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

doi:10.1152/ajpendo.00059.2019

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

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.

Original language	English
Journal	American journal of physiology. Endocrinology and metabolism
Volume	317
Issue number	3
Pages (from-to)	E513-E525
ISSN	0193-1849
DOIs	https://doi.org/10.1152/ajpendo.00059.2019
Publication status	Published - Sept 2019

Keywords

ADP sensitivity
aging
exercise
mitochondria
PGC-1α
ROS

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Halling, J. F., Jessen, H., Nøhr-Meldgaard, J., Buch, B. T., Christensen, N. M., Gudiksen, A., Ringholm, S., Neufer, P. D., Prats, C., & Pilegaard, H. (2019). PGC-1α regulates mitochondrial properties beyond biogenesis with aging and exercise training. American journal of physiology. Endocrinology and metabolism, 317(3), E513-E525. https://doi.org/10.1152/ajpendo.00059.2019

Halling, JF, Jessen, H, Nøhr-Meldgaard, J, Buch, BT, Christensen, NM, Gudiksen, A , Ringholm, S, Neufer, PD, Prats, C & Pilegaard, H 2019, 'PGC-1α regulates mitochondrial properties beyond biogenesis with aging and exercise training', American journal of physiology. Endocrinology and metabolism, vol. 317, no. 3, pp. E513-E525. https://doi.org/10.1152/ajpendo.00059.2019

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title = "PGC-1α regulates mitochondrial properties beyond biogenesis with aging and exercise training",

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.",

keywords = "ADP sensitivity, aging, exercise, mitochondria, PGC-1α, ROS",

author = "Halling, {Jens Frey} and Henrik Jessen and Jacob N{\o}hr-Meldgaard and Buch, {Bj{\o}rg Thiellesen} and Christensen, {Natascha Masselkhi} and Anders Gudiksen and Stine Ringholm and Neufer, {P. Darrell} and Clara Prats and Henriette Pilegaard",

year = "2019",

month = sep,

doi = "10.1152/ajpendo.00059.2019",

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T1 - PGC-1α regulates mitochondrial properties beyond biogenesis with aging and exercise training

AU - Halling, Jens Frey

AU - Jessen, Henrik

AU - Nøhr-Meldgaard, Jacob

AU - Buch, Bjørg Thiellesen

AU - Christensen, Natascha Masselkhi

AU - Gudiksen, Anders

AU - Ringholm, Stine

AU - Neufer, P. Darrell

AU - Prats, Clara

AU - Pilegaard, Henriette

PY - 2019/9

Y1 - 2019/9

N2 - 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.

AB - 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.

KW - ADP sensitivity

KW - aging

KW - exercise

KW - mitochondria

KW - PGC-1α

KW - ROS

U2 - 10.1152/ajpendo.00059.2019

DO - 10.1152/ajpendo.00059.2019

M3 - Journal article

C2 - 31265325

SN - 0193-1849

VL - 317

SP - E513-E525

JO - American journal of physiology. Endocrinology and metabolism

JF - American journal of physiology. Endocrinology and metabolism

IS - 3

ER -

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

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Keywords

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