The role of PGC-1 coactivators in aging skeletal muscle and heart

Abstract

Aging is the progressive decline in cellular, tissue, and organ function. This complex process often manifests as loss of muscular strength, cardiovascular function, and cognitive ability. Mitochondrial dysfunction and decreased mitochondrial biogenesis are believed to participate in metabolic abnormalities and loss of organ function, which will eventually contribute to aging and decreased lifespan. In this review, we discuss what is currently known about mitochondrial dysfunction in the aging skeletal muscle and heart. We focused our discussion on the role of PGC-1 coactivators in the regulation of mitochondrial biogenesis and function and possible therapeutic benefits of increased mitochondrial biogenesis in compensating for mitochondrial dysfunction and circumventing aging and aging-related diseases.

Figure 1

PGC-1 coactivators are master regulators of mitochondrial biogenesis. PGC-1 coactivators regulate mitochondrial biogenesis by coordinating the expression of mitochondrial proteins encoded by both the nuclear and mitochondrial genome. To accomplish this, they activate transcription factors such as NRF-1/2 and ERRα, thereby increasing the expression of nuclear DNA-encoded mitochondrial proteins. These mitochondrial proteins are then imported into the mitochondria. One such protein is TFAM, which when upregulated, leads to increased mtDNA replication and increased expression of mtDNA-encoded proteins. These processes initiate an increase in mitochondrial biogenesis.

Figure 2

Decreased PGC-1α expression and mitochondrial dysfunction contribute to skeletal muscle and heart aging. During aging, there is a decrease in PGC-1α expression in the heart and skeletal muscle, which contributes to decrease in mitochondrial protein expression, mtDNA levels, and OXPHOS. This mitochondrial dysfunction is associated with sarcopenia and may contribute to atrophy, protein degradation, and denervation in the skeletal muscle. The adult heart depends primarily on mitochondrial FAO for ATP production. Therefore, decreased PGC-1α expression and mitochondrial dysfunction are believed to contribute to decrease in FAO and increased reliance on carbohydrate metabolism for ATP. This shift in energy metabolism is associated with cardiomyopathy and other cardiovascular diseases. Recent studies have shown that increased PGC-1α expression, whether by exercise/pharmacological agents, leads to increased mitochondrial biogenesis and OXPHOS and may be able to impede the development of sarcopenia and cardiovascular diseases in the aging skeletal muscle and heart, respectively. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]