PGC-1α regulates mitochondrial properties beyond biogenesis with aging and exercise training

Jens Frey Halling, Henrik Jessen, Jacob Nøhr-Meldgaard, Bjørg Thiellesen Buch, Natascha Masselkhi Christensen, Anders Gudiksen, Stine Ringholm, P. Darrell Neufer, Clara Prats, Henriette Pilegaard

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

47 Citationer (Scopus)

Abstract

Impaired mitochondrial function has been implicated in the pathogenesis of age-associated metabolic diseases through regulation of cellular redox balance. Exercise training is known to promote mitochondrial biogenesis in part through induction of the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). Recently, mitochondrial ADP sensitivity has been linked to reactive oxygen species (ROS) emission with potential impact on age-associated physiological outcomes, but the underlying molecular mechanisms remain unclear. Therefore, the present study investigated the effects of aging and exercise training on mitochondrial properties beyond biogenesis, including respiratory capacity, ADP sensitivity, ROS emission, and mitochondrial network structure, in myofibers from inducible muscle-specific PGC-1α-knockout mice and control mice. Aged mice displayed lower running endurance and mitochondrial respiratory capacity than young mice. This was associated with intermyofibrillar mitochondrial network fragmentation, diminished submaximal ADP-stimulated respiration, increased mitochondrial ROS emission, and oxidative stress. Exercise training reversed the decline in maximal respiratory capacity independent of PGC-1α, whereas exercise training rescued the age-related mitochondrial network fragmentation and the impaired submaximal ADP-stimulated respiration in a PGC-1α-dependent manner. Furthermore, lack of PGC-1α was associated with altered phosphorylation and carbonylation of the inner mitochondrial membrane ADP/ATP exchanger adenine nucleotide translocase 1. In conclusion, the present study provides evidence that PGC-1α regulates submaximal ADP-stimulated respiration, ROS emission, and mitochondrial network structure in mouse skeletal muscle during aging and exercise training.

OriginalsprogEngelsk
TidsskriftAmerican journal of physiology. Endocrinology and metabolism
Vol/bind317
Udgave nummer3
Sider (fra-til)E513-E525
ISSN0193-1849
DOI
StatusUdgivet - 2019

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