The role of mitochondrial dynamics and mitophagy in skeletal muscle atrophy: from molecular mechanisms to therapeutic insights.

Skeletal muscle is the largest metabolic organ of the human body. Maintaining the best quality control and functional integrity of mitochondria is essential for the health of skeletal muscle. However, mitochondrial dysfunction characterized by mitochondrial dynamic imbalance and mitophagy disruption can lead to varying degrees of muscle atrophy, but the underlying mechanism of action is still unclear. Although mitochondrial dynamics and mitophagy are two different mitochondrial quality control mechanisms, a large amount of evidence has indicated that they are interrelated and mutually regulated. The former maintains the balance of the mitochondrial network, eliminates damaged or aged mitochondria, and enables cells to survive normally. The latter degrades damaged or aged mitochondria through the lysosomal pathway, ensuring cellular functional health and metabolic homeostasis. Skeletal muscle atrophy is considered an urgent global health issue. Understanding and gaining knowledge about muscle atrophy caused by mitochondrial dysfunction, particularly focusing on mitochondrial dynamics and mitochondrial autophagy, can greatly contribute to the prevention and treatment of muscle atrophy. In this review, we critically summarize the recent research progress on mitochondrial dynamics and mitophagy in skeletal muscle atrophy, and expound on the intrinsic molecular mechanism of skeletal muscle atrophy caused by mitochondrial dynamics and mitophagy. Importantly, we emphasize the potential of targeting mitochondrial dynamics and mitophagy as therapeutic strategies for the prevention and treatment of muscle atrophy, including pharmacological treatment and exercise therapy, and summarize effective methods for the treatment of skeletal muscle atrophy.

A Novel tRNA-Derived Fragment, tRFGlnCTG, Regulates Angiogenesis by Targeting Antxr1 mRNA.

As a novel non-coding RNA with important functions corresponding to various cellular stresses, the function of tRFs in angiogenesis remains unclear. Firstly, small RNA sequencing was performed on normal and post-muscle injury mouse tibialis anterior muscle to identify and analyse differentially expressed tRF/tiRNA. tRNA GlnCTG-derived fragments (tRFGlnCTG) were found to be overexpressed in high abundance in the damaged muscle. Subsequent in vitro experiments revealed that the overexpression of tRFGlnCTG suppressed the vascular endothelial cells' viability, cell cycle G1/S transition, proliferation, migration, and tube-formation capacity. Similarly, in vivo experiments showed that the tRFGlnCTG decreased the relative mRNA levels of vascular endothelial cell markers and pro-angiogenic factors and reduced the proportion of CD31-positive cells. Finally, luciferase activity analysis confirmed that the tRFGlnCTG directly targeted the 3'UTR of Antxr1, leading to a significant reduction in the mRNA expression of the target gene. These results suggest that tRFGlnCTG is a key regulator of vascular endothelial cell function. The results provide a new idea for further exploration of the molecular mechanisms that regulate angiogenesis.

Dynamic changes in the transcriptome of tRNA-derived small RNAs related with fat metabolism.

The prevalence of obesity and overweight is steadily rising, posing a significant global challenge for humanity. The fundamental cause of obesity and overweight lies in the abnormal accumulation of adipose tissue. While numerous regulatory factors related to fat deposition have been identified in previous studies, a considerable number of regulatory mechanisms remain unknown. tRNA-derived small RNAs (tsRNAs), a novel class of non-coding RNAs, have emerged as significant regulators in various biological processes. In this study, we obtained small RNA sequencing data from subcutaneous white adipose tissue and omental white adipose tissue of lean and obese pigs. In addition, we similarly obtained tsRNAs profiles from scapular brown adipose tissue (BAT), inguinal white adipose tissue (iWAT) and epigonadal white adipose tissue (eWAT) of normal mice. Finally, we successfully identified a large number of expressed tsRNAs in each tissue type and identified tsRNAs conserved in different adipose tissues of pigs and mice. These datasets will be a valuable resource for elucidating the epigenetic mechanisms of fat deposition.

miRNAs derived from cobra venom exosomes contribute to the cobra envenomation.

Currently, there is an increasing amount of evidence indicating that exosomes and the miRNAs they contain are crucial players in various biological processes. However, the role of exosomes and miRNAs in snake venom during the envenomation process remains largely unknown. In this study, fresh venom from Naja atra of different ages (2-month-old, 1-year-old, and 5-year-old) was collected, and exosomes were isolated through ultracentrifugation. The study found that exosomes with inactivated proteins and enzymes can still cause symptoms similar to cobra envenomation, indicating that substances other than proteins and enzymes in exosomes may also play an essential role in cobra envenomation. Furthermore, the expression profiles of isolated exosome miRNAs were analyzed. The study showed that a large number of miRNAs were co-expressed and abundant in cobra venom exosomes (CV-exosomes) of different ages, including miR-2904, which had high expression abundance and specific sequences. The specific miR-2094 derived from CV-exosomes (CV-exo-miR-2904) was overexpressed both in vitro and in vivo. As a result, CV-exo-miR-2904 induced symptoms similar to cobra envenomation in mice and caused liver damage, demonstrating that it plays a crucial role in cobra envenomation. These results reveal that CV-exosomes and the miRNAs they contain play a significant regulatory role in cobra envenomation. Our findings provide new insights for the treatment of cobra bites and the development of snake venom-based medicines.

The global perspective on peroxisome proliferator-activated receptor γ (PPARγ) in ectopic fat deposition: A review.

Excessive expansion of adipocytes can have unhealthy consequences as excess free fatty acids enter other tissues and cause ectopic fat deposition by resynthesizing triglycerides. This lipid accumulation in various tissues is harmful and can increase the risk of related metabolic diseases such as type II diabetes, cardiovascular disease, and insulin resistance. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily that play a key role in energy metabolism as fatty acid metabolism sensors, and peroxisome proliferator-activated receptor γ (PPARγ) is the main subtype responsible for fat cell differentiation and adipogenesis. In this paper, we introduce the main structure and function of PPARγ and its regulatory role in the process of lipogenesis in the liver, kidney, skeletal muscle, and pancreas. This information can serve as a reference for further understanding the regulatory mechanisms and measures of the PPAR family in the process of ectopic fat deposition.

tsRNA Landscape and Potential Function Network in Subcutaneous and Visceral Pig Adipose Tissue.

Noncoding RNAs (ncRNAs) called tsRNAs (tRNA-derived short RNAs) have the ability to regulate gene expression. The information on tsRNAs in fat tissue is, however, limited. By sequencing, identifying, and analyzing tsRNAs using pigs as animal models, this research reports for the first time the characteristics of tsRNAs in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). A total of 474 tsRNAs, 20 and 21 of which were particularly expressed in VAT and SAT, respectively, were found in WAT. According to the analysis of the tsRNA/miRNA/mRNA co-expression network, the tsRNAs with differential expression were primarily engaged in the endocrine and immune systems, which fall under the classification of organic systems, as well as the global and overview maps and lipid metropolis, which fall under the category of metabolism. This research also discovered a connection between the activity of the host tRNA engaged in translation and the production of tsRNAs. This research also discovered that tRF-Gly-GCC-037/tRF-Gly-GCC-042/tRF-Gly-CCC-016 and miR-218a/miR281b may be involved in the regulation of fatty acid metabolism in adipose tissue through SCD based on the tsRNA/miRNA/mRNA/fatty acid network. In conclusion, our findings enrich the understanding of ncRNAs in WAT metabolism and health regulation, as well as reveal the differences between SAT and VAT at the level of tsRNAs.

Cooked pork-derived exosome nanovesicles mediate metabolic disorder-microRNA could be the culprit.

In this study, exosomes from cooked meat were extracted by ultra-high-speed centrifugation. Approximately 80% of exosome vesicles were within 20-200 nm. In addition, the surface biomarkers of isolated exosomes were evaluated using flow cytometry. Further studies showed the exosomal microRNA profiles were different among cooked porcine muscle, fat and liver. Cooked pork-derived exosomes were chronically administered to ICR mice by drinking for 80 days. The mice plasma levels of miR-1, miR-133a-3p, miR-206 and miR-99a were increased to varying degrees after drinking exosome enriched water. Furthermore, GTT and ITT results confirmed an abnormal glucose metabolism and insulin resistance in mice. Moreover, the lipid droplets were significantly increased in the mice liver. A transcriptome analysis performed with mice liver samples identified 446 differentially expressed genes (DEGs). Functional enrichment analysis found that DEGs were enriched in metabolic pathways. Overall, the results suggest that microRNAs derived form cooked pork may function as a critical regulator of metabolic disorder in mice.

tRNA-derived small RNA, 5'tiRNA-Gly-CCC, promotes skeletal muscle regeneration through the inflammatory response.

BACKGROUND: Increasing evidence shows that tRNA-derived small RNAs (tsRNAs) are not only by-products of transfer RNAs, but they participate in numerous cellular metabolic processes. However, the role of tsRNAs in skeletal muscle regeneration remains unknown. METHODS: Small RNA sequencing revealed the relationship between tsRNAs and skeletal muscle injury. The dynamic expression level of 5'tiRNA-Gly after muscle injury was confirmed by real-time quantitative PCR (q-PCR). In addition, q-PCR, flow cytometry, the 5-ethynyl-2'-deoxyuridine (Edu), cell counting kit-8, western blotting and immunofluorescence were used to explore the biological function of 5'tiRNA-Gly. Bioinformatics analysis and dual-luciferase reporter assay were used to further explore the mechanism of action under the biological function of 5'tiRNA-Gly. RESULTS: Transcriptome analysis revealed that tsRNAs were significantly enriched during inflammatory response immediately after muscle injury. Interestingly, we found that 5'tiRNA-Gly was significantly up-regulated after muscle injury (P < 0.0001) and had a strong positive correlation with inflammation in vivo. In vitro experiments showed that 5'tiRNA-Gly promoted the mRNA expression of proinflammatory cytokines (IL-1ß, P = 0.0468; IL-6, P = 0.0369) and the macrophages of M1 markers (TNF-α, P = 0.0102; CD80, P = 0.0056; MCP-1, P = 0.0002). On the contrary, 5'tiRNA-Gly inhibited the mRNA expression of anti-inflammatory cytokines (IL-4, P = 0.0009; IL-10, P = 0.0007; IL-13, P = 0.0008) and the mRNA expression of M2 markers (TGF-ß1, P = 0.0016; ARG1, P = 0.0083). Flow cytometry showed that 5'tiRNA-Gly promoted the percentage of CD86+ macrophages (16%, P = 0.011) but inhibited that of CD206+ macrophages (10.5%, P = 0.012). Immunofluorescence showed that knockdown of 5'tiRNA-Gly increased the infiltration of M2 macrophages to the skeletal muscles (13.9%, P = 0.0023) and inhibited the expression of Pax7 (P = 0.0089) in vivo. 5'tiRNA-Gly promoted myoblast the expression of myogenic differentiation marker genes (MyoD, P = 0.0002; MyoG, P = 0.0037) and myotube formation (21.3%, P = 0.0016) but inhibited the positive rate of Edu (27.7%, P = 0.0001), cell viability (22.6%, P = 0.003) and the number of myoblasts in the G2 phase (26.3%, P = 0.0016) in vitro. Mechanistically, we found that the Tgfbr1 gene is a direct target of 5'tiRNA-Gly mediated by AGO1 and AGO3. 5'tiRNA-Gly dysregulated the expression of downstream genes related to inflammatory response, activation of satellite cells and differentiation of myoblasts through the TGF-ß signalling pathway by targeting Tgfbr1. CONCLUSIONS: These results reveal that 5'tiRNA-Gly potentially regulated skeletal muscle regeneration by inducing inflammation via the TGF-ß signalling pathway. The findings of this study uncover a new potential target for skeletal muscle regeneration treatment.

Genistein Promotes Skeletal Muscle Regeneration by Regulating miR-221/222.

Genistein (GEN), a phytoestrogen, has been reported to regulate skeletal muscle endocrine factor expression and muscle fiber type switching, but its role in skeletal muscle regeneration is poorly understood. As a class of epigenetic regulators widely involved in skeletal muscle development, microRNAs (miRNAs) have the potential to treat skeletal muscle injury. In this study, we identified miR-221 and miR-222 and their target genes MyoG and Tnnc1 as key regulators during skeletal muscle regeneration, and both were regulated by GEN. C2C12 myoblasts and C2C12 myotubes were then used to simulate the proliferation and differentiation of muscle satellite cells during skeletal muscle regeneration. The results showed that GEN could inhibit the proliferation of satellite cells and promote the differentiation of satellite cells by inhibiting the expression of miR-221/222. Subsequent in vitro and in vivo experiments showed that GEN improved skeletal muscle regeneration mainly by promoting satellite cell differentiation in the middle and late stages, by regulating miR-221/222 expression. These results suggest that miR-221/222 and their natural regulator GEN have potential applications in skeletal muscle regeneration.