Mitsugumin 53 promotes mitochondrial autophagy through regulating Ambra1 expression in C2C12 myoblast cells

Abstract

In this study, we investigated the function of Mitsugumin 53 (MG53) in regulation of mitochondrial autophagy in skeletal muscle cells and explored its potential application in the prevention and treatment of skeletal muscle atrophy in rats with chronic kidney disease (CKD). The expression of autophagy beclin 1 regulator 1 (Ambra1) and MG53 in skeletal muscles of 5/6 nephrectomized rats was measured, and the effect of MG53 on mitochondrial autophagy of C2C12 myoblasts was investigated by in vitro experiments. Our results show the expression of Ambra1 and MG53 in the skeletal muscle of CKD rats was significantly decreased. In vitro experiments showed that MG53 overexpression could promote the expression of Ambra1 and mitochondrial autophagy in C2C12 cells, suggesting that recovery of autophagy by MG53 intervention may help remove abnormal mitochondria and alleviate muscle atrophy. In conclusion, the damaged or functionally incomplete mitochondria in CKD rats could not be effectively removed, which may be related to the low activity of Ambra1. In vitro experiments showed that MG53 overexpression could promote the expression of Ambra1 in C2C12 cells and restore mitochondrial autophagy. Whether MG53 can help remove abnormal mitochondria and relieve CKD‐induced muscle atrophy requires further study.

Mitophagy in Cancer: A Tale of Adaptation

“…For example, TNFα and IL-6 trans-signaling induced by the cancer cells accelerates autophagy/mitophagy in skeletal muscle, hereby promoting cachexia [326,336]. Intriguingly, AMBRA1 has been associated with muscular atrophy [337], and has been recently shown to modulate the IL6-STAT3 axis [338], although no direct link to cancer-associated cachexia has been drawn yet.…”

MG53: A potential therapeutic target for kidney disease

“…MG53 relieves CKD‐induced muscle atrophy by restoring mitochondrial autophagy. 42 Signaling crosstalk between different organ systems plays an important role in maintaining the normal function of the body. 43 , 44 Many proteins or cytokines are involved in this crosstalk between signaling, such as activin A, a protein characterized as an endogenous antagonist to the hormone inhibin, and MG53.…”

“… 43 , 44 Many proteins or cytokines are involved in this crosstalk between signaling, such as activin A, a protein characterized as an endogenous antagonist to the hormone inhibin, and MG53. 42 , 45 These proteins or cytokines secreted from one organ can lead to functional disorders in other organs and even exacerbate organ disease. 46 Studies have reported that skeletal muscle atrophy and muscle dysfunction are causes of CKD.…”

“…MG53 overexpression promotes mitochondrial autophagy in vitro, indicating that MG53 alleviates muscle atrophy in CKD by removing abnormal mitochondria. 42 …”

Multi-Cellular Functions of MG53 in Muscle Calcium Signaling and Regeneration

“…Since HFD feeding induces an elevation in mitochondrial activity as a result of increased production of ROS, MG53 is thought to play a protective role (Ma et al, 2015). More recently, MG53 overexpression was also suggested to promote mitochondrial autophagy to help remove damaged mitochondria to relieve CKD-induced muscle atrophy in skeletal muscle cells by upregulating autophagy and beclin 1 regulator 1 (Ambra1), a key regulator involved in autophagosome formation (Lijie et al, 2019). These studies herald the opening of new avenues regarding the widening reach of the activity of MG53.…”