Abstract
The accumulation of mitochondrial DNA (mtDNA) mutations is a suspected driver of aging and age‐related diseases, but forestalling these changes has been a major challenge. One of the best‐studied models is the prematurely aging mtDNA mutator mouse, which carries a homozygous knock‐in of a proofreading deficient version of the catalytic subunit of mtDNA polymerase‐γ (PolgA). We investigated how voluntary exercise affects the progression of aging phenotypes in this mouse, focusing on mitochondrial and protein homeostasis in both brain and peripheral tissues. Voluntary exercise significantly ameliorated several aspects of the premature aging phenotype, including decreased locomotor activity, alopecia, and kyphosis, but did not have major effects on the decreased lifespan of mtDNA mutator mice. Exercise also decreased the mtDNA mutation load. In‐depth tissue proteomics revealed that exercise normalized the levels of about half the proteins, with the majority involved in mitochondrial function and nuclear–mitochondrial crosstalk. There was also a specific increase in the nuclear‐encoded proteins needed for the tricarboxylic acid cycle and complex II, but not in mitochondrial‐encoded oxidative phosphorylation proteins, as well as normalization of enzymes involved in coenzyme Q biosynthesis. Furthermore, we found tissue‐specific alterations, with brain coping better as compared to muscle and with motor cortex being better protected than striatum, in response to mitochondrial dysfunction. We conclude that voluntary exercise counteracts aging in mtDNA mutator mice by counteracting protein dysregulation in muscle and brain, decreasing the mtDNA mutation burden in muscle, and delaying overt aging phenotypes.
Highlights
A large proportion of humans, as well as laboratory mice kept in stan‐ dard size cages, lack sufficient daily physical activity and benefit from planned exercise
The mice have been used to model a worst‐case scenario of mitochondrial DNA (mtDNA) mutation load and to study possible effects of treatments, including forced treadmill exercise (Clark‐Matott et al, 2015; Safdar et al, 2011, 2016), high‐fat diet (Wall et al, 2015), and caloric re‐ striction (Someya et al, 2017), as well as overexpression of proteins involved in mitochondrial biogenesis, such as the peroxisome pro‐ liferator‐activated receptor γ coactivator‐1α (PGC‐1α) (Dillon et al, 2012) and drug treatments (Shabalina et al, 2017)
We found that voluntary exercise improves sponta‐ neous activity and counteracts visible aging phenotypes without any major alterations in lifespan, as well as normalizes many, but not all protein alterations found in skeletal muscle and brain tissue from mtDNA mutator mice
Summary
A large proportion of humans, as well as laboratory mice kept in stan‐ dard size cages, lack sufficient daily physical activity and benefit from planned exercise. We found that voluntary exercise improves sponta‐ neous activity and counteracts visible aging phenotypes without any major alterations in lifespan, as well as normalizes many, but not all protein alterations found in skeletal muscle and brain tissue from mtDNA mutator mice. Histological analysis of the gastrocnemius muscle from 30‐week‐old males using H&E staining did not reveal major changes in the mu‐ tator mice comparing exercising and sedentary individuals, neither did PAS staining to evaluate levels of glycogen, glycoproteins and glycolipids, or COX/SDH dual‐labeling histochemistry (Ross, 2011) to monitor mitochondrial respiratory function. In‐depth proteomics revealed significantly lower levels of intra‐mitochondrial coenzyme Q10A (COQ10A) in skeletal muscle in sedentary mtDNA mutator mice as compared to WT mice This confirms what was previously found in heart from several mouse models of OXPHOS deficiency (Kühl et al, 2017). Exercise normalized dysregulated COQ10A protein levels in muscle and striatum, as well as several addi‐ tional biosynthetic enzymes in striatum (COQ3, COQ5, COQ6, COQ7), suggesting that exercise and coenzyme Q supple‐ mentation could be used together to treat patients with OXPHOS dysfunction
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