iron (NTBI), resulting in bones The accumulation of free iron ions induces iron death of skeletal muscle.

Skeletal muscle iron accumulation in aging mice induces skeletal muscle iron death

In order to further study the molecular mechanism of the low expression of Tfr1 in muscle satellite cells of aging mice, we constructed muscle satellite cell-specific Tfr1 knockout mice and conditionally induced Tfr1 knockout by intraperitoneal injection of tamoxifen. After skeletal muscle injury and regeneration, we It was found that mice with Tfr1 knockout of muscle satellite cells had severe aplastic disorders, and it was accompanied by iron accumulation, unsaturated fatty acid synthesis, glutathione metabolism disorders and lipid peroxidation, which induced skeletal muscle iron death.

Tfr1 knockout of muscle satellite cells induces iron death of skeletal muscle and delays skeletal muscle regeneration

To further clarify the physiological significance of skeletal muscle iron death, the research team compared and analyzed the transcriptome sequencing data of skeletal muscle and muscle satellite cell-specific Tfr1 knockout mice in aging and young mice. 2203 shared biological targets were identified in the data set. Among them, 72 genes were significantly up-regulated, and 132 genes were significantly down-regulated. Through the KEGG pathway enrichment analysis, there are 2203 biomarkers in common. Iron death, glutathione metabolism and fatty acid biosynthesis are significantly enriched in aging skeletal muscle, indicating that skeletal muscle aging may be accompanied by iron death. Assess serum and TA muscle non-heme iron levels. Compared with young mice, old mice have significantly higher iron levels.

The expression of Tfr1, Nrf2, Gpx4 and Fth1 is lower in aging TA muscle, but the expression of Slc39a14 is higher (TA total protein). Most importantly, the TA membrane Tfr1 protein was reduced to an undetectable level, but the expression level of Scl39a14 was significantly higher. These observations indicate that lc39a14 may promote the absorption of NTBI in elderly skeletal muscles, leading to iron accumulation in TA muscles, which activates iron death.

At the same time, after intramuscular injection of CTX, Ferrostatin-1, a ferroptosis inhibitor, was injected intraperitoneally into old mice to induce injury and regeneration. Thirty days after the injection, the mice’s running ability, such as running time and distance, was significantly improved. By detecting whether the iron death pathway in the skeletal muscle of the aging population is activated, the fluorescence quantitative PCR is used to detect the young (less than 30 years old)
Iron metabolism, fat metabolism and iron death gene expression in skeletal muscle of aging (over 60 years old) individuals. These data indicate that, in addition to known forms of cell death (including apoptosis, autophagy and necrosis), iron death is An unrecognized and reported form of cell death in elderly skeletal muscle.

Iron death of aging skeletal muscle affects skeletal muscle physiological function

All in all, the current research shows that the lack of Tfr1 in muscle satellite cells can lead to skeletal muscle dysplasia and induce iron death. This process is accompanied by a functional transformation of Tfr1-Slc39a14, which mediates non-transferrin-bound iron (NTBI) absorption and leads to the accumulation of free iron ions in skeletal muscle. The same phenotype was also observed in the skeletal muscle of aging mice, which provides new targets and new ideas for the development of therapeutic strategies to prevent skeletal muscle aging and related diseases.

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