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RNA-sequencing Reveals a Gene Expression Signature in Skeletal Muscle of a Mouse Model of Age-associated Postoperative Functional Decline.

ABSTRACT: This study aimed to characterize the effects of laparotomy on postoperative physical function and skeletal muscle gene expression in male C57BL/6N mice at 3, 20, and 24 months of age to investigate late-life vulnerability and resiliency to acute surgical stress. Pre and postoperative physical functioning was assessed by forelimb grip strength on postoperative day (POD) 1 and 3 and motor coordination on POD 2 and 4. Laparotomy-induced an age-associated postoperative decline in forelimb grip strength that was the greatest in the oldest mice. While motor coordination declined with increasing age at baseline, it was unaffected by laparotomy. Baseline physical function as stratified by motor coordination performance (low functioning vs high functioning) in 24-month-old mice did not differentially affect postlaparotomy reduction in grip strength. RNA sequencing of soleus muscles showed that laparotomy-induced age-associated differential gene expression and canonical pathway activation with the greatest effects in the youngest mice. Examples of such age-associated, metabolically important pathways that were only activated in the youngest mice after laparotomy included oxidative phosphorylation and NRF2-mediated oxidative stress response. Analysis of lipid mediators in serum and gastrocnemius muscle showed alterations in profiles during aging and confirmed an association between such changes and functional status in gastrocnemius muscle. These findings demonstrate a mouse model of laparotomy which recapitulated some features of postoperative skeletal muscle decline in older adults, and identified age-associated, laparotomy-induced molecular signatures in skeletal muscles. Future research can build upon this model to study molecular mechanisms of late-life vulnerability and resiliency to acute surgical stress.

SUBMITTER: Asche-Godin SL

PROVIDER: S-EPMC9536457 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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RNA-sequencing Reveals a Gene Expression Signature in Skeletal Muscle of a Mouse Model of Age-associated Postoperative Functional Decline.

Asche-Godin Samantha L SL Graham Zachary A ZA Israel Adina A Harlow Lauren M LM Huang Weihua W Wang Zhiying Z Brotto Marco M Mobbs Charles C Cardozo Christopher P CP Ko Fred C FC

The journals of gerontology. Series A, Biological sciences and medical sciences 20221001 10

This study aimed to characterize the effects of laparotomy on postoperative physical function and skeletal muscle gene expression in male C57BL/6N mice at 3, 20, and 24 months of age to investigate late-life vulnerability and resiliency to acute surgical stress. Pre and postoperative physical functioning was assessed by forelimb grip strength on postoperative day (POD) 1 and 3 and motor coordination on POD 2 and 4. Laparotomy-induced an age-associated postoperative decline in forelimb grip stren ...[more]

PMID: 35172336

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Project description:BACKGROUNDPhysical frailty in older individuals is characterized by subjective symptoms of fatigue and exercise intolerance (EI). Objective abnormalities in skeletal muscle (SM) mitochondrial high-energy phosphate (HEP) metabolism contribute to EI in inherited myopathies; however, their presence or link to EI in the frail older adult is unknown.METHODSHere, we studied 3 groups of ambulatory, community-dwelling adults with no history of significant coronary disease: frail older (FO) individuals (81 ± 2.7 years, mean ± SEM), nonfrail older (NFO) individuals (79 ± 2.0 years), and healthy middle-aged individuals, who served as controls (CONT, 51 ± 2.1 years). Lower extremity SM HEP levels and mitochondrial function were measured with 31P magnetic resonance (MR) techniques during graded multistage plantar flexion exercise (PFE). EI was quantified by a 6-minute walk (6MW) and peak oxygen consumption during cardiopulmonary testing (peak VO2).RESULTSDuring graded exercise, FO, NFO, and CONT individuals all fatigued at similar SM HEP levels, as measured by 31P-MR. However, FO individuals fatigued fastest, with several-fold higher rates of PFE-induced HEP decline that correlated closely with shorter exercise duration in the MR scanner and with 6MW distance and lower peak oxygen consumption on cardiopulmonary testing (P < 0.001 for all). SM mitochondrial oxidative capacity was lower in older individuals and correlated with rapid HEP decline but less closely with EI.CONCLUSIONSeveral-fold faster SM energetic decline during exercise occurs in FO individuals and correlates closely with multiple measures of EI. Rapid energetic decline represents an objective, functional measure of SM metabolic changes and a potential new target for mitigating frailty-associated physical limitations.FUNDINGThis work was supported by NIH R21 AG045634, R01 AG063661, R01 HL61912, the Johns Hopkins University Claude D. Pepper Older Americans Independence Center P30AG021334, and the Clarence Doodeman Endowment in Cardiology at Johns Hopkins.

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RNA-sequencing Reveals a Gene Expression Signature in Skeletal Muscle of a Mouse Model of Age-associated Postoperative Functional Decline.

Publications

RNA-sequencing Reveals a Gene Expression Signature in Skeletal Muscle of a Mouse Model of Age-associated Postoperative Functional Decline.

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