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RNAseq analysis of skeletal muscle transcriptomes from wild-type, LONP1 skeletal muscle specific knockout (LONP1 mKO) and LONP1ATF4 skeletal muscle double-knockout (LONP1ATF4 DmKO) mice.

ABSTRACT: Studying the molecular basis for the skeletal muscle mitochondrial stress response could potentially be targeted to counteract metabolic disorders such as obesity. We uncovered a crucial role for the mitochondrial protease LONP1 in controlling the muscle mitochondrial proteostasis stress response that governs systemic metabolic homeostasis. Skeletal muscle-specific ablation of LONP1 led to broad genomic reprogramming of muscle and protected the mice from HFD-induced obesity. To thoroughly analyze pathways that are affected by ATF4 deficiency in the context of LONP1 mKO, we performed RNA-Seq transcriptome analysis of skeletal muscles from WT, LONP1 mKO and LONP1ATF4 DmKO mice. We identified a total of 3017 differentially expressed genes with a cutoff of 1.5-fold, and p < 0.05. Surprisingly, we found that ATF4 loss blunted a subset of regulated genes in LONP1 mKO muscles, whereas the majority of differentially regulated genes in LONP1 mKO muscles were not affected by ATF4 ablation. GO analysis of ATF4-dependent genes regulated by LONP1 ablation revealed significant enrichment in amino acid metabolic processes, Interestingly, however, LONP1 deficiency induced activation of muscle UPR and UPR-related RNA processing as well as myokine pathways were not affected by ATF4 ablation. Therefore, our results highlight a ATF4-independent mechanism in mediating the UPRmt in mammals.

ORGANISM(S): Mus musculus

PROVIDER: GSE192990 | GEO | 2022/07/28

REPOSITORIES: GEO

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Project description:This experiment was conducted to identify the mitochondrial protein changes in the presence and absence of LONP1 in skeletal muscle. The following abstract from the submitted manuscript describes the major findings of this work.Disuse-associated loss of muscle LONP1 impairs mitochondrial quality and causes reduced skeletal muscle mass and strength. Zhisheng Xu, Tingting Fu, Qiqi Guo, Danxia Zhou, Wanping Sun, Zheng Zhou, Lin Liu, Liwei Xiao, Yujing Yin, Yuhuan Jia, Xin Pan, Lei Fang, Min-sheng Zhu, Wenyong Fei, Bin Lu and Zhenji Gan. Mitochondrial proteolysis is an evolutionarily conserved quality control mechanism to maintain proper mitochondrial integrity and function. However, the physiological relevance of stress-induced impaired mitochondrial protein quality remains unclear. Here, we demonstrate that LONP1, a major mitochondrial protease resides in the matrix, plays a critical role in controlling mitochondrial quality as well as skeletal muscle mass and strength in response to muscle disuse. In humans and mice, disuse-related muscle loss is associated with decreased mitochondrial LONP1 protein. Skeletal muscle-specific ablation of LONP1 in mice resulted in impaired mitochondrial protein turnover, leading to mitochondrial dysfunction. This caused reduced muscle fiber size and strength. Mechanistically, aberrant accumulation of mitochondrial-retained protein in muscle upon loss of LONP1 induces the activation of autophagy-lysosome degradation program of muscle loss. Overexpressing a mitochondrial-retained mutant ornithine transcarbamylase (ΔOTC), a known protein degraded by LONP1, in skeletal muscle induces mitochondrial dysfunction, autophagy activation, and cause muscle loss and weakness. Thus, these findings reveal a pivotal role of LONP1-dependent mitochondrial protein quality-control in safeguarding mitochondrial function and preserving skeletal muscle mass and strength, and unravel an intriguing link between mitochondrial protein quality and muscle mass maintenance during muscle disuse.

Project description:Age-related skeletal muscle atrophy is a debilitating condition that has significant negative impacts on health and quality of life. Despite broad clinical impact, the molecular basis of age-related skeletal muscle atrophy is not well understood. Here, we determined protein turnover rates in skeletal muscle of 22-month-old control mice and 22-month-old muscle-specific ATF4 knockout (ATF4 mKO) mice, which are partially resistant to age-related muscle atrophy. All samples were analyzed by DDA TripleTOF 6600 mass spectrometer for downstream analysis of protein turnover. Quantitative MS1 peak areas were extracted from DDA raw files in the Skyline-Daily software platform. ProteinPilot search results were imported into the Skyline software to build a spectral library, followed by import of raw MS files for extraction of chromatographic peak areas. A custom skyline report containing all peptide and protein characteristics, annotations, and quantitative information including isotopologue peak areas was exported and used for downstream analysis and calculation of protein turnover rates in R using in-house R scripts (TurnoveR tool). Precursor-pool corrected protein turnover rates were calculated using the same approach employed in previous studies using the Topograph software platform. For calculation of protein abundance changes, DIA acquisitions from six samples (3 ATF4 KO and 3 WT samples) were quantitatively processed using Spectronaut v14. Analysis of protein turnover indicates that most proteins with altered turnover rates in ATF4 mKO muscles have decreased half-lives and are components of the mitochondrion. These proteins include subunits of the ATP Synthase (Atp5b, Atp5o), Ubiquinol-Cytochrome C Reductase (Uqcrc1, Uqcrh) and Cytochrome C Oxidase (Cox6b1) complexes, among others. These findings implicate increased rates of mitochondrial protein turnover as a mechanism that underlies, at least in part, the protection from age-induced muscle atrophy in ATF4 mKO mice.

Dataset Information

RNAseq analysis of skeletal muscle transcriptomes from wild-type, LONP1 skeletal muscle specific knockout (LONP1 mKO) and LONP1ATF4 skeletal muscle double-knockout (LONP1ATF4 DmKO) mice.

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