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Molecular and epigenetic changes associated with age-related skeletal muscle loss and sacropenia

Molecular and epigenetic changes associated with age-related skeletal muscle loss and sacropenia
Molecular and epigenetic changes associated with age-related skeletal muscle loss and sacropenia
Sarcopenia is defined as the age-related loss of muscle mass and function and is common in both men and women over the age of 65, with a worldwide prevalence estimated at between 3-30%. As the population is becoming more aged, the prevalence of sarcopenia in the community is increasing and with that, an increase in the number of adverse physical and metabolic outcomes including frailty, disability, metabolic disorders and osteoporosis. However, the molecular pathways altered during muscle ageing and how they contribute to sarcopenia are poorly understood. Previous studies have investigated the mechanisms contributing to muscle ageing and the pathogenesis of sarcopenia. However to date, there have been no investigations into the variability in skeletal muscle mass and function in the elderly, using age-matched controls to investigate the pathogenesis of sarcopenia. Using both genome-wide and candidate gene approaches, skeletal muscle tissue and myoblasts from participants of the Hertfordshire Sarcopenia Study were utilized and the signalling pathways that contribute to the variability in muscle mass and function among community-dwelling older people were investigated. Genome-wide transcriptome analysis highlighted mitochondrial function, DNA damage and myogenesis as the major pathways altered in sarcopenia. RT-PCR validation of the RNAseq data confirmed an association between reduced muscle mass and higher expression of the long non-coding RNA H19, with a concomitant increase in miR-675-3p/5p expression and decreased SMAD1/5 expression, resulting in reduced muscle hypertrophy. Singlecell transcriptomics of the isolated myoblasts from the muscle biopsies showed that many of the pathways altered with respect to muscle mass were intrinsic to the muscle cells. Changes in transcription were also accompanied by genome wide changes in DNA methylation with pathways related to calcium signalling, denervation/muscle atrophy and muscle development being changed and enriched for the polycomb regulator EZH2. Moreover, the epigenetic signatures related to muscle mass and strength were conserved in primary myoblasts after culture. Skeletal muscle myoblasts isolated from sarcopenic muscle also exhibited altered mitochondrial respiration, with reduced ATP production and maximal respiration compared to healthy elderly people, as well as increased levels of senescence in myoblasts as suggested by an increase in p16INK4a expression and a decrease in ANRIL expression.

Taken together, these findings suggest an impairment in the balance between muscle hypertrophy and atrophy in sarcopenia. This impairment is intrinsic to myogenic cells, with increased cell death, in combination with increased mitochondrial dysfunction, cellular senescence and DNA damage. This may result in the impaired regenerative capacity of skeletal muscle, and together with reduced hypertrophic signalling, a reduced capability to efficiently repair skeletal muscle in the elderly. Understanding these mechanisms may provide better insight into the development of therapeutics for the treatment of sarcopenia, while the muscle-derived myoblasts provide an in vitro model system to investigate the efficacy of new treatments. The methylation changes associated with the measures of muscle mass and function may also provide potential biomarkers to identify those at increased risk of developing sarcopenia, allowing early intervention for prevention and treatment.
University of Southampton
Antoun, Elie
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Antoun, Elie
23e4ee54-9652-41cd-9eb0-066cfcc598c9
Godfrey, Keith
0931701e-fe2c-44b5-8f0d-ec5c7477a6fd
Lillycrop, Karen
eeaaa78d-0c4d-4033-a178-60ce7345a2cc
Patel, Harnish
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Antoun, Elie (2018) Molecular and epigenetic changes associated with age-related skeletal muscle loss and sacropenia. University of Southampton, Doctoral Thesis, 349pp.

Record type: Thesis (Doctoral)

Abstract

Sarcopenia is defined as the age-related loss of muscle mass and function and is common in both men and women over the age of 65, with a worldwide prevalence estimated at between 3-30%. As the population is becoming more aged, the prevalence of sarcopenia in the community is increasing and with that, an increase in the number of adverse physical and metabolic outcomes including frailty, disability, metabolic disorders and osteoporosis. However, the molecular pathways altered during muscle ageing and how they contribute to sarcopenia are poorly understood. Previous studies have investigated the mechanisms contributing to muscle ageing and the pathogenesis of sarcopenia. However to date, there have been no investigations into the variability in skeletal muscle mass and function in the elderly, using age-matched controls to investigate the pathogenesis of sarcopenia. Using both genome-wide and candidate gene approaches, skeletal muscle tissue and myoblasts from participants of the Hertfordshire Sarcopenia Study were utilized and the signalling pathways that contribute to the variability in muscle mass and function among community-dwelling older people were investigated. Genome-wide transcriptome analysis highlighted mitochondrial function, DNA damage and myogenesis as the major pathways altered in sarcopenia. RT-PCR validation of the RNAseq data confirmed an association between reduced muscle mass and higher expression of the long non-coding RNA H19, with a concomitant increase in miR-675-3p/5p expression and decreased SMAD1/5 expression, resulting in reduced muscle hypertrophy. Singlecell transcriptomics of the isolated myoblasts from the muscle biopsies showed that many of the pathways altered with respect to muscle mass were intrinsic to the muscle cells. Changes in transcription were also accompanied by genome wide changes in DNA methylation with pathways related to calcium signalling, denervation/muscle atrophy and muscle development being changed and enriched for the polycomb regulator EZH2. Moreover, the epigenetic signatures related to muscle mass and strength were conserved in primary myoblasts after culture. Skeletal muscle myoblasts isolated from sarcopenic muscle also exhibited altered mitochondrial respiration, with reduced ATP production and maximal respiration compared to healthy elderly people, as well as increased levels of senescence in myoblasts as suggested by an increase in p16INK4a expression and a decrease in ANRIL expression.

Taken together, these findings suggest an impairment in the balance between muscle hypertrophy and atrophy in sarcopenia. This impairment is intrinsic to myogenic cells, with increased cell death, in combination with increased mitochondrial dysfunction, cellular senescence and DNA damage. This may result in the impaired regenerative capacity of skeletal muscle, and together with reduced hypertrophic signalling, a reduced capability to efficiently repair skeletal muscle in the elderly. Understanding these mechanisms may provide better insight into the development of therapeutics for the treatment of sarcopenia, while the muscle-derived myoblasts provide an in vitro model system to investigate the efficacy of new treatments. The methylation changes associated with the measures of muscle mass and function may also provide potential biomarkers to identify those at increased risk of developing sarcopenia, allowing early intervention for prevention and treatment.

Text
Final Thesis Elie Antoun - Version of Record
Restricted to Repository staff only until 22 May 2021.
Available under License University of Southampton Thesis Licence.

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Published date: May 2018

Identifiers

Local EPrints ID: 435486
URI: http://eprints.soton.ac.uk/id/eprint/435486
PURE UUID: 71ca5e02-6ff6-47d3-ac8f-4f115b4a6f00
ORCID for Keith Godfrey: ORCID iD orcid.org/0000-0002-4643-0618
ORCID for Karen Lillycrop: ORCID iD orcid.org/0000-0001-7350-5489

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Date deposited: 07 Nov 2019 17:30
Last modified: 20 May 2020 00:29

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Contributors

Author: Elie Antoun
Thesis advisor: Keith Godfrey ORCID iD
Thesis advisor: Karen Lillycrop ORCID iD
Thesis advisor: Harnish Patel

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