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AMPK inhibition and elevated angiogenin are associated with tRNA fragmentation in the male germline exposed to a high-fat diet

ABSTRACT: The existence of an inherent intergenerational rewiring of metabolic regulation has been demonstrated through studies of obese mice that are fed a normal diet and produce offspring with metabolic disorders. tRNA-derived fragments (tRFs) have been suggested as a potential mediator of this inheritance. To explore a mechanism underlying metabolic stress-induced tRNA fragmentation, we examined the effects of a HFD on tRFs in sperm. Small RNA sequencing on sperm revealed that HFD-induced metabolic changes affect the tRF profiles, showing a trend of decreased 5’-derived tRFs and increased 3’-derived tRFs, suggesting a shift in tRNA cleavage patterns under HFD feeding. In conjunction with the alteration of tRFs, the expression of Ang, which encodes the ribonuclease angiogenin, was significantly increased in the testis. Transcriptome and metabolome analyses indicated that AMPK-mTOR signaling pathway was the possible mediator of these effects, with decreased AMPK activity and increased mTOR activity confirmed at the protein level in the testis. Moreover, in vitro experiments showed that AMPK inhibition led to increased angiogenin expression level and alterations in tRF profile. In vitro angiogenin induction experiments, designed to mimic HFD conditions, produced changes in tRF profiles similar to those observed in HFD-fed mice, although the resulting tRF profiles did not completely recapitulate the in vivo HFD-induced profiles. Our findings suggest that AMPK inhibition by HFD may induce Ang expression and tRF remodeling, potentially acting as a mediator of intergenerational transmission of diet-induced metabolic dysregulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE323392 | GEO | 2026/04/09

REPOSITORIES: GEO

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Project description:Background: As couples struggle with infertility and livestock producers wish to rapidly improve genetic merit in their herd, assisted reproductive technologies (ART) have become increasingly popular in human medicine as well as the livestock industry. Utilizing ART can cause an increased risk of congenital overgrowth syndromes, such as Large Offspring Syndrome (LOS) in ruminants. A dysregulation of transcripts has been observed in bovine fetuses with LOS, which is suggested to be a cause of the phenotype. Our recent study identified variations in tRNA expression in LOS individuals, leading us to hypothesize that variations in tRNA expression can influence the availability of their processed regulatory products, tRNA-derived fragments (tRFs). Due to their resemblance in size to microRNAs, studies suggest that tRFs target mRNA transcripts and regulate gene expression. Thus, we have sequenced small RNA isolated from skeletal muscle and liver of day 105 bovine fetuses to elucidate the mechanisms contributing to LOS. Moreover, we have utilized our previously generated tRNA sequencing data to analyze the contribution of tRNA availability to tRF abundance. Results: 22,289 and 7,737 unique tRFs were predicted in the liver and muscle tissue respectively. The greatest number of reads originated from 5′ tRFs in muscle and 5′ halves in liver. In addition, mitochondrial (MT) and nuclear derived tRF expression was tissue-specific with most MT-tRFs and nuclear tRFs derived from LysUUU and iMetCAU in muscle, and AsnGUU and GlyGCC in liver. Despite variation in tRF abundance within treatment groups, we identified differentially expressed (DE) tRFs across Control-AI, ART-Normal, and ART-LOS groups with the most DE tRFs between ART-Normal and ART-LOS groups. Many DE tRFs target transcripts enriched in pathways related to growth and development in the muscle and tumor development in the liver. Finally, we found positive correlation coefficients between tRNA availability and tRF expression in muscle (R = 0.47) and liver (0.6). Conclusion: Our results highlight the dysregulation of tRF expression and its regulatory roles in LOS. These tRFs were found to target both imprinted and non-imprinted genes in muscle as well as genes linked to tumor development in the liver. Furthermore, we found that tRNA transcription is a highly modulated event that plays a part in the biogenesis of tRFs. This study is the first to investigate the relationship between tRNA and tRF expression in combination with ART-induced LOS.

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AMPK inhibition and elevated angiogenin are associated with tRNA fragmentation in the male germline exposed to a high-fat diet

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