Peroxisome proliferator‐activated receptor γ coactivator 1α regulates mitochondrial calcium homeostasis, sarcoplasmic reticulum stress, and cell death to mitigate skeletal muscle aging

Gill, Jonathan F.; Delezie, Julien; Santos, Gesa; McGuirk, Shawn; Schnyder, Svenia; Frank, Stephan; Rausch, Martin; St‐Pierre, Julie; Handschin, Christoph

doi:10.1111/acel.12993

Cited by 23 publications

(24 citation statements)

References 45 publications

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“…In line with the age-associated mitochondrial decline, PGC1-α and -β expression decreases during muscle aging [ 33 ]. The specific deletion of PGC1-α in skeletal muscle displays a premature aging phenotype characterized by fiber damage; elevated inflammation markers; and decreased mitochondrial function, muscle force, running capacity, and balance and motor coordination [ 34 , 35 , 36 , 37 ]. On the other hand, muscle-specific PGC1-α transgenic mice have a delayed aging process with several features that resemble younger muscles such as the transcriptome, markers for mitochondrial function, neuromuscular junction morphology, improved calcium handling, increased autophagy markers, and decreased proteasome markers, and a slight but significant increase in lifespan [ 35 , 38 ].…”

Section: Mitochondrial Plasticity Declines In Aging Sarcopeniamentioning

confidence: 99%

The Interplay between Mitochondrial Morphology and Myomitokines in Aging Sarcopenia

Romanello

2020

IJMS

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Sarcopenia is a chronic disease characterized by the progressive loss of skeletal muscle mass, force, and function during aging. It is an emerging public problem associated with poor quality of life, disability, frailty, and high mortality. A decline in mitochondria quality control pathways constitutes a major mechanism driving aging sarcopenia, causing abnormal organelle accumulation over a lifetime. The resulting mitochondrial dysfunction in sarcopenic muscles feedbacks systemically by releasing the myomitokines fibroblast growth factor 21 (FGF21) and growth and differentiation factor 15 (GDF15), influencing the whole-body homeostasis and dictating healthy or unhealthy aging. This review describes the principal pathways controlling mitochondrial quality, many of which are potential therapeutic targets against muscle aging, and the connection between mitochondrial dysfunction and the myomitokines FGF21 and GDF15 in the pathogenesis of aging sarcopenia.

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Section: Mitochondrial Plasticity Declines In Aging Sarcopeniamentioning

confidence: 99%

The Interplay between Mitochondrial Morphology and Myomitokines in Aging Sarcopenia

Romanello

2020

IJMS

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“…In the cell, energy shortage with low ATP/AMP sensed by AMPK elevates cellular NAD + levels and activates sirtuin 1 (SIRT1) to upregulate PGC-1α which leads to consequential mitochondrial biogenesis ( Joo et al, 2016 ). Similarly, Ca 2+ release from mitochondria during exercising and cold stress can also activates PGC-1α through promoting the mitochondrial biogenesis activation of protein kinase A (PKA) and cAMP-response element binding protein (CREB) ( Chen et al, 2010 ; Gill and La Merrill, 2017 ; Gill et al, 2019 ).…”

Section: Mitochondrial Inter-talk With Nucleusmentioning

confidence: 99%

Quality Matters? The Involvement of Mitochondrial Quality Control in Cardiovascular Disease

Lin

Chen

Lin

et al. 2021

Front. Cell Dev. Biol.

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Cardiovascular diseases are one of the leading causes of death and global health problems worldwide. Multiple factors are known to affect the cardiovascular system from lifestyles, genes, underlying comorbidities, and age. Requiring high workload, metabolism of the heart is largely dependent on continuous power supply via mitochondria through effective oxidative respiration. Mitochondria not only serve as cellular power plants, but are also involved in many critical cellular processes, including the generation of intracellular reactive oxygen species (ROS) and regulating cellular survival. To cope with environmental stress, mitochondrial function has been suggested to be essential during bioenergetics adaptation resulting in cardiac pathological remodeling. Thus, mitochondrial dysfunction has been advocated in various aspects of cardiovascular pathology including the response to ischemia/reperfusion (I/R) injury, hypertension (HTN), and cardiovascular complications related to type 2 diabetes mellitus (DM). Therefore, mitochondrial homeostasis through mitochondrial dynamics and quality control is pivotal in the maintenance of cardiac health. Impairment of the segregation of damaged components and degradation of unhealthy mitochondria through autophagic mechanisms may play a crucial role in the pathogenesis of various cardiac disorders. This article provides in-depth understanding of the current literature regarding mitochondrial remodeling and dynamics in cardiovascular diseases.

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“…PLN, a negative regulator of SR Ca 2+ release, and NCX, a fast buffer dissipating cytosolic Ca 2+ increments, contribute to stricter and improved Ca 2+ handling [ 206 ]. Therefore, aiming to activate PGC-1α signalling pathways through regular exercise should promote metabolic flexibility as well as retardation of age-associated cardiomyopathy [ 205 ] and skeletal muscle sarcopenia [ 207 , 208 ].…”

Section: Reactive Oxygen Species—a Thin Line Between Fit and Failedmentioning

confidence: 99%

Re-Evaluating the Oxidative Phenotype: Can Endurance Exercise Save the Western World?

Kolodziej

O’Halloran

2021

Antioxidants

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Mitochondria are popularly called the “powerhouses” of the cell. They promote energy metabolism through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation, which in contrast to cytosolic glycolysis are oxygen-dependent and significantly more substrate efficient. That is, mitochondrial metabolism provides substantially more cellular energy currency (ATP) per macronutrient metabolised. Enhancement of mitochondrial density and metabolism are associated with endurance training, which allows for the attainment of high relative VO2 max values. However, the sedentary lifestyle and diet currently predominant in the Western world lead to mitochondrial dysfunction. Underdeveloped mitochondrial metabolism leads to nutrient-induced reducing pressure caused by energy surplus, as reduced nicotinamide adenine dinucleotide (NADH)-mediated high electron flow at rest leads to “electron leak” and a chronic generation of superoxide radicals (O2−). Chronic overload of these reactive oxygen species (ROS) damages cell components such as DNA, cell membranes, and proteins. Counterintuitively, transiently generated ROS during exercise contributes to adaptive reduction-oxidation (REDOX) signalling through the process of cellular hormesis or “oxidative eustress” defined by Helmut Sies. However, the unaccustomed, chronic oxidative stress is central to the leading causes of mortality in the 21st century—metabolic syndrome and the associated cardiovascular comorbidities. The endurance exercise training that improves mitochondrial capacity and the protective antioxidant cellular system emerges as a universal intervention for mitochondrial dysfunction and resultant comorbidities. Furthermore, exercise might also be a solution to prevent ageing-related degenerative diseases, which are caused by impaired mitochondrial recycling. This review aims to break down the metabolic components of exercise and how they translate to athletic versus metabolically diseased phenotypes. We outline a reciprocal relationship between oxidative metabolism and inflammation, as well as hypoxia. We highlight the importance of oxidative stress for metabolic and antioxidant adaptation. We discuss the relevance of lactate as an indicator of critical exercise intensity, and inferring from its relationship with hypoxia, we suggest the most appropriate mode of exercise for the case of a lost oxidative identity in metabolically inflexible patients. Finally, we propose a reciprocal signalling model that establishes a healthy balance between the glycolytic/proliferative and oxidative/prolonged-ageing phenotypes. This model is malleable to adaptation with oxidative stress in exercise but is also susceptible to maladaptation associated with chronic oxidative stress in disease. Furthermore, mutations of components involved in the transcriptional regulatory mechanisms of mitochondrial metabolism may lead to the development of a cancerous phenotype, which progressively presents as one of the main causes of death, alongside the metabolic syndrome.

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Peroxisome proliferator‐activated receptor γ coactivator 1α regulates mitochondrial calcium homeostasis, sarcoplasmic reticulum stress, and cell death to mitigate skeletal muscle aging

Cited by 23 publications

References 45 publications

The Interplay between Mitochondrial Morphology and Myomitokines in Aging Sarcopenia

The Interplay between Mitochondrial Morphology and Myomitokines in Aging Sarcopenia

Quality Matters? The Involvement of Mitochondrial Quality Control in Cardiovascular Disease

Re-Evaluating the Oxidative Phenotype: Can Endurance Exercise Save the Western World?

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