PGC-1α-mediated regulation of mitochondrial function and physiological implications

Halling, Jens Frey; Pilegaard, Henriette

doi:10.1139/apnm-2020-0005

Cited by 175 publications

(115 citation statements)

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“…Indeed, silencing both LANCL1 and LANCL2 greatly reduced the expression of PGC-1α ( Figure 3 D, upper right panel), a master regulator of mitochondrial function [ 22 ]. Interestingly, silencing both LANCL1 and LANCL2 also greatly reduced (by approx.…”

Section: Resultsmentioning

confidence: 99%

LANCL1 binds abscisic acid and stimulates glucose transport and mitochondrial respiration in muscle cells via the AMPK/PGC-1α/Sirt1 pathway

Spinelli

Begani

Guida

et al. 2021

Molecular Metabolism

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Objective Abscisic acid (ABA) is a plant hormone also present and active in animals. In mammals, ABA regulates blood glucose levels by stimulating insulin-independent glucose uptake and metabolism in adipocytes and myocytes through its receptor LANCL2. The objective of this study was to investigate whether another member of the LANCL protein family, LANCL1, also behaves as an ABA receptor and, if so, which functional effects are mediated by LANCL1. Methods ABA binding to human recombinant LANCL1 was explored by equilibrium-binding experiments with [ 3 H]ABA, circular dichroism, and surface plasmon resonance. Rat L6 myoblasts overexpressing either LANCL1 or LANCL2, or silenced for the expression of both proteins, were used to investigate the basal and ABA-stimulated transport of a fluorescent glucose analog (NBDG) and the signaling pathway downstream of the LANCL proteins using Western blot and qPCR analysis. Finally, glucose tolerance and sensitivity to ABA were compared in LANCL2 −/− and wild-type (WT) siblings. Results Human recombinant LANCL1 binds ABA with a K d between 1 and 10 μM, depending on the assay (i.e., in a concentration range that lies between the low and high-affinity ABA binding sites of LANCL2). In L6 myoblasts, LANCL1 and LANCL2 similarly, i) stimulate both basal and ABA-triggered NBDG uptake (4-fold), ii) activate the transcription and protein expression of the glucose transporters GLUT4 and GLUT1 (4-6-fold) and the signaling proteins AMPK/PGC-1α/Sirt1 (2-fold), iii) stimulate mitochondrial respiration (5-fold) and the expression of the skeletal muscle (SM) uncoupling proteins sarcolipin (3-fold) and UCP3 (12-fold). LANCL2 −/− mice have a reduced glucose tolerance compared to WT. They spontaneously overexpress LANCL1 in the SM and respond to chronic ABA treatment (1 μg/kg body weight/day) with an improved glycemia response to glucose load and an increased SM transcription of GLUT4 and GLUT1 (20-fold) of the AMPK/PGC-1α/Sirt1 pathway and sarcolipin, UCP3, and NAMPT (4- to 6-fold). Conclusions LANCL1 behaves as an ABA receptor with a somewhat lower affinity for ABA than LANCL2 but with overlapping effector functions: stimulating glucose uptake and the expression of muscle glucose transporters and mitochondrial uncoupling and respiration via the AMPK/PGC-1α/Sirt1 pathway. Receptor redundancy may have been advantageous in animal evolution, given the role of the ABA/LANCL system in the insulin-independent stimulation of cell glucose uptake and energy metabolism.

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Section: Resultsmentioning

confidence: 99%

LANCL1 binds abscisic acid and stimulates glucose transport and mitochondrial respiration in muscle cells via the AMPK/PGC-1α/Sirt1 pathway

Spinelli

Begani

Guida

et al. 2021

Molecular Metabolism

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“…Stimulation of gene expression by acute exercise in skeletal muscle is a mechanism to increase production of protein in muscle ( Egan and Zierath, 2013 ). In this regard, PGC-1α gene expression has central role in increasing mitochondrial biogenesis ( Ventura-Clapier et al, 2008 ; Kang and Li Ji, 2012 ; Halling and Pilegaard, 2020 ). In line with previous findings ( De Filippis et al, 2008 ), we show that subjects with obesity have impaired PGC-1α mRNA expression in muscle in response to acute exercise.…”

Section: Discussionmentioning

confidence: 99%

“…Rapid increase in gene expression in skeletal muscle in response to acute exercise enhances translational processing and elevates protein synthesis in muscle ( Egan and Zierath, 2013 ). PGC-1α has central role in regulating mitochondrial biogenesis ( Ventura-Clapier et al, 2008 ; Kang and Li Ji, 2012 ; Halling and Pilegaard, 2020 ), and thus upregulation of PGC-1α by exercise may be necessary to acutely increase mitochondrial protein synthesis in muscle as a result of aerobic exercise. In this regard, increase in mitochondrial protein synthesis in muscle is observed concomitant with increase in PGC-1α gene expression in muscle ( Donges et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

“…Although expression of PGC-1α increases immediately in response to aerobic exercise ( Wright et al, 2007 ; De Filippis et al, 2008 ; Harber et al, 2010 ; Donges et al, 2012 ), the same response is not evident in muscle of humans with obesity ( De Filippis et al, 2008 ). Based on this evidence, and the central role of PGC-1α gene expression in regulating mitochondrial biogenesis ( Ventura-Clapier et al, 2008 ; Kang and Li Ji, 2012 ; Halling and Pilegaard, 2020 ), we hypothesized that muscle mitochondrial protein synthesis increases during the collective time period that includes aerobic exercise and post-exercise recovery in humans without obesity, but not in humans with obesity.…”

Section: Introductionmentioning

confidence: 99%

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Lack of Increase in Muscle Mitochondrial Protein Synthesis During the Course of Aerobic Exercise and Its Recovery in the Fasting State Irrespective of Obesity

et al. 2021

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Acute aerobic exercise induces skeletal muscle mitochondrial gene expression, which in turn can increase muscle mitochondrial protein synthesis. In this regard, the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), is a master regulator of mitochondrial biogenesis, and thus mitochondrial protein synthesis. However, PGC-1α expression is impaired in muscle of humans with obesity in response to acute aerobic exercise. Therefore, we sought to determine whether muscle mitochondrial protein synthesis is also impaired under the same conditions in humans with obesity. To this end, we measured mitochondrial and mixed-muscle protein synthesis in skeletal muscle of untrained subjects with (body fat: 34.7 ± 2.3%) and without (body fat: 25.3 ± 3.3%) obesity in a basal period and during a continuous period that included a 45 min cycling exercise (performed at an intensity corresponding to 65% of heart rate reserve) and a 3-h post-exercise recovery. Exercise increased PGC-1α mRNA expression in muscle of subjects without obesity, but not in subjects with obesity. However, muscle mitochondrial protein synthesis did not increase in either subject group. Similarly, mixed-muscle protein synthesis did not increase in either group. Concentrations of plasma amino acids decreased post-exercise in the subjects without obesity, but not in the subjects with obesity. We conclude that neither mitochondrial nor mixed-muscle protein synthesis increase in muscle of humans during the course of a session of aerobic exercise and its recovery period in the fasting state irrespective of obesity.Trial Registration: The study has been registered within ClinicalTrials.gov (NCT01824173).

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“…Moreover, it was also demonstrated that increased SIRT3 activity can suppress mPT pore formation by which it can prevent mitochondrial dysfunctions [ 166 ]. It was also demonstrated that PGC-1α activation can enhance mitochondrial biogenesis and improve mitochondrial energy metabolism, therefore increasing lifespan and protecting against neurodegenerative diseases [ 167 ]. PGC-1α can bind and co-activate the transcription factor PPARγ (belongs to the superfamily of nuclear receptors) and promotes not only mitochondrial biogenesis, but also SOD and catalase activity, glucose metabolism and oxidative phosphorylation [ 162 , 168 , 169 , 170 ], whereas reduces the level of NF-κB and pro-inflammatory cytokines [ 171 , 172 ], as well as Aβ generation [ 173 , 174 ].…”

Section: Main Features Of Aging Processesmentioning

confidence: 99%

Beneficial Effects of Exogenous Ketogenic Supplements on Aging Processes and Age-Related Neurodegenerative Diseases

2021

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Life expectancy of humans has increased continuously up to the present days, but their health status (healthspan) was not enhanced by similar extent. To decrease enormous medical, economical and psychological burden that arise from this discrepancy, improvement of healthspan is needed that leads to delaying both aging processes and development of age-related diseases, thereby extending lifespan. Thus, development of new therapeutic tools to alleviate aging processes and related diseases and to increase life expectancy is a topic of increasing interest. It is widely accepted that ketosis (increased blood ketone body levels, e.g., β-hydroxybutyrate) can generate neuroprotective effects. Ketosis-evoked neuroprotective effects may lead to improvement in health status and delay both aging and the development of related diseases through improving mitochondrial function, antioxidant and anti-inflammatory effects, histone and non-histone acetylation, β-hydroxybutyrylation of histones, modulation of neurotransmitter systems and RNA functions. Administration of exogenous ketogenic supplements was proven to be an effective method to induce and maintain a healthy state of nutritional ketosis. Consequently, exogenous ketogenic supplements, such as ketone salts and ketone esters, may mitigate aging processes, delay the onset of age-associated diseases and extend lifespan through ketosis. The aim of this review is to summarize the main hallmarks of aging processes and certain signaling pathways in association with (putative) beneficial influences of exogenous ketogenic supplements-evoked ketosis on lifespan, aging processes, the most common age-related neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis), as well as impaired learning and memory functions.

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PGC-1α-mediated regulation of mitochondrial function and physiological implications

Cited by 175 publications

References 106 publications

LANCL1 binds abscisic acid and stimulates glucose transport and mitochondrial respiration in muscle cells via the AMPK/PGC-1α/Sirt1 pathway

LANCL1 binds abscisic acid and stimulates glucose transport and mitochondrial respiration in muscle cells via the AMPK/PGC-1α/Sirt1 pathway

Lack of Increase in Muscle Mitochondrial Protein Synthesis During the Course of Aerobic Exercise and Its Recovery in the Fasting State Irrespective of Obesity

Beneficial Effects of Exogenous Ketogenic Supplements on Aging Processes and Age-Related Neurodegenerative Diseases

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