ArticlePublisher preview available

The influence of aerobic exercise on mitochondrial quality control in skeletal muscle

Wiley
The Journal of Physiology
Authors:
Ashleigh Philp at UNSW Sydney
Ashleigh Philp
Nicholas Saner at Victoria University
Nicholas Saner
Michael Lazarou at Monash University (Australia)
Michael Lazarou
Ian G. Ganley
Ian G. Ganley
Ian G. Ganley
  • This person is not on ResearchGate, or hasn't claimed this research yet.
Show all 5 authorsHide
Read publisher preview
Download citation
To read the full-text of this research, you can request a copy directly from the authors.

Abstract and Figures

Mitochondria are dynamic organelles, intricately designed to meet cellular energy requirements. To accommodate alterations in energy demand, mitochondria have a high degree of plasticity, changing in response to transient activation of numerous stress‐related pathways. This adaptive response is particularly relevant in highly metabolic tissues such as skeletal muscle, where mitochondria support numerous biological processes related to metabolism, growth and regeneration. Aerobic exercise is a potent stimulus for skeletal muscle remodelling, leading to alterations in substrate utilisation, fibre‐type composition and performance. Underlying these physiological responses is a change in mitochondrial quality control (MQC), a term encompassing the co‐ordination of mitochondrial synthesis (biogenesis), remodelling (dynamics) and degradation (mitophagy) pathways. Understanding of MQC in skeletal muscle and the regulatory role of aerobic exercise of this process are rapidly advancing, as are the molecular techniques allowing the study of MQC in vivo. Given the emerging link between MQC and the onset of numerous non‐communicable diseases, understanding the molecular regulation of MQC, and the role of aerobic exercise in this process, will have substantial future impact on therapeutic approaches to manipulate MQC and maintain mitochondrial function across health span. image
Overview of mitochondrial quality control in skeletal muscle Mitochondrial remodelling is initiated in skeletal muscle via alterations in cellular homeostasis, mediated via an acute stress response (1). Disturbance in cellular homeostasis leads to modulation of mitochondrial dynamics, allowing cyclical changes in fusion and fission (2). Fission stimulates the recruitment of damaged mitochondria to the autophagosome for mitophagy, whilst fusion promotes mitochondrial reticulum expansion and an increase in biogenesis, which ultimately increases mitochondrial protein balance (3). The cumulative effect of alterations in mitochondrial dynamics, biogenesis and mitophagy is an increase in mitochondrial function (4).
Overview of mitochondrial quality control in skeletal muscle Mitochondrial remodelling is initiated in skeletal muscle via alterations in cellular homeostasis, mediated via an acute stress response (1). Disturbance in cellular homeostasis leads to modulation of mitochondrial dynamics, allowing cyclical changes in fusion and fission (2). Fission stimulates the recruitment of damaged mitochondria to the autophagosome for mitophagy, whilst fusion promotes mitochondrial reticulum expansion and an increase in biogenesis, which ultimately increases mitochondrial protein balance (3). The cumulative effect of alterations in mitochondrial dynamics, biogenesis and mitophagy is an increase in mitochondrial function (4).
… 
Reversible phosphorylation regulates DRP1 activity in vivo Drp1 activity is modulated via reversible phosphorylation at conserved serine residues. In response to cytokine stimulation, Pim‐1 kinase phosphorylates Drp1Ser637, whilst alterations in cAMP availability leads to PKA activation and Drp1 Ser637 and Drp1 Ser656 phosphorylation. Both phosphorylation events lead to Drp1 inhibition and Drp1 export from the mitochondria. In contrast, Drp1Ser616 phosphorylation by PKC‐δ, ERK2, CDK1 and CDK5 leads to an increase in Drp1 activity and increased mitochondrial fission through Drp1 association with MFF, MiD49 and MiD51. In parallel, Ca²⁺‐mediated increases in calcineurin activity, lead to activation of Drp1 via Drp1 Ser637/Ser656 dephosphorylation.
Reversible phosphorylation regulates DRP1 activity in vivo Drp1 activity is modulated via reversible phosphorylation at conserved serine residues. In response to cytokine stimulation, Pim‐1 kinase phosphorylates Drp1Ser637, whilst alterations in cAMP availability leads to PKA activation and Drp1 Ser637 and Drp1 Ser656 phosphorylation. Both phosphorylation events lead to Drp1 inhibition and Drp1 export from the mitochondria. In contrast, Drp1Ser616 phosphorylation by PKC‐δ, ERK2, CDK1 and CDK5 leads to an increase in Drp1 activity and increased mitochondrial fission through Drp1 association with MFF, MiD49 and MiD51. In parallel, Ca²⁺‐mediated increases in calcineurin activity, lead to activation of Drp1 via Drp1 Ser637/Ser656 dephosphorylation.
… 
Regulation of mitophagy via ubiquitin‐dependent and ‐independent pathways Ubiquitin‐dependent mitophagy is predominantly thought to be initiated via the coordinated activation of the PINK1/Parkin pathway. Following mitochondrial depolarisation, PINK1 phosphorylates ubiquitin (Ub)Ser65 and ParkinSer65, leading to Parkin recruitment to the mitochondria. In addition, Parkin recruitment has also been observed in PINK1–/– cardiomyocytes, suggesting additional nodes of Parkin activation. The development of ubiquitin chains recruits the mitophagy receptors optineurin (OPTN), NDP52 and p62 to support autophagosomal generation through interaction with LC3 proteins. This process is facilitated by TBK1Ser172 and ULK1Ser555 phosphorylation, which are downstream substrates of AMPK. Once autophagosome generation has been completed, mitochondrial‐autophagosome complexes are transferred to the lysosome for mitophagy. Ubiquitin‐independent mitophagy is facilitated via the mitophagy receptors FUNDC1, cardiolipin, BNIP3 and NIX, which following activation via numerous cellular stress processes, recruit LC3/GABARAP proteins to initiate autophagosome generation and targeting to the lysosome for mitophagy.
Regulation of mitophagy via ubiquitin‐dependent and ‐independent pathways Ubiquitin‐dependent mitophagy is predominantly thought to be initiated via the coordinated activation of the PINK1/Parkin pathway. Following mitochondrial depolarisation, PINK1 phosphorylates ubiquitin (Ub)Ser65 and ParkinSer65, leading to Parkin recruitment to the mitochondria. In addition, Parkin recruitment has also been observed in PINK1–/– cardiomyocytes, suggesting additional nodes of Parkin activation. The development of ubiquitin chains recruits the mitophagy receptors optineurin (OPTN), NDP52 and p62 to support autophagosomal generation through interaction with LC3 proteins. This process is facilitated by TBK1Ser172 and ULK1Ser555 phosphorylation, which are downstream substrates of AMPK. Once autophagosome generation has been completed, mitochondrial‐autophagosome complexes are transferred to the lysosome for mitophagy. Ubiquitin‐independent mitophagy is facilitated via the mitophagy receptors FUNDC1, cardiolipin, BNIP3 and NIX, which following activation via numerous cellular stress processes, recruit LC3/GABARAP proteins to initiate autophagosome generation and targeting to the lysosome for mitophagy.
… 
Figures - available from: The Journal of Physiology
This content is subject to copyright. Terms and conditions apply.
A preview of this full-text is provided by Wiley.
Learn more
Content available from The Journal of Physiology 
This content is subject to copyright. Terms and conditions apply.
J Physiol 599.14 (2021) pp 3463–3476 3463
The Journal of Physiology
SYMPOSIUM REVIEW
The inuence of aerobic exercise on mitochondrial quality
control in skeletal muscle
Ashleigh M. Philp1,2,NicholasJ.Saner
3,MichaelLazarou
4, Ian G. Ganley5and Andrew Philp1,2
1Healthy Ageing Research Theme, Garvan Institute of Medical Research, 384 Victoria Street, Sydney, New South Wales, 2010, Australia
2St Vincent’s Medical School, UNSW Medicine, UNSW Sydney, Sydney, New South Wales, 2010, Australia
3Sports Cardiology, Baker Heart and Diabetes Institute, Melbourne, Australia
4Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
5Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK
Edited by: Ian Forsythe, Russell Hepple
Abstract Mitochondria are dynamic organelles, intricately designed to meet cellular energy
requirements. To accommodate alterations in energy demand, mitochondria have a high degree
of plasticity, changing in response to transient activation of numerous stress-related pathways.
This adaptive response is particularly relevant in highly metabolic tissues such as skeletal
muscle, where mitochondria support numerous biological processes related to metabolism,
growth and regeneration. Aerobic exercise is a potent stimulus for skeletal muscle remodelling,
A. M. Philp and N. J. Saner contributed equally to this work.
This review was presented at the joint Australian Physiological Society and Australian Society for Biophysics Meeting symp osium ‘Unravelling the
mysteriesofmitochondriainhealthanddisease’organisedbyLiviaHool(UniversityofWA),whichtookplaceattheAustralianNationalUniversity,
Acton Campus, Canberra, Australia, 2 December 2019.
© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society DOI: 10.1113/JP279411
... Mitochondria support the metabolic activity, growth, and regeneration of skeletal muscles, with mitochondrial dysfunction being associated with a reduction in oxidative capacity and a decline in fatigue resistance [69,70]. Thus, mitochondrial biogenesis is essential for promoting changes in substrate utilization, muscle fiber composition, and exercise performance. ...
Effects of 3-(4-Hydroxy-3-methoxyphenyl)propionic Acid on Regulating Oxidative Stress and Muscle Fiber Composition
Article
Full-text available
  • Feb 2025
Background/Objectives: Our previous study demonstrated that 3-(4-hydroxy-3-methoxyphenyl)propionic acid (HMPA) administration improved grip strength and reduced blood urea nitrogen levels, but its underlying mechanisms remain unclear. This study aimed to investigate the effects of HMPA on oxidative stress and muscle fiber composition, emphasizing its potential role in modulating redox signaling pathways and influencing muscle development. Methods: Eight-week-old male C57BL/6 mice were orally administered HMPA solution (50 or 500 mg/kg/day) or distilled water (10 mL/kg) for 14 days, and then divided into sedentary and exhaustive exercise groups to evaluate oxidative stress status, myosin heavy chain (MHC) isoform expression, and underlying mechanisms. Results: Both low and high doses of HMPA reduced oxidative stress by decreasing plasma reactive oxygen metabolites. High-dose HMPA reduced plasma nitrite/nitrate levels and enhanced antioxidant capacity post-exercise, accompanied by changes in the mRNA abundance of antioxidant enzymes (e.g., Sod1 and Nqo1) and reductions in the mRNA abundance of nitric oxide synthases (e.g., Nos2 and Nos3) in the soleus. Additionally, high-dose HMPA administration increased the protein expression of MYH4 in the soleus, while low-dose HMPA enhanced the gene expression of Myh4 and Igf1, suggesting that HMPA may promote fast-twitch fiber hypertrophy through the activation of the IGF-1 pathway. Furthermore, low-dose HMPA significantly increased the gene expression of Sirt1 and Nrf1, as well as AMPK phosphorylation post-exercise, suggesting low-dose HMPA may improve mitochondrial biogenesis and exercise adaptation. Conclusions: These findings suggest that HMPA may serve as a dietary supplement to regulate redox balance, enhance antioxidant defenses, and promote the formation of fast-twitch fibers.
View
... This process is driven by the upregulation of PGC-1α. Increased PGC-1α expression in response to physical activity promotes the replication and growth of mitochondria, thereby improving the overall capacity of cells to produce ATP [146]. This enhancement in mitochondrial function is particularly beneficial for Multiple Sclerosis patients, as it helps to counteract the energy deficits caused by impaired oxidative phosphorylation. ...
Impact of Physical Activity on Cellular Metabolism Across Both Neurodegenerative and General Neurological Conditions: A Narrative Review
Article
Full-text available
  • Nov 2024
Background: Regular physical activity plays a crucial role in modulating cellular metabolism and mitigating the progression of neurodegenerative diseases such as Alzheimer's, Parkin-son's, and Multiple Sclerosis. Objective: The objective of this review is to evaluate the molecular mechanisms by which exercise influences cellular metabolism, with a focus on its potential as a therapeutic intervention for neurological disorders. Methods: A comprehensive literature review was conducted using peer-reviewed scientific articles, with a focus on the period between 2015 and 2024, to analyze the effects of exercise on mitochondrial function, oxidative stress, and metabolic health. Results: The findings indicate that exercise promotes mitochondrial biogenesis, enhances oxidative phosphorylation, and reduces reactive oxygen species, contributing to improved energy production and cellular resilience. These metabolic adaptations are associated with delayed disease progression and reduced symptoms in patients with neurodegenerative conditions. Additionally, integrating exercise with nutritional strategies may further enhance therapeutic outcomes by addressing metabolic disturbances comprehensively. Conclusion: This review concludes that person-alized exercise protocols should be developed to optimize metabolic benefits for patients with neu-rological diseases, while future research should focus on biomarker development for individualized treatment approaches. These findings highlight the importance of non-pharmacological interventions in managing neurodegenerative diseases.
View
... Regular physical activity decreases ROS-driven damage to DNA and increases mitochondrial turnover and quantity, which directly improves mitochondrial function and effectively reduces the agerelated decline in mitochondrial function and quantity (Barbieri et al., 2015;Hakkinen et al., 2002;Parise et al., 2005;Philp et al., 2021;Romanello & Sandri, 2015;Tarnopolsky, 2009). Importantly, peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α) is upregulated by exercise training and is a strong mitochondrial function modulator. ...
Exercise training to preserve vitality capacity in ageing
Article
Full-text available
Ageing is an escalating global health issue, with the World Health Organization (WHO) reporting that one in six individuals will be 60 years or older by the year 2030. Therefore, understanding the mechanisms of complex biological ageing processes and associated healthcare challenges has become increasingly important. Intrinsic capacity (IC), defined by WHO as the composite of all physical and mental capacities an individual possesses, can be used as a proxy for defining healthy ageing. IC has five key components: locomotion, cognition, psychological, sensory, and vitality capacity (VC). This review paper specifically focuses on exercise as an effective tool to preserve VC in ageing populations. The physiological domains of VC discussed include energy and metabolism, neuromuscular function, immune and stress response, mitochondrial function, and the methylation clock. Additionally, we highlight potential outcome measures for assessing each of these domains. This review also covers areas of focus for future research and possible interventions. We ultimately conclude that ageing is a complex, multifaceted process resulting in deficits across multiple VC components. However, regular exercise is capable of producing physiological adaptations that may be beneficial in the context of healthy ageing and improving or preserving the status of VC components.
View
... Aerobic exercise serves as a potent stimulus to enhance mitochondrial mass and improve skeletal muscle function (56). This type of exercise is beneficial for enhancing the immune system and preventing or managing chronic conditions such as cardiovascular disease and diabetes (57). ...
Relationship between physical activities and mental health in older people: a bibliometric analysis
Article
Full-text available
  • Oct 2024
Objective To summarize the general situation and focal points of research on the physical activity and mental health of older people over the past 15 years and provide references for future research. Methods Literature published between January 1, 2009, and December 31, 2023, was retrieved from the Web of Science core database. A bibliometric visualization analysis of countries/regions, institutions, authors, keywords, and references was conducted using CiteSpace6.1.R6. Results A total of 4,329 articles were included, and the annual number of articles published over the past 15 years showed an upward trend. The articles were primarily from 65 countries/regions and 626 institutions. The most represented country and institution were the USA and the University of Pittsburgh, respectively. Among the authors identified, Schuch and Callow were the most influential. The research focuses on four areas: the psychological effects of physical activity in older people; physical activity intervention approaches to the mental health of older people; physical activity and mental health assessment questionnaires; and the impact of physical activity on multidimensional aging. Research frontiers involve emerging topics such as the assessment and intervention of mental health in older people and the relationship between their physical activity and cognitive function. Conclusion This study conducted a comprehensive, objective, and visual analysis of publications and revealed the status of relevant studies, trending topics, and trends concerning the physical activity and mental health of older people from 2009 to 2023. We hope that this work will help researchers identify new perspectives on potential collaborators, important topics, and research frontiers.
View
... 30 It does generate a mitochondrial energetic deficit, similar to caloric restriction, which has been recognized as a hormetic mechanism, 31 involving ROS production, mitochondrial unfolded protein response (UPRmt), and release of mitochondria-derived peptides (MDPs) with beneficial metabolic effects. 32 Exercise also has a positive effect on the acceleration of mitochondrial turnover 33 since it increases mitophagy and biogenesis, 34 and it can reduce most of the described hallmarks of aging 33 counteracting age-related decline. 35 Our group has developed a model to evaluate ageassociated osteosarcopenic obesity in female rats, where long-term HFD supplementation was given by feeding them from weaning to 15 months of age. ...
Sedentary Lifestyles and a Hypercaloric Diets During Middle Age, are Binomial Conducive to Fatal Progression, That is Counteracted by the Hormetic Treatment of Exercise, Metformin, and Tert-Butyl Hydroquinone: An Analysis of Female Middle-Aged Rat Liver Mitochondria
Article
Full-text available
  • Oct 2024
The world’s population continuous to shift towards older, less active and more sedentary lifestyles especially during middle age. In addition consumption of high-caloric diets, increases the risk of metabolic and cardiovascular afflictions. Developing clinical strategies to mitigate those health complications represent a difficult challenge. Our group has previously shown that combining metformin (MTF) and tert-butyl hydroquinone (tBHQ) treatments, in addition to exercise, partially prevents liver damage associated with obesity. Hence, we evaluated the role of exercise in combination with MTF and tBHQ (triple-treatment) to counteract mitochondrial damage in the liver from obese middle-aged female rats. Animals were fed a high-fat diet (HFD) starting at 21 days till 15 months of age. The treated groups performed a Fartlek-type exercise 5 days/week for 30 min/session. MTF and tBHQ were administered at a dose of 250 mg/kg/day, and 10 mg/kg/day, respectively, for 7 days/month from 10 to 15 months of age. Triple-treatment therapeutic approach promoted animal survival, and increased AMPK and PGC1α expression. Treatments increased mitochondrial ATP synthesis and OXPHOS complexes activities, recovered membrane potential, and decreased ROS production. In summary, exercise in combination with intermittent tBHQ and MTF treatments proved to be an excellent intervention to prevent mitochondrial damage caused by HFD.
View
The role of exosomes for sustained specific cardiorespiratory and metabolic improvements in males with type 2 diabetes after detraining
Article
  • Dec 2024
Background High-intensity interval training (HIIT) has been shown to improve cardiorespiratory fitness (V˙O2 max) but may ameliorate insulin sensitivity only in insulin-resistant humans. It is yet unclear whether these benefits persist after detraining and to which extent duration and effectiveness of metabolic improvements differ between individuals without and with prediabetes or type 2 diabetes (T2D). Understanding these differences is relevant for developing targeted exercise training modes for individuals with different stages of dysglycemia. Methods Men with (20 T2D) and without T2D (12 insulin-sensitive, IS-NDM; 10 insulin-resistant, IR-NDM) underwent hyperinsulinemic-euglycemic clamps, spiroergometry, ectopic lipid quantification and muscle biopsies at baseline, after 12-week HIIT and after 4-week detraining. Findings After detraining, the HIIT-stimulated V˙O2 max declined in T2D and IR-NDM, but remained higher compared to baseline in all groups. The HIIT-induced changes in hepatic insulin sensitivity and ectopic lipid content were sustained after detraining in T2D and IR-NDM, whereas improvements of whole-body insulin sensitivity were abolished in T2D. T2D and IR-NDM showed persistent increases in the number of small extracellular vesicles, which carry among others antioxidant proteins. The ratio of reduced-to-oxidized glutathione further decreased after detraining in all groups, whereas changes in proteins involved in mitochondrial turnover were dependent on insulin sensitivity, with some evidence for upregulation of fusion and mitophagy in T2D and IR-NDM and upregulation of fission in IS-NDM. Levels of different lipolytic proteins were reduced in all participants after detraining. Interpretation HIIT offers sustained improvement of energy metabolism and hepatic insulin sensitivity in insulin-resistant humans, but long-term adherence is required to maintain these benefits. Funding Funding bodies that contributed to this study are listed in the Acknowledgements section.
View
The Acute and Chronic influence of Exercise on Mitochondrial Dynamics in Skeletal Muscle
Article
  • Oct 2024
  • AM J PHYSIOL-ENDOC M
Exercise and nutritional modulation are potent stimuli for eliciting increases in mitochondrial mass and function. Collectively, these beneficial adaptations are increasingly recognized to coincide with improvements to skeletal muscle health. Mitochondrial dynamics of fission and fusion are increasingly implicated as having a central role in mediating aspects of key organelle adaptions that are seen with exercise. Exercise-induced mitochondrial adaptations that dynamics have been implicated in are: 1) Increases to mitochondrial turnover, resulting from elevated rates of mitochondrial synthesis (biogenesis) and degradative (mitophagy) processes. 2) Morphological changes to the 3D tubular network, known as the mitochondrial reticulum, that mitochondria form in skeletal muscle. Notably, mitochondrial fission has also been implicated in coordinating increases in mitophagy, following acute exercise. Further, increased fusion following exercise training promotes increased connectivity of the mitochondrial reticulum and is associated with improved metabolism and mitochondrial function. However, the molecular basis and fashion in which exercise infers beneficial mitochondrial adaptations through mitochondrial dynamics remains poorly understood. This review attempts to highlight recent developments investigating the effects of exercise on mitochondrial dynamics, while attempting to offer a perspective of the methodological refinements and potential variables, such as substrate/glycogen availability, which should be considered going forward.
View
Normobaric hypoxia accelerates high-intensity intermittent training-induced mitochondrial biogenesis (PGC-1α)- and dynamics (OPA1)-related protein expressions in rat gastrocnemius muscle
Article
  • Oct 2024
High-intensity intermittent training (HIIT) in a normobaric hypoxic environment enhances exercise capacity, possibly by increasing the mitochondrial content in skeletal muscle; however, the molecular mechanisms underlying these adaptations are not well understood. Therefore, we investigated whether HIIT under normobaric hypoxia can enhance the expression of proteins involved in mitochondrial biogenesis and dynamics in rat gastrocnemius muscle. Five-week-old male Wistar rats (n = 24) were randomly assigned to the following four groups: (1) sedentary under normoxia (20.9% O2) (NS), (2) training under normoxia (NT), (3) sedentary under normobaric hypoxia (14.5% O2) (HS), and (4) training under normobaric hypoxia (HT). The training groups in both conditions were engaged in HIIT on a treadmill five to six days per week for nine weeks. From the fourth week of the training period, the group assigned to hypoxic conditions was exposed to normobaric hypoxia. Forty-eight hours after completing the final training session, gastrocnemius muscles were surgically removed, and mitochondrial enzyme activity and mitochondrial biogenesis and dynamics regulatory protein levels were determined. Citrate synthase (CS) activity and mitochondrial oxygen phosphorylation (OXPHOS) subunits in the gastrocnemius muscle in the HT significantly exceeded those in the other three groups. Moreover, the levels of a master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and a mitochondrial fusion-related protein, optic atrophy 1 (OPA1), were significantly increased by HIIT under normobaric hypoxia. Our data indicates that HIIT and normobaric hypoxia increase the expression of mitochondrial biogenesis- and dynamics-related proteins in skeletal muscles.
View
View
Chemerin regulates glucose and lipid metabolism by changing mitochondrial structure and function associated with androgen/androgen receptor
Article
  • May 2024
  • AM J PHYSIOL-ENDOC M
The adipokine chemerin contributes to exercise-induced improvements in glucose and lipid metabolism; however, the underlying mechanism remains unclear. We aimed to confirm the impact of reduced chemerin expression on exercise-induced improvement in glycolipid metabolism in male diabetic (DM) mice through exogenous chemerin administration. Furthermore, the underlying mechanism of chemerin involved in changes in muscle mitochondria function mediated by androgen/androgen receptor (AR) was explored by generating adipose-specific and global chemerin knockout (adipo-chemerin-/- and chemerin-/-) mice. DM mice were categorized into the DM, exercised DM (EDM), and EDM + chemerin supplementation groups. Adipo-chemerin-/- and chemerin-/- mice were classified in the sedentary or exercised groups and fed either a normal or high-fat diet. Exercise mice underwent a 6-week aerobic exercise regimen. The serum testosterone and chemerin levels, glycolipid metabolism indices, mitochondrial function, and protein levels involved in mitochondrial biogenesis and dynamics were measured. Notably, exogenous chemerin reversed exercise-induced improvements in glycolipid metabolism, AR protein levels, mitochondrial biogenesis, and mitochondrial fusion in DM mice. Moreover, adipose-specific chemerin knockout improved glycolipid metabolism, enhanced exercise-induced increases in testosterone and AR levels in exercised mice, and alleviated the detrimental effects of a high-fat diet on mitochondrial morphology, biogenesis, and dynamics. Finally, similar improvements in glucose metabolism (but not lipid metabolism), mitochondrial function, and mitochondrial dynamics were observed in chemerin-/- mice. In conclusion, decreased chemerin levels affect exercise-induced improvements in glycolipid metabolism in male mice by increasing mitochondrial number and function, likely through changes in androgen/AR signaling.
View
Fidelity and coordination of mitochondrial protein synthesis in health and disease
Article
Full-text available
The evolutionary acquisition of mitochondria has given rise to the diversity of eukaryotic life. Mitochondria have retained their ancestral α‐proteobacterial traits through the maintenance of double membranes and their own circular genome. Their genome varies in size from very large in plants to the smallest in animals and their parasites. The mitochondrial genome encodes essential genes for protein synthesis and has to coordinate its expression with the nuclear genome from which it sources most of the proteins required for mitochondrial biogenesis and function. The mitochondrial protein synthesis machinery is unique because it is encoded by both the nuclear and mitochondrial genomes thereby requiring tight regulation to produce the respiratory complexes that drive oxidative phosphorylation for energy production. The fidelity and coordination of mitochondrial protein synthesis are essential for ATP production. Here we compare and contrast the mitochondrial translation mechanisms in mammals and fungi to bacteria and reveal that their diverse regulation can have unusual impacts on the health and disease of these organisms. We highlight that in mammals the rate of protein synthesis is more important than the fidelity of translation, enabling coordinated biogenesis of the mitochondrial respiratory chain with respiratory chain proteins synthesised by cytoplasmic ribosomes. Changes in mitochondrial protein fidelity can trigger the activation of the diverse cellular signalling networks in fungi and mammals to combat dysfunction in energy conservation. The physiological consequences of altered fidelity of protein synthesis can range from liver regeneration to the onset and development of cardiomyopathy. image
View
Transcriptomic profiling of skeletal muscle adaptations to exercise and inactivity
Article
Full-text available
  • Jan 2020
The molecular mechanisms underlying the response to exercise and inactivity are not fully understood. We propose an innovative approach to profile the skeletal muscle transcriptome to exercise and inactivity using 66 published datasets. Data collected from human studies of aerobic and resistance exercise, including acute and chronic exercise training, were integrated using meta-analysis methods (www.metamex.eu). Here we use gene ontology and pathway analyses to reveal selective pathways activated by inactivity, aerobic versus resistance and acute versus chronic exercise training. We identify NR4A3 as one of the most exercise- and inactivity-responsive genes, and establish a role for this nuclear receptor in mediating the metabolic responses to exercise-like stimuli in vitro. The meta-analysis (MetaMEx) also highlights the differential response to exercise in individuals with metabolic impairments. MetaMEx provides the most extensive dataset of skeletal muscle transcriptional responses to different modes of exercise and an online interface to readily interrogate the database. The pathways that underlie the effects of exercise on metabolism remain incompletely described. Here, the authors perform a meta-analysis of transcriptomic data from 66 published datasets of human skeletal muscle. They identify pathways selectively activated by inactivity, aerobic or resistance exercise, and characterize NR4A3 as one of the genes responsive to inactivity.
View
High Levels of Physical Activity in Later Life Are Associated With Enhanced Markers of Mitochondrial Metabolism
Article
Full-text available
  • Jan 2020
The age-associated reduction in muscle mass is well characterised, however less is known regarding the mechanisms responsible for the decline in oxidative capacity also observed with advancing age. The purpose of the current study was therefore to compare mitochondrial gene expression and protein content between young and old recreationally active, and older highly active individuals. Muscle biopsies were obtained from the vastus lateralis of young males (YG: 22±3 years) and older (OG: 67±2 years) males not previously engaged in formal exercise and older male master cyclists (OT: 65±5 years) who had undertaken cycling exercise for 32±17 yrs. Comparison of gene expression between YG, OG and OT groups revealed greater expression of mitochondrial-related genes, namely electron transport chain (ETC) complexes II, III, IV (p<.05) in OT compared to YG and OG. Gene expression of mitofusion (MFN)-1/2, mitochondrial fusion genes, were greater in OT compared to OG (p<.05). Similarly, protein content of ETC complexes I, II and IV were significantly greater in OT compared to both YG and OG (p<.001). Protein content of peroxisome proliferator-activated receptor gamma, coactivator 1 α (PGC-1α), was greater in OT compared to YG and OG (p<.001). Our results suggest that the aging process per se, is not associated with a decline in gene expression and protein content of ETC complexes. Mitochondrial-related gene expression and protein content is substantially greater in OT, suggesting that exercise-mediated increases in mitochondrial content can be maintained into later life.
View
Skeletal muscle unloading results in increased mitophagy and decreased mitochondrial biogenesis regulation
Article
Full-text available
  • Sep 2019
Introduction: Physical inactivity significantly contributes to loss of muscle mass and performance in bed-bound patients. Loss of skeletal muscle mitochondrial content has been well-established in muscle unloading models, but the underlying molecular mechanism remains unclear. We hypothesized that apparent unloading-induced loss of muscle mitochondrial content is preceded by increased mitophagy- and decreased mitochondrial biogenesis-signaling during the early stages of unloading. Methods: We analyzed a comprehensive set of molecular markers involved in mitochondrial-autophagy, -biogenesis, -dynamics, and -content, in the gastrocnemius muscle of C57BL/6J mice subjected to 0- and 3-days hind limb suspension, and in biopsies from human vastus lateralis muscle obtained before and after 7-days of one-leg immobilization. Results: In both mice and men, short-term skeletal muscle unloading results in molecular marker patterns indicative of increased receptor-mediated mitophagy and decreased mitochondrial biogenesis regulation, before apparent loss of mitochondrial content. Discussion: these results emphasize the early-onset of skeletal muscle disuse-induced mitochondrial remodeling. This article is protected by copyright. All rights reserved.
View
Regular Endurance Exercise Promotes Fission, Mitophagy, and Oxidative Phosphorylation in Human Skeletal Muscle Independently of Age
Article
Full-text available
  • Aug 2019
This study investigated whether regular endurance exercise maintains basal mitophagy and mitochondrial function during aging. Mitochondrial proteins and total mRNA were isolated from vastus lateralis biopsies (n = 33) of young sedentary (YS), old sedentary (OS), young active (YA), and old active (OA) men. Markers for mitophagy, fission, fusion, mitogenesis, and mitochondrial metabolism were assessed using qRT-PCR, Western blot, and immunofluorescence staining. Independently of age, fission protein Fis1 was higher in active vs. sedentary subjects (+80%; P < 0.05). Mitophagy protein PARKIN was more elevated in OA than in OS (+145%; P = 0.0026). mRNA expression of Beclin1 and Gabarap, involved in autophagosomes synthesis, were lower in OS compared to YS and OA (P < 0.05). Fusion and oxidative phosphorylation proteins were globally more elevated in the active groups (P < 0.05), while COx activity was only higher in OA than in OS (P = 0.032). Transcriptional regulation of mitogenesis did not vary with age or exercise. In conclusion, physically active lifestyle seems to participate in the maintenance of lifelong mitochondrial quality control by increasing fission and mitophagy.
View
Human muscular mitochondrial fusion in athletes during exercise
Article
Full-text available
The main objective of this work was to investigate whether mitochondrial fusion occurs in the skeletal muscle of well‐trained athletes in response to high‐intensity exercise. Well‐trained swimmers (n = 9) performed a duration‐matched sprint interval training (SIT) and high‐intensity high‐volume training (HIHVT) session on separate days. Muscle samples from triceps brachii were taken before, immediately after, and 3 h after the training sessions. Transmission electron microscopy (TEM) was applied to assess mitochondrial morphology. Moreover, expression of genes coding for regulators of mitochondrial fusion and fission were assessed by real‐time quantitative PCR. In addition, mitofusin (MFN)2 and optic atrophy 1 (OPA1) were quantified by Western blot analysis. TEM analyses showed that mitochondrial morphology remained altered for 3 h after HIHVT, whereas SIT‐induced changes were only evident immediately after exercise. Only SIT increased MFN1 and MFN2 mRNA expression, whereas SIT and HIHVT both increased MFN2 protein content 3 h after exercise. Notably, only HIHVT increased OPA1 protein content. Mitochondrial morphologic changes that suggest fusion occurs in well‐adapted athletes during exercise. However, HIHVT appears as a more robust inducer of mitochondrial fusion events than SIT. Indeed, SIT induces a rapid and transient change in mitochondrial morphology.—Huertas, J. R., Ruiz‐Ojeda, F. J., Plaza‐Díaz, J., Nordsborg, N. B., Martín‐Albo, J., Rueda‐Robles, A., Casuso, R. A. Human muscular mitochondrial fusion in athletes during exercise. FASEB J. 33, 12087‐12098 (2019). www.fasebj.org
View
Folding the Mitochondrial UPR into the Integrated Stress Response
Article
  • Apr 2020
  • TRENDS CELL BIOL
Eukaryotic cells must accurately monitor the integrity of the mitochondrial network to overcome environmental insults and respond to physiological cues. The mitochondrial unfolded protein response (UPRmt) is a mitochondrial-to-nuclear signaling pathway that maintains mitochondrial proteostasis, mediates signaling between tissues, and regulates organismal aging. Aberrant UPRmt signaling is associated with a wide spectrum of disorders, including congenital diseases as well as cancers and neurodegenerative diseases. Here, we review recent research into the mechanisms underlying UPRmt signaling in Caenorhabditis elegans and discuss emerging connections between the UPRmt signaling and a translational regulation program called the ‘integrated stress response’. Further study of the UPRmt will potentially enable development of new therapeutic strategies for inherited metabolic disorders and diseases of aging.
View
Mitochondrial Dynamics and Its Involvement in Disease
Article
  • Oct 2019
The dynamic properties of mitochondria—including their fusion, fission, and degradation—are critical for their optimal function in energy generation. The interplay of fusion and fission confers widespread benefits on mitochondria, including efficient transport, increased homogenization of the mitochondrial population, and efficient oxidative phosphorylation. These benefits arise through control of morphology, content exchange, equitable inheritance of mitochondria, maintenance of high-quality mitochondrial DNA, and segregation of damaged mitochondria for degradation. The key components of the machinery mediating mitochondrial fusion and fission belong to the dynamin family of GTPases that utilize GTP hydrolysis to drive mechanical work on biological membranes. Defects in this machinery cause a range of diseases that especially affect the nervous system. In addition, several common diseases, including neurodegenerative diseases and cancer, strongly affect mitochondrial dynamics. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 15 is January 24, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
View
Outstanding Questions in Mitophagy: What We Do and Do Not Know
Article
  • Jul 2019
The elimination of mitochondria via autophagy, termed mitophagy, is an evolutionarily conserved mechanism for mitochondrial quality control and homeostasis. Mitophagy, therefore, has an important contribution to cell function and integrity, which extends to the whole organism for development and survival. Research in mitophagy has boomed in recent years, and it is becoming clear that mitophagy is a complex and multi-factorial cellular response that depends on tissue, energetic, stress and signaling contexts. However, we know very little of its physiological regulation and the direct contribution of mitophagy to pathologies like neurodegenerative diseases. In this review, we aim to discuss the outstanding questions (and questions outstanding) in the field and reflect on our current understanding of mitophagy, the current challenges and the future directions to take.
View
Epigenetics and Exercise
Article
  • Jul 2019
  • TRENDS ENDOCRIN MET
Epigenetics can be defined as 'the structural adaptation of chromosomal regions so as to register, signal, or perpetuate altered activity states.' Increased transcription of key regulatory, metabolic, and myogenic genes is an early response to exercise and is important in mediating subsequent adaptations in skeletal muscle. DNA hypomethylation and histone hyperacetylation are emerging as important crucial events for increased transcription. The complex interactions between multiple epigenetic modifications and their regulation by metabolic changes and signaling events during exercise, with implications for enhanced understanding of the acute and chronic adaptations to exercise, are questions for further investigation.
View