Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice

Safdar, Adeel; Bourgeois, Jacqueline M.; Ogborn, Daniel I.; Little, Jonathan P.; Hettinga, Bart P.; Akhtar, Mahmood; Thompson, James E.; Melov, Simon; Mocellin, Nicholas J.; Kujoth, Gregory C.; Prolla, Tomas A.; Tarnopolsky, Mark A.

doi:10.1073/pnas.1019581108

Cited by 323 publications

(354 citation statements)

References 58 publications

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“…The importance of exonucleolytic proofreading during mtDNA replication is clear from the phenotype of mice lacking mitochondrial polymerase proofreading through mutation of POLG, which show early-onset of many age-related phenotypes (Trifunovic et al 2004). 7 Mice carrying high levels of mitochondrial DNA mutation show sarcopenia and mitochondrial dysfunction in skeletal muscle (Hiona et al 2010), although this can be blunted by endurance exercise (Safdar et al 2011). They also show an accelerated age-related loss of retinal function (Kong et al 2011).…”

Section: Mitochondrial Nucleasesmentioning

confidence: 99%

The role of DNA exonucleases in protecting genome stability and their impact on ageing

Mason

Cox

2011

AGE

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Exonucleases are key enzymes involved in many aspects of cellular metabolism and maintenance and are essential to genome stability, acting to cleave DNA from free ends. Exonucleases can act as proofreaders during DNA polymerisation in DNA replication, to remove unusual DNA structures that arise from problems with DNA replication fork progression, and they can be directly involved in repairing damaged DNA. Several exonucleases have been recently discovered, with potentially critical roles in genome stability and ageing. Here we discuss how both intrinsic and extrinsic exonuclease activities contribute to the fidelity of DNA polymerases in DNA replication. The action of exonucleases in processing DNA intermediates during normal and aberrant DNA replication is then assessed, as is the importance of exonucleases in repair of double-strand breaks and interstrand crosslinks. Finally we examine how exonucleases are involved in maintenance of mitochondrial genome stability. Throughout the review, we assess how nuclease mutation or loss predisposes to a range of clinical diseases and particularly ageing.

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Section: Mitochondrial Nucleasesmentioning

confidence: 99%

The role of DNA exonucleases in protecting genome stability and their impact on ageing

Mason

Cox

2011

AGE

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“…Despite being conceptualized as a simple model of progeria, an increasing number of recent studies have suggested that the POLG phenotype is more complicated. For example, an endurance exercise intervention was reportedly able to impede the manifestation of progeria (8). Despite the apparent accumulation of mitochondrial defects, POLG mice lack signs of increased reactive oxygen species (ROS), with only recent evidence of oxidative damage in skeletal muscle (9,10).…”

mentioning

confidence: 99%

High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice

Wall

Whyte

Suh

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Mitochondria are highly adaptable organelles that can facilitate communication between tissues to meet the energetic demands of the organism. However, the mechanisms by which mitochondria can nonautonomously relay stress signals remain poorly understood. Here we report that mitochondrial mutations in the young, preprogeroid polymerase gamma mutator (POLG) mouse produce a metabolic state of starvation. As a result, these mice exhibit signs of metabolic imbalance including thermogenic defects in brown adipose tissue (BAT). An unexpected benefit of this adaptive response is the complete resistance to diet-induced obesity when POLG mice are placed on a high-fat diet (HFD). Paradoxically, HFD further increases oxygen consumption in part by inducing thermogenesis and mitochondrial biogenesis in BAT along with enhanced expression of fibroblast growth factor 21 (FGF21). Collectively, these findings identify a mechanistic link between FGF21, a long-known marker of mitochondrial disease, and systemic metabolic adaptation in response to mitochondrial stress.

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“…It is also possible that cardiovascular abnormalities in addition to muscle weakness might have limited the ability of the Zmpste24 −/− mice to run. These preliminary results are in contrast to exercise rescuing the aging phenotype in another mouse model of progeria (Safdar et al 2011).…”

Section: Discussionmentioning

confidence: 62%

Skeletal muscle contractile function and neuromuscular performance in Zmpste24 −/− mice, a murine model of human progeria

Greising

Call

Lund

et al. 2011

AGE

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Human progeroid syndromes and premature aging mouse models present as segmental, accelerated aging because some tissues and not others are affected. Skeletal muscle is detrimentally changed by normal aging but whether it is an affected tissue in progeria has not been resolved. We hypothesized that mice which mimic Hutchinson-Gilford progeria syndrome would exhibit age-related alterations of skeletal muscle. Zmpste24 −/− and Zmpste24 +/+ littermates were assessed for skeletal muscle functions, histo-morphological characteristics, and ankle joint mechanics. Twenty-four-hour active time, ambulation, grip strength, and whole body tension were evaluated as markers of neuromuscular performance, each of which was at least 33% lower in Zmpste24 −/− mice compared with littermates (p<0.06). Contractile capacity of the posterior leg muscles were not affected in Zmpste24 −/− mice, but muscles of the anterior leg were 30-90% weaker than those of Zmpste24 +/+ mice (p< 0.01). Leg muscles were 32-47% smaller in the Zmpste24 −/− mice and contained~60% greater collagen relative to littermates (p<0.01). Soleus and extensor digitorum longus muscles of Zmpste24 −/− mice had excessive myonuclei and altered fiber size distributions but, otherwise, appeared normal. Ankle range of motion was 70% lower and plantar-and dorsiflexion passive torques were nearly 3-fold greater in Zmpste24 −/− than Zmpste24 +/+ mice (p≤0.01). The combined factors of muscle atrophy, collagen accumulation, and perturbed joint mechanics likely contributed to poor neuromuscular performance and selective muscle weakness displayed by Zmpste24 −/− mice. In summary, these characteristics are similar to those of aged mice indicating accelerated aging of skeletal muscle in progeria.Keywords Aging . Lamin . Range of motion . Sarcopenia . Strength Abbreviations EDLExtensor digitorum longus HGPS Hutchinson-Gilford progeria syndrome P o Maximal isometric tetanic force ROM Range of motion AGE (2012) 34:805-819

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Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice

Cited by 323 publications

References 58 publications

The role of DNA exonucleases in protecting genome stability and their impact on ageing

The role of DNA exonucleases in protecting genome stability and their impact on ageing

High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice

Skeletal muscle contractile function and neuromuscular performance in Zmpste24 −/− mice, a murine model of human progeria

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