Age-related mitochondrial alterations in brain and skeletal muscle of the YAC128 model of Huntington disease

Kristina Bečanović, Asghar Muhammad, Izabella Gadawska, Shiny Sachdeva, David Walker, Eduardo R. Lazarowski, Sonia Franciosi, Kevin H.J. Park, Hélène C.F. Côté, Blair R. Leavitt

Research output: Contribution to journalArticlepeer-review

Abstract

Mitochondrial dysfunction and bioenergetics failure are common pathological hallmarks in Huntington’s disease (HD) and aging. In the present study, we used the YAC128 murine model of HD to examine the effects of mutant huntingtin on mitochondrial parameters related to aging in brain and skeletal muscle. We have conducted a cross-sectional natural history study of mitochondrial DNA changes in the YAC128 mouse. Here, we first show that the mitochondrial volume fraction appears to increase in the axons and dendrite regions adjacent to the striatal neuron cell bodies in old mice. Mitochondrial DNA copy number (mtDNAcn) was used as a proxy measure for mitochondrial biogenesis and function. We observed that the mtDNAcn changes significantly with age and genotype in a tissue-specific manner. We found a positive correlation between aging and the mtDNAcn in striatum and skeletal muscle but not in cortex. Notably, the YAC128 mice had lower mtDNAcn in cortex and skeletal muscle. We further show that mtDNA deletions are present in striatal and skeletal muscle tissue in both young and aged YAC128 and WT mice. Tracking gene expression levels cross-sectionally in mice allowed us to identify contributions of age and genotype to transcriptional variance in mitochondria-related genes. These findings provide insights into the role of mitochondrial dynamics in HD pathogenesis in both brain and skeletal muscle, and suggest that mtDNAcn in skeletal muscle tissue may be a potential biomarker that should be investigated further in human HD.

Original languageEnglish
Article number26
Journalnpj Aging and Mechanisms of Disease
Volume7
Issue number1
DOIs
StatePublished - Dec 2021

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