Muscle atrophy is a common complication of many chronic diseases including heart failure, cancer cachexia, aging, etc. Unhealthy habits and usage of hormones such as dexamethasone can also lead to muscle atrophy. However, the underlying mechanisms of muscle atrophy are not completely understood. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), play vital roles in muscle atrophy. This review mainly discusses the regulation of ncRNAs in muscle atrophy induced by various factors such as heart failure, cancer cachexia, aging, chronic obstructive pulmonary disease (COPD), peripheral nerve injury (PNI), chronic kidney disease (CKD), unhealthy habits, and usage of hormones; highlights the findings of ncRNAs as common regulators in multiple types of muscle atrophy; and summarizes current therapies and underlying mechanisms for muscle atrophy. This review will deepen the understanding of skeletal muscle biology and provide new strategies and insights into gene therapy for muscle atrophy.

Adipose tissue loss seen with cancer-associated cachexia (CAC) may functionally drive cachexia development. Using single-cell transcriptomics, we unveil a large-scale comprehensive cellular census of the stromal vascular fraction of white adipose tissues from patients with or without CAC. We report depot- and disease-specific clusters and developmental trajectories of adipose progenitors and immune cells. In adipose tissues with CAC, clear pro-inflammatory transitions were discovered in adipose progenitors, macrophages and CD8⁺ T cells, with dramatically remodeled cell interactome among these cells, implicating a synergistic effect in promoting tissue inflammation. Remarkably, activated CD8⁺ T cells contributed specifically to increased IFNG expression in adipose tissues from cachexia patients, and displayed a significant pro-catabolic effect on adipocytes in vitro; whereas macrophage depletion resulted in significantly rescued adipose catabolism and alleviated cachexia in a CAC animal model. Taken together, these results unveil causative mechanisms underlying the chronical inflammation and adipose wasting in CAC.

Cardiomyocyte apoptosis has been characterized as one of the major mechanisms underlying doxorubicin (DOX)-induced cardiomyopathy. MicroRNA-21-5p (miR-21-5p) was reported to mitigate ischemia-induced cardiomyocyte apoptosis and cardiac injury. However, to our knowledge, the functional role of miR-21-5p in DOX-induced cardiomyopathy is unclear. In this study, we explored the role of miR-21-5p in DOX-induced cardiac injury. The expression level of miR-21-5p was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Dual luciferase reporter assay was used to verify the potential target gene of miR-21-5p. The apoptosis rate of NRCMs was detected by TUNEL staining assay. Western blot analysis was used to detect the protein expression levels of Bax, Bcl-2, Caspase3, cleaved-Caspase3 and BTG2. For animal studies, mice were injected with AAV9-miR-21-5p or AAV9-Empty viruses, and treated with DOX at a dose of 5 mg/kg per week through intraperitoneally administration. After 4 weeks of DOX treatment, mice were subjected to echocardiography to measure the left ventricular ejection fraction (EF) and fractional shortening (FS). Results showed that miR-21-5p was upregulated in both DOX-treated primary cardiomyocytes and mouse heart tissues. Interestingly, enhanced miR-21-5p expression inhibited DOX-induced cardiomyocyte apoptosis and oxidative stress, while decreased miR-21-5p expression promoted cardiomyocyte apoptosis and oxidative stress. Furthermore, cardiac overexpression of miR-21-5p protected against DOX-induced cardiac injury. The mechanistic study indicated that BTG2 was a target gene of miR-21-5p. The anti-apoptotic effect of miR-21-5p could be inhibited by BTG2 overexpression. Conversely, inhibition of BTG2 rescued the pro-apoptotic effect of miR-21-5p inhibitor. Taken together, our study showed that miR-21-5p could prevent DOX-induced cardiomyopathy by downregulating BTG2.

Diabetic cardiomyopathy (DCM) is highly prevalent and increases the risk of heart failure and sudden death. Therefore, proper and effective treatments for DCM are in urgent demand. Danlou tablet (Dan) is reported to confer protective effects on several heart diseases. However, to our knowledge, whether Dan provides protection against DCM is unclear. In this study, we explored the effect of Dan on DCM with the in vitro DCM model using AC16 cardiomyocytes. We found that Dan treatment significantly reduced cardiomyocyte apoptosis and oxidative stress in high-glucose (HG)-treated cardiomyocytes, as evidenced by decreased Annexin V-FITC+ cardiomyocytes, intracellular reactive oxygen species (ROS) levels, Bax/Bcl2 ratio, and cleaved-Caspase3/Caspase3 ratio. Interestingly, Dan treatment caused a decreased level of microRNA-34a (miR-34a), which could enhance cardiomyocyte apoptosis. Furthermore, miR-34a mimic blocked Dan's effect in apoptosis prevention. Finally, we observed that the miR-34a mimic effectively decreased the level of sirtuin 1 (SIRT1), while the miR-34a inhibitor increased the level of SIRT1. And downregulation of SIRT1 effectively reversed the effect of miR-34a inhibitor on cardiomyocyte apoptosis. Taken together, our study showed that Dan prevented HG-induced cardiomyocyte apoptosis through downregulating miR-34a and upregulating SIRT1. Our study has provided experimental support for the potential use of Dan in treating DCM. Further detailed study of Dan and the underlying mechanisms may shed light on the prevention and treatment of DCM.

Identification of safe and effective compounds to increase or activate UCP1 expression in brown or white adipocytes remains a potent therapeutic strategy to combat obesity. Here we reported that, glyburide, one of the FDA-approved drugs currently used to treat type 2 diabetes, can significantly enhance UCP1 expression in both brown and white adipocytes. Glyburide-fed mice exhibited a clear resistance to high-fat diet-induced obesity, reduced blood triglyceride level, and increased UCP1 expression in brown adipose tissue. Moreover, in situ injection of glyburide to inguinal white adipose tissue remarkably enhanced UCP1 expression and increased thermogenesis. Further mechanistic studies indicated that the glyburide effect in UCP1 expression in adipocytes was KATP channel independent but may involve the regulation of the Ca2+-Calcineurin-NFAT signal pathway. Overall, our findings revealed the significant effects of glyburide in regulating UCP1 expression and thermogenesis in adipocytes, which can be potentially repurposed to treat obesity.