Increased mitochondrial biogenesis in muscle improves aging phenotypes in the mtDNA mutator mouse

Abstract

Aging is an intricate process that increases susceptibility to sarcopenia and cardiovascular diseases. The accumulation of mitochondrial DNA (mtDNA) mutations is believed to contribute to mitochondrial dysfunction, potentially shortening lifespan. The mtDNA mutator mouse, a mouse model with a proofreading-deficient mtDNA polymerase γ, was shown to develop a premature aging phenotype, including sarcopenia, cardiomyopathy and decreased lifespan. This phenotype was associated with an accumulation of mtDNA mutations and mitochondrial dysfunction. We found that increased expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a crucial regulator of mitochondrial biogenesis and function, in the muscle of mutator mice increased mitochondrial biogenesis and function and also improved the skeletal muscle and heart phenotypes of the mice. Deep sequencing analysis of their mtDNA showed that the increased mitochondrial biogenesis did not reduce the accumulation of mtDNA mutations but rather caused a small increase. These results indicate that increased muscle PGC-1α expression is able to improve some premature aging phenotypes in the mutator mice without reverting the accumulation of mtDNA mutations.

Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat

“…The concept of increased mtDNA replication as a means to overcome mtDNA mutations has been advanced by a number of studies (17,25,52,101,113). However it remains unclear if this is a stable or transient event, and whether it expands or dilutes the mtDNA mutation pool.…”

PGC1α and mitochondrial metabolism – emerging concepts and relevance in ageing and neurodegenerative disorders

“…In order to test whether increasing mitochondrial metabolism through PGC1a expression could ameliorate the phenotype of POLG mice, these mice were crossed with MCK-PGC1a Tg mice (Lin et al, 2002b). Mice that express both mutant POLG and PGC1a have increased mitochondrial activity in heart and skeletal muscle, which leads to improved functions of these tissues compared with mice expressing mutant POLG alone (Dillon et al, 2012). These data highlight that elevated mitochondrial functions can have beneficial effects in ageing that are independent of the presence of mutations to the mtDNA.…”

The role of axonal transport and mitochondrial dysfunction in neurodegeneration-focusing on Huntington's disease

“…This is in line with other experiments that showed that transgenic overexpression of FL-PGC-1α is able to attenuate symptoms of mitochondrial diseases in a tissue specific manner (Wenz et al, 2008(Wenz et al, , 2009Dillon et al, 2012;Srivastava et al, 2009). Moreover PGC-1α overexpression selectively in skeletal muscle of transgenic mouse model of ALS improved muscle endurance and locomotor activity at symptomatic stages of the disease (Da Cruz et al, 2012).…”

“…It is considered as a compensatory mechanism mitigating a compromised energy metabolism (Michel et al, 2012). Consistent with this view, muscle overexpression of FL-PGC-1α, leading to remarkable mitochondrial proliferation, is broadly protective for muscle function in mitochondrial myopathies (Wenz et al, 2008;Dillon et al, 2012), also in amyotrophic lateral sclerosis (Da Cruz et al, 2012). Albeit mitochondrial proliferation might also be detrimental through alterations of mitochondrial regulatory functions such as apoptosis, calcium metabolism or oxidative stress.…”