White Rose University Consortium logo
University of Leeds logo University of Sheffield logo York University logo

Muscle energetics and ageing in the context of RYR1 variants.

Nicoll Baines, Katie Mhairi (2017) Muscle energetics and ageing in the context of RYR1 variants. PhD thesis, University of Leeds.

[img]
Preview
Text (PhD Thesis)
KNB_Thesis_2017.pdf - Final eThesis - complete (pdf)
Available under License Creative Commons Attribution-Noncommercial-Share Alike 2.0 UK: England & Wales.

Download (22Mb) | Preview

Abstract

In aged muscle, from humans and mice, the ryanodine receptor (RyR1) is leaky, leading to increased levels of resting Ca2+ in the myoplasm. This is also a feature of skeletal muscle disorders caused by variants in RyR1 such as malignant hyperthermia (MH), central core disease (CCD), exertional heat illness (EHI) and late-onset axial myopathy (LOAM). Elevated Ca2+ is damaging to mitochondria, leading to production of reactive oxygen and nitrogen species associated with MH susceptibility to inhalational anaesthetics. Mice with Ryr1 variants show premature muscle ageing and highlight the cycle of inefficient calcium handling and oxidative damage to mitochondria that impairs skeletal muscle energetics. Caenorhabditis elegans models of MH CCD EHI and LOAM variants, both homozygous and heterozygous forms, showed increased sensitivity to halothane. Altered caffeine sensitivity was evident in MH and CCD models, and at very high concentrations in EHI models. Strains with RyR1 variants exhibit age-related accelerated myosin disorganisation. Whole genome Affymetrix arrays revealed genes and pathways correlated with skeletal muscle ageing and MH. Of additional genes of interest investigated UNC13, CASQ1, ORAI1, MCU and MICU1 showed altered expression with age. Array data from blood has been used to identify a signature for MH susceptibility. There is loss of mitochondrial membrane integrity and alteration in mitochondrial number in MH. New apparatus, capable of quantifying heat produced during muscle contraction, has enabled calculation of skeletal muscle efficiency. Preliminary data indicates that there was loss of skeletal muscle efficiency in aged muscle from wild type mice. This work provides new information on the role of RYR1 variants in skeletal muscle ageing and the importance of calcium handling in muscle energetics.

Item Type: Thesis (PhD)
Keywords: Skeletal muscle, ageing, RYR1, Malignant Hyperthermia, energetics, calcium handling
Academic Units: The University of Leeds > Faculty of Biological Sciences (Leeds) > Institute of Integrative and Comparative Biology (Leeds)
Identification Number/EthosID: uk.bl.ethos.714287
Depositing User: Katie M Nicoll Baines
Date Deposited: 06 Jun 2017 11:44
Last Modified: 11 Jul 2020 09:53
URI: http://etheses.whiterose.ac.uk/id/eprint/17288

You do not need to contact us to get a copy of this thesis. Please use the 'Download' link(s) above to get a copy.
You can contact us about this thesis. If you need to make a general enquiry, please see the Contact us page.

Actions (repository staff only: login required)