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An unexplained but consistent feature of PP is that a phenotype transition occurs around the age of 40, in which the severity of potassium\u2010induced muscle weakness declines but onset of fixed, progressive weakness is reported. This phenotype transition coincides with the age at which muscle mass and optimal motor function start to decline in healthy individuals. We sought to determine if the phenotype transition in PP is linked to the normal ageing phenotype transition and to explore the mechanisms involved.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A mouse model of hyperkalaemic PP was compared with wild\u2010type littermates across a range of ages (13\u2013104\u00a0weeks). Only male mice were used as penetrance is incomplete in females. We adapted the muscle velocity recovery cycle technique from humans to examine murine muscle excitability <jats:italic>in vivo<\/jats:italic>. We then examined changes in potassium\u2010induced weakness or caffeine contracture force with age using <jats:italic>ex vivo<\/jats:italic> muscle tension testing. Muscles were further characterized by either Western blot, histology or energy charge measurement. For normally distributed data, a student's <jats:italic>t<\/jats:italic>\u2010test (\u00b1\u00a0Welch correction) or one\u2010 or two\u2010way analysis of variance (ANOVA) was performed to determine significance. For data that were not normally distributed, Welch rank test, Mann Whitney U test or Kruskal\u2013Wallis ANOVA was performed. When an ANOVA was significant (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), post hoc Tukey testing was used.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Both WT (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.009) and PP (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.007) muscles exhibit increased resistance to potassium\u2010induced weakness with age. Our data suggest that healthy\u2010old muscle develops mechanisms to maintain force <jats:italic>despite<\/jats:italic> sarcolemmal depolarization and sodium channel inactivation. In contrast, reduced caffeine contracture force (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.00005), skeletal muscle energy charge (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.004) and structural core pathology (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.005) were specific to Draggen muscle, indicating that they are caused, or at least accelerated by, chronic genetic ion channel dysfunction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The phenotype transition with age is replicated in a mouse model of PP. Intrinsic muscle ageing protects against potassium\u2010induced weakness in HyperPP mice. However, it also appears to accelerate impairment of sarcoplasmic reticulum calcium release, mitochondrial impairment and the development of core\u2010like regions, suggesting acquired RyR1 dysfunction as the potential aetiology. This work provides a first description of mechanisms involved in phenotype transition with age in PP. It also demonstrates how studying phenotype transition with age in monogenic disease can yield novel insights into both disease physiology and the ageing process itself.<\/jats:p><\/jats:sec>","DOI":"10.1002\/rco2.41","type":"journal-article","created":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T14:15:21Z","timestamp":1620224121000},"page":"245-259","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Ageing contributes to phenotype transition in a mouse model of periodic paralysis"],"prefix":"10.1002","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6505-9404","authenticated-orcid":false,"given":"Karen J.","family":"Suetterlin","sequence":"first","affiliation":[{"name":"Department of Neuromuscular Diseases UCL Queen Square Institute of Neurology  London UK"},{"name":"MRC Centre for Neuromuscular Diseases UCL Queen Square Institute of Neurology and National Hospital for Neurology and Neurosurgery  London UK"},{"name":"AGE Research Group, NIHR Newcastle Biomedical Research Centre Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University  Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6983-3081","authenticated-orcid":false,"given":"S. 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