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Changes in Protein Fluxes and Gene Expression in Non-Injured Muscle Tissue Distant from an Acute Myotoxic Injury in Male Mice

ABSTRACT: The response to acute myotoxic injury requires stimulation of local repair mechanisms in the damaged tissue. However, satellite cells in muscle distant from acute injury have been reported to enter a functional state between quiescence and active proliferation. Here, we asked whether protein flux rates are altered in muscle distant from acute local myotoxic injury and how they compare to changes in gene expression from the same tissue. Broad and significant alterations in protein turnover were observed across the proteome in the limb contralateral to injury during the first 10 days after. Interestingly, mRNA changes had almost no correlation with directly measured protein turnover rates. In summary, we show consistent and striking changes in protein flux rates in muscle tissue contralateral to myotoxic injury, with no correlation between changes in mRNA levels and protein synthesis rates. This work motivates further investigation of the mechanisms, including potential neurologic factors, responsible for this distant effect.

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Alec Bizieff

PROVIDER: PXD051860 | JPOST Repository | Tue Apr 30 00:00:00 BST 2024

REPOSITORIES: jPOST

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			Action	DRS
	0226M_AMB000495_TA-PBS1_DPrimingContra_MS_rep1Q3-27APxxx.d	Other
	0227M_AMB000495_TA-PBS2_DPrimingContra_MS_rep1Q3-27APxxx.d	Other
	0228M_AMB000495_TA-PBS3_DPrimingContra_MS_rep1Q3-27APxxx.d	Other
	0229M_AMB000495_TA-PBS4_DPrimingContra_MS_rep1Q3-27APxxx.d	Other
	0230M_AMB000495_TA-PBS5_DPrimingContra_MS_rep1Q3-27APxxx.d	Other

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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

Changes in Protein Fluxes and Gene Expression in Non-Injured Muscle Tissue Distant from an Acute Myotoxic Injury in Male Mice

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