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

Aging Cell ◽  
2019 ◽  
Vol 18 (5) ◽  
Author(s):  
Jonathan F. Gill ◽  
Julien Delezie ◽  
Gesa Santos ◽  
Shawn McGuirk ◽  
Svenia Schnyder ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cell Death ◽  
Sarcoplasmic Reticulum ◽  
Calcium Homeostasis ◽  
Mitochondrial Calcium ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Muscle Aging ◽  
Skeletal Muscle Aging

scholarly journals PGC-1α regulates mitochondrial calcium homeostasis, SR stress and cell death to mitigate skeletal muscle aging

2018 ◽  
Author(s):  
Jonathan F. Gill ◽  
Julien Delezie ◽  
Gesa Santos ◽  
Shawn McGuirk ◽  
Svenia Schnyder ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Function ◽  
Binding Protein ◽  
Mitochondrial Calcium ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Muscle Aging ◽  
Age Related ◽  
Inositol 1,4,5 Trisphosphate ◽  
Estrogen Related Receptor

AbstractAge-related impairment of muscle function severely affects the health of an increasing elderly population. While causality and the underlying mechanisms remain poorly understood, exercise is an efficient intervention to blunt these aging effects. We thus investigated the role of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a potent regulator of mitochondrial function and exercise adaptation, in skeletal muscle during aging. We demonstrate that PGC-1α overexpression improves mitochondrial dynamics and calcium buffering in an estrogen-related receptor α (ERRα)-dependent manner. Moreover, we show that sarcoplasmic reticulum stress is attenuated by PGC-1α. As a result, PGC-1α prevents tubular aggregate formation and fiber apoptosis in old muscle. Similarly, the pro-apoptotic effects of ceramide and thapsigargin were blunted by PGC-1α in muscle cells. Accordingly, mice with muscle-specific gain- and loss-of-function of PGC-1α exhibit a delayed and premature aging phenotype, respectively. Together, our data reveal a key protective effect of PGC-1α on muscle function and overall health span in aging.Statement of significanceThe loss of muscle function in aging results in a massive impairment in life quality, e.g. by reducing motor function, strength, endurance, the ability to perform daily tasks or social interactions. Unfortunately, the mechanistic aspects underlying age-related muscle disorders remain poorly understood and treatments improving the disease are extremely limited. We now show that PGC-1α, a transcriptional coactivator, is a key regulator of mitochondrial calcium homeostasis, cellular stress and death, all of which are linked to muscle aging and dysfunction. As a result, inhibition of the age-related decline in muscle PGC-1α considerably reduces aging of muscle and constitutes a promising target to prevent and treat the deterioration of muscle function in the elderly.AbbreviationsBNIP3, BCL2/Adenovirus E1B 19kDa interacting protein 3; Cpt1b, carnitine palmitoyltransferase 1B; CSQ1, calsequestrin 1; Drp1, dynamin-related protein 1; ER stress, endoplasmic reticulum stress; ERRα, estrogen-related receptor α; Fis1, fission 1; GRP75, Glucose-Regulated Protein 75; IGFBP5, insulin like growth factor binding protein 5; IP3, inositol 1,4,5-trisphosphate; IP3R1, inositol 1,4,5-trisphosphate receptor type 1; Letm1, leucine zipper and EF-hand containing transmembrane protein 1; MAMs, mitochondria-associated ER membranes; Mcad, medium-chain acyl-CoA dehydrogenase; Opa1, optic atrophy 1; OXPHOS, oxidative phosphorylation; PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1α; pH2AX, phospho-H2A Histone Family Member X; ppRB, phospho-preproretinoblastoma-associated protein; Puma, BCL2 Binding Component 3; ROS, reactive oxygen species; SR, sarcoplasmic reticulum; TA, tibialis anterior; TBP, TATA binding protein; TPG, thapsigargin; Ucp3, uncoupling protein 3; VDAC, voltage-dependent anion channel; XBP1, X-Box Binding Protein 1; Xiap, X-linked inhibitor of apoptosis protein

scholarly journals MICU3 regulates mitochondrial Ca2+-dependent antioxidant response in skeletal muscle aging

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Yun-Fei Yang ◽  
Wu Yang ◽  
Zhi-Yin Liao ◽  
Yong-Xin Wu ◽  
Zhen Fan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Calcium Uptake ◽  
Mitochondrial Calcium ◽  
Muscle Aging ◽  
Skeletal Muscle Aging ◽  
And Function ◽  
Mitochondrial Calcium Uptake

AbstractAge-related loss of skeletal muscle mass and function, termed sarcopenia, could impair the quality of life in the elderly. The mechanisms involved in skeletal muscle aging are intricate and largely unknown. However, more and more evidence demonstrated that mitochondrial dysfunction and apoptosis also play an important role in skeletal muscle aging. Recent studies have shown that mitochondrial calcium uniporter (MCU)-mediated mitochondrial calcium affects skeletal muscle mass and function by affecting mitochondrial function. During aging, we observed downregulated expression of mitochondrial calcium uptake family member3 (MICU3) in skeletal muscle, a regulator of MCU, which resulted in a significant reduction in mitochondrial calcium uptake. However, the role of MICU3 in skeletal muscle aging remains poorly understood. Therefore, we investigated the effect of MICU3 on the skeletal muscle of aged mice and senescent C2C12 cells induced by d-gal. Downregulation of MICU3 was associated with decreased myogenesis but increased oxidative stress and apoptosis. Reconstitution of MICU3 enhanced antioxidants, prevented the accumulation of mitochondrial ROS, decreased apoptosis, and increased myogenesis. These findings indicate that MICU3 might promote mitochondrial Ca2+ homeostasis and function, attenuate oxidative stress and apoptosis, and restore skeletal muscle mass and function. Therefore, MICU3 may be a potential therapeutic target in skeletal muscle aging.

scholarly journals Muscle-specific inositide phosphatase (MIP/MTMR14) is reduced with age and its loss accelerates skeletal muscle aging process by altering calcium homeostasis

Aging ◽  
2010 ◽  
Vol 2 (8) ◽  
pp. 504-513 ◽  
Author(s):  
Sandra Romero-Suarez ◽  
Jinhua Shen ◽  
Leticia Brotto ◽  
Todd Hall ◽  
ChengLin Mo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Calcium Homeostasis ◽  
Aging Process ◽  
Muscle Aging ◽  
Skeletal Muscle Aging

Influence of irisin on diet-induced metabolic syndrome in experimental rat model

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Dalia Medhat ◽  
Mona A. El-Bana ◽  
Sherien M. El-Daly ◽  
Magdi N. Ashour ◽  
Tahany R. Elias ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Lipid Profile ◽  
Histopathological Examination ◽  
Retinol Binding Protein ◽  
Albino Rats ◽  
Standard Diet ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Alcoholic Fatty Liver ◽  
Kidney Functions

Abstract Objective To evaluate the influence of irisin on the experimental paradigm of non-alcoholic fatty liver (NAFL) as a part of MetS cluster. Methods Forty male albino rats were divided into four groups; normal control, standard diet + irisin, high carbohydrate and fat diet (HCHF), and HCHF + irisin. After the experimental period, levels of fasting blood sugar (FBS), insulin, lipid profile, kidney functions, salusin-alpha (Sal-α), adropin, and retinol-binding protein-4 (RBP-4) were evaluated. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) expression in skeletal muscle was evaluated by quantitative real-time PCR. Aorta, liver, pancreas, and skeletal muscle tissue samples were prepared for histopathological examination. Results Rats administrated HCHF showed elevated levels of FBS, lipid profile, kidney functions, RBP-4, and downregulation of PGC-1α expression along with a decline in levels of insulin, Sal-α, and adropin while administration of irisin significantly attenuated these levels. Conclusions Irisin as based therapy could emerge as a new line of treatment against MetS and its related diseases.

scholarly journals Skeletal muscle PGC-1β signaling is sufficient to drive an endurance exercise phenotype and to counteract components of detraining in mice

2017 ◽  
Vol 312 (5) ◽  
pp. E394-E406 ◽  
Author(s):  
Samuel Lee ◽  
Teresa C. Leone ◽  
Lisa Rogosa ◽  
John Rumsey ◽  
Julio Ayala ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Exercise Training ◽  
Early Stage ◽  
Peroxisome Proliferator ◽  
Disuse Atrophy ◽  
Proof Of Concept ◽  
Peroxisome Proliferator Activated Receptor ◽  
Muscle Disuse ◽  
Training Response

Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α and -1β serve as master transcriptional regulators of muscle mitochondrial functional capacity and are capable of enhancing muscle endurance when overexpressed in mice. We sought to determine whether muscle-specific transgenic overexpression of PGC-1β affects the detraining response following endurance training. First, we established and validated a mouse exercise-training-detraining protocol. Second, using multiple physiological and gene expression end points, we found that PGC-1β overexpression in skeletal muscle of sedentary mice fully recapitulated the training response. Lastly, PGC-1β overexpression during the detraining period resulted in partial prevention of the detraining response. Specifically, an increase in the plateau at which O2 uptake (V̇o2) did not change from baseline with increasing treadmill speed [peak V̇o2 (ΔV̇o2max)] was maintained in trained mice with PGC-1β overexpression in muscle 6 wk after cessation of training. However, other detraining responses, including changes in running performance and in situ half relaxation time (a measure of contractility), were not affected by PGC-1β overexpression. We conclude that while activation of muscle PGC-1β is sufficient to drive the complete endurance phenotype in sedentary mice, it only partially prevents the detraining response following exercise training, suggesting that the process of endurance detraining involves mechanisms beyond the reversal of muscle autonomous mechanisms involved in endurance fitness. In addition, the protocol described here should be useful for assessing early-stage proof-of-concept interventions in preclinical models of muscle disuse atrophy.

scholarly journals Role of PGC-1α during acute exercise-induced autophagy and mitophagy in skeletal muscle

2015 ◽  
Vol 308 (9) ◽  
pp. C710-C719 ◽  
Author(s):  
Anna Vainshtein ◽  
Liam D. Tryon ◽  
Marion Pauly ◽  
David A. Hood
Keyword(s):  
Skeletal Muscle ◽  
Acute Exercise ◽  
Transmembrane Protein ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Lipid Trafficking ◽  
Mitochondrial Transcription Factor ◽  
Energy Demands ◽  
Niemann Pick ◽  
Exercise Induced

Regular exercise leads to systemic metabolic benefits, which require remodeling of energy resources in skeletal muscle. During acute exercise, the increase in energy demands initiate mitochondrial biogenesis, orchestrated by the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). Much less is known about the degradation of mitochondria following exercise, although new evidence implicates a cellular recycling mechanism, autophagy/mitophagy, in exercise-induced adaptations. How mitophagy is activated and what role PGC-1α plays in this process during exercise have yet to be evaluated. Thus we investigated autophagy/mitophagy in muscle immediately following an acute bout of exercise or 90 min following exercise in wild-type (WT) and PGC-1α knockout (KO) animals. Deletion of PGC-1α resulted in a 40% decrease in mitochondrial content, as well as a 25% decline in running performance, which was accompanied by severe acidosis in KO animals, indicating metabolic distress. Exercise induced significant increases in gene transcripts of various mitochondrial (e.g., cytochrome oxidase subunit IV and mitochondrial transcription factor A) and autophagy-related (e.g., p62 and light chain 3) genes in WT, but not KO, animals. Exercise also resulted in enhanced targeting of mitochondria for mitophagy, as well as increased autophagy and mitophagy flux, in WT animals. This effect was attenuated in the absence of PGC-1α. We also identified Niemann-Pick C1, a transmembrane protein involved in lysosomal lipid trafficking, as a target of PGC-1α that is induced with exercise. These results suggest that mitochondrial turnover is increased following exercise and that this effect is at least in part coordinated by PGC-1α. Anna Vainshtein received the AJP-Cell 2015 Paper of the Year award. Listen to a podcast with Anna Vainshtein and coauthor David A. Hood at http://ajpcell.podbean.com/e/ajp-cell-paper-of-the-year-2015-award-podcast/ .

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