Long-Term Bezafibrate Treatment Improves Skin and Spleen Phenotypes of the mtDNA Mutator Mouse

Lloye M Dillon,Sofia Garcia,Aline Hida,Carlos T Moraes,Tomas A Prolla,Yidong Bai

doi:10.1371/journal.pone.0044335

Lloye M Dillon, Sofia Garcia + Show 4 more

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https://doi.org/10.1371/journal.pone.0044335

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Journal: PloS one	Publication Date: Sep 4, 2012
Citations: 58	License type: CC BY 4.0

Affiliation: University of Miami, University of Wisconsin–Madison

Abstract

Pharmacological agents, such as bezafibrate, that activate peroxisome proliferator-activated receptors (PPARs) and PPAR γ coactivator-1α (PGC-1α) pathways have been shown to improve mitochondrial function and energy metabolism. The mitochondrial DNA (mtDNA) mutator mouse is a mouse model of aging that harbors a proofreading-deficient mtDNA polymerase γ. These mice develop many features of premature aging including hair loss, anemia, osteoporosis, sarcopenia and decreased lifespan. They also have increased mtDNA mutations and marked mitochondrial dysfunction. We found that mutator mice treated with bezafibrate for 8-months had delayed hair loss and improved skin and spleen aging-like phenotypes. Although we observed an increase in markers of fatty acid oxidation in these tissues, we did not detect a generalized increase in mitochondrial markers. On the other hand, there were no improvements in muscle function or lifespan of the mutator mouse, which we attributed to the rodent-specific hepatomegaly associated with fibrate treatment. These results showed that despite its secondary effects in rodent’s liver, bezafibrate was able to improve some of the aging phenotypes in the mutator mouse. Because the associated hepatomegaly is not observed in primates, long-term bezafibrate treatment in humans could have beneficial effects on tissues undergoing chronic bioenergetic-related degeneration.

Highlights

Many recent studies have linked mitochondrial dysfunction with aging and aging-associated diseases [1]
We recently showed that increasing mitochondrial biogenesis and function in muscle, by transgenic overexpression of peroxisome proliferator-activated receptor (PPAR) c coactivator-1a (PGC1a), improved skeletal muscle and heart phenotypes of Mut mice [4]
We found that PPARc mRNA levels were elevated in the spleen of MutSD compared with WTSD mice and its levels were restored in MutBD mice (Fig. 3F)

Summary

Introduction

Many recent studies have linked mitochondrial dysfunction with aging and aging-associated diseases [1]. The mitochondrial DNA (mtDNA) mutator mouse is a mouse model of premature aging that supports this connection. This mouse has a mutant mtDNA polymerase c (POLG) that lacks its proofreading ability [2,3]. Mutator mice (designated Mut mice), were shown to develop many features of premature aging such as early hair loss, anemia, osteoporosis, sarcopenia, cardiomyopathy and decreased lifespan [2,3]. These aging-like phenotypes were associated with increased mtDNA mutation and mitochondrial dysfunction [2,3]. We recently showed that increasing mitochondrial biogenesis and function in muscle, by transgenic overexpression of peroxisome proliferator-activated receptor (PPAR) c coactivator-1a (PGC1a), improved skeletal muscle and heart phenotypes of Mut mice [4]

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