Age associated low mitochondrial biogenesis may be explained by lack of response of PGC-1α to exercise training

Abstract

Low mitochondriogenesis is critical to explain loss of muscle function in aging and in the development of frailty. The aim of this work was to explain the mechanism by which mitochondriogenesis is decreased in aging and to determine to which extent it may be prevented by exercise training. We used aged rats and compared them with peroxisome proliferator-activated receptor-γ coactivator-1α deleted mice (PGC-1α KO). PGC-1α KO mice showed a significant decrease in the mitochondriogenic pathway in muscle. In aged rats, we found a loss of exercise-induced expression of PGC-1α, nuclear respiratory factor-1 (NRF-1), and of cytochrome C. Thus muscle mitochondriogenesis, which is activated by exercise training in young animals, is not in aged or PGC-1α KO ones. Other stimuli to increase PGC-1α synthesis apart from exercise training, namely cold induction or thyroid hormone treatment, were effective in young rats but not in aged ones. To sum up, the low mitochondrial biogenesis associated with aging may be due to the lack of response of PGC-1α to different stimuli. Aged rats behave as PGC-1α KO mice. Results reported here highlight the role of PGC-1α in the loss of mitochondriogenesis associated with aging and point to this important transcriptional coactivator as a target for pharmacological interventions to prevent age-associated sarcopenia.

Oxygen Consumption and Usage During Physical Exercise: The Balance Between Oxidative Stress and ROS-Dependent Adaptive Signaling

“…B Activates expression of genes regulating cellular growth, respiration, heme biosynthesis, and mitochondrial DNA transcription and replication E Regular physical activity increased expression of NRF1 in young, and a single exercise bout decreased its expression in sketal muscle of both young and old individuals (41) 5-week endurance training increased NRF-1 protein levels in skeletal muscle of young Wistar rats, but not in old ones (80) Treadmill training increases nuclear levels of NRF-2 in skeletal muscle of adult and old rats (105) Correlation of VO2peak with NRF-1 mRNA levels in skeletal muscle of healthy human (102) One bout of 3-h swimming in Wistar rats increases NRF-1-and NRF-2-binding activity (20) Acute exercise did not change NRF-1 mRNA expression in leg skeletal muscle of trained or untrained human (286) In healthy trained male cyclist, 10-km cycling increases skeletal muscle NRF-2 mRNA levels (58) …”

Nutritional supplementations and administration considerations for sarcopenia in older adults

“…Among various proposed mechanisms in sarcopenia, impairment in mitochondria and increased oxidative stress are strongly supported by the literature [76][77][78][79]. Aging results in reduced content and bioenergetics of mitochondria within skeletal muscle and consequently, oxidative phosphorylation capacity will be diminished in myocytes [76,78].…”

“…Aging results in reduced content and bioenergetics of mitochondria within skeletal muscle and consequently, oxidative phosphorylation capacity will be diminished in myocytes [76,78]. Decreased functionality of mitochondria, not only leads to less adenosine triphosphate (ATP) production, but also contributes to greater production and release of ROS from mitochondria [76].…”

Transcriptional Repression of Mitochondrial Function in Aging: A Novel Role for the Silencing Mediator of Retinoid and Thyroid Hormone Receptors Co-Repressor

“…The AMPK/SIRT1-PGC-1a-PPAR axis plays a prominent role in promoting mitochondrial functions; however, this axis is down-regulated in older animals (20,64), suggesting the involvement of dominant negative regulatory mechanisms in the process of aging. Of note, the transcriptional activities of nuclear receptors are negatively regulated by two major corepressors: silencing mediator of retinoid and thyroid hormone receptors (SMRT) and nuclear receptor co-repressor (NCoR).…”