Mesenchymal Stem Cell-Derived Exosomes Protect Muscle Loss by miR-145-5p Activity Targeting Activin A Receptors

Abstract

Skeletal muscle mass is decreased under a wide range of pathologic conditions. In particular, chemotherapy is well known for inducing muscle loss and atrophy. Previous studies using tonsil-derived mesenchymal stem cells (T-MSCs) or a T-MSC-conditioned medium showed effective recovery of total body weight in the chemotherapy-preconditioned bone marrow transplantation mouse model. This study investigated whether extracellular vesicles of T-MSCs, such as exosomes, are a key player in the recovery of body weight and skeletal muscle mass in chemotherapy-treated mice. T-MSC exosomes transplantation significantly decreased loss of total body weight and muscle mass in the busulfan-cyclophosphamide conditioning regimen in BALB/c recipient mice containing elevated serum activin A. Additionally, T-MSC exosomes rescued impaired C2C12 cell differentiation in the presence of activin A in vitro. We found that T-MSC exosomes possess abundant miR-145-5p, which targets activin A receptors, ACVR2A, and ACVR1B. Indeed, T-MSC exosomes rescue muscle atrophy both in vivo and in vitro via miR-145-5p dependent manner. These results suggest that T-MSC exosomes have therapeutic potential to maintain or improve skeletal muscle mass in various activin A elevated pathologic conditions.

Extracellular Vesicles and Their Zeta Potential as Future Markers Associated with Nutrition and Molecular Biomarkers in Breast Cancer

“…The presence of miRNA-145 in EVs has been documented in small EVs in several diseases including cancer, such as ovarian cancer [ 104 ], where miRNA-145 has even been suggested as the most promising biomarker for the preoperative diagnosis of ovarian cancer [ 105 ]. miRNA-145 has also been reported in urinary EVs from prostate cancer patients [ 106 ], in vascular smooth muscle cells [ 107 ], colorectal cancer [ 108 ], hepatocarcinoma [ 109 ], cerebral injury [ 110 ], as well as its active role in the recovery of skeletal muscle mass in mice with chemotherapy [ 111 ], osteoarthritis [ 112 ], and pancreatic cancer [ 113 ].…”

The role of extracellular vesicles in skeletal muscle wasting

“…While most of the reported EV‐associated miRNAs play promotive roles in the process of muscle wasting, a few studies focus on the inhibitive functions of those miRNAs. For instance, miR‐145‐5p present in EVs of tonsil‐derived mesenchymal stem cells (T‐MSCs) was found to be able to rescue muscle wasting both in vitro and in vivo 53 . MiR‐145‐5p can target two of the activin A receptors, ACVR2A and ACVR1B, therefore inhibiting the binding of activin A and its downstream processes, which regulate gene transcriptions of proteolytic enzymes 53 .…”

“…For instance, miR‐145‐5p present in EVs of tonsil‐derived mesenchymal stem cells (T‐MSCs) was found to be able to rescue muscle wasting both in vitro and in vivo 53 . MiR‐145‐5p can target two of the activin A receptors, ACVR2A and ACVR1B, therefore inhibiting the binding of activin A and its downstream processes, which regulate gene transcriptions of proteolytic enzymes 53 . And in this way, EV‐transferred miR‐145‐5p can inhibit muscle proteolysis and rescue skeletal muscle wasting induced by activin A 53 .…”

“…MiR‐145‐5p can target two of the activin A receptors, ACVR2A and ACVR1B, therefore inhibiting the binding of activin A and its downstream processes, which regulate gene transcriptions of proteolytic enzymes 53 . And in this way, EV‐transferred miR‐145‐5p can inhibit muscle proteolysis and rescue skeletal muscle wasting induced by activin A 53 . In another study, Li et al demonstrated that miR‐486‐5p internalized by bone marrow mesenchymal stem cell (BMSC)‐EVs attenuated muscle wasting caused by dexamethasone by downregulating the nuclear translocation of FoxO1, which is a potent regulator of muscle proteolysis, suggesting that EV‐associated miRNA can play a protective role in muscle wasting 54 .…”

Role of exosomes and exosomal microRNA in muscle–Kidney crosstalk in chronic kidney disease

“…In another study, the authors showed that activin A induced Smad2/3 and FoxO1 nuclear translocation and transcriptional upregulation of Atrogin-1 and MuRF-1 genes, which resulted in muscle atrophy. Exosomal miR-145-5p released from tonsil-derived mesenchymal stem cells has been shown to maintain or improve skeletal muscle mass in various activin-A-elevated pathologic conditions ( Cho et al, 2021 ).…”