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 Novel Intriguing Strategies Attenuating to Sarcopenia

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Kunihiro Sakuma ◽  
Akihiko Yamaguchi
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Ursolic Acid ◽  
Proteasome Inhibition ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mitochondrial Homeostasis ◽  
Age Related ◽  
Increased Risk ◽  
Risk Of Fall

Sarcopenia, the age-related loss of skeletal muscle mass, is characterized by a deterioration of muscle quantity and quality leading to a gradual slowing of movement, a decline in strength and power, increased risk of fall-related injury, and, often, frailty. Since sarcopenia is largely attributed to various molecular mediators affecting fiber size, mitochondrial homeostasis, and apoptosis, the mechanisms responsible for these deleterious changes present numerous therapeutic targets for drug discovery. Resistance training combined with amino acid-containing supplements is often utilized to prevent age-related muscle wasting and weakness. In this review, we summarize more recent therapeutic strategies (myostatin or proteasome inhibition, supplementation with eicosapentaenoic acid (EPA) or ursolic acid, etc.) for counteracting sarcopenia. Myostatin inhibitor is the most advanced research with a Phase I/II trial in muscular dystrophy but does not try the possibility for attenuating sarcopenia. EPA and ursolic acid seem to be effective as therapeutic agents, because they attenuate the degenerative symptoms of muscular dystrophy and cachexic muscle. The activation of peroxisome proliferator-activated receptorγcoactivator 1α(PGC-1α) in skeletal muscle by exercise and/or unknown supplementation would be an intriguing approach to attenuating sarcopenia. In contrast, muscle loss with age may not be influenced positively by treatment with a proteasome inhibitor or antioxidant.

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

2020 ◽  
Vol 45 (9) ◽  
pp. 927-936
Author(s):  
Jens Frey Halling ◽  
Henriette Pilegaard
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Current Evidence ◽  
Peroxisome Proliferator ◽  
Control Mechanisms ◽  
Peroxisome Proliferator Activated Receptor ◽  
Age Related ◽  
Mitochondrial Functions

The majority of human energy metabolism occurs in skeletal muscle mitochondria emphasizing the importance of understanding the regulation of myocellular mitochondrial function. The transcriptional co-activator peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) has been characterized as a major factor in the transcriptional control of several mitochondrial components. Thus, PGC-1α is often described as a master regulator of mitochondrial biogenesis as well as a central player in regulating the antioxidant defense. However, accumulating evidence suggests that PGC-1α is also involved in the complex regulation of mitochondrial quality beyond biogenesis, which includes mitochondrial network dynamics and autophagic removal of damaged mitochondria. In addition, mitochondrial reactive oxygen species production has been suggested to regulate skeletal muscle insulin sensitivity, which may also be influenced by PGC-1α. This review aims to highlight the current evidence for PGC-1α-mediated regulation of skeletal muscle mitochondrial function beyond the effects on mitochondrial biogenesis as well as the potential PGC-1α-related impact on insulin-stimulated glucose uptake in skeletal muscle. Novelty PGC-1α regulates mitochondrial biogenesis but also has effects on mitochondrial functions beyond biogenesis. Mitochondrial quality control mechanisms, including fission, fusion, and mitophagy, are regulated by PGC-1α. PGC-1α-mediated regulation of mitochondrial quality may affect age-related mitochondrial dysfunction and insulin sensitivity.

scholarly journals Dysregulated Autophagy Mediates Sarcopenic Obesity and Its Complications via AMPK and PGC1α Signaling Pathways: Potential Involvement of Gut Dysbiosis as a Pathological Link

2020 ◽  
Vol 21 (18) ◽  
pp. 6887
Author(s):  
Ji Yeon Ryu ◽  
Hyung Muk Choi ◽  
Hyung-In Yang ◽  
Kyoung Soo Kim
Keyword(s):  
Insulin Resistance ◽  
Signaling Pathways ◽  
Nutrient Sensing ◽  
Sarcopenic Obesity ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Gut Dysbiosis ◽  
Muscle Aging ◽  
Age Related ◽  
Significant Mechanism

Sarcopenic obesity (SOB), which is closely related to being elderly as a feature of aging, is recently gaining attention because it is associated with many other age-related diseases that present as altered intercellular communication, dysregulated nutrient sensing, and mitochondrial dysfunction. Along with insulin resistance and inflammation as the core pathogenesis of SOB, autophagy has recently gained attention as a significant mechanism of muscle aging in SOB. Known as important cellular metabolic regulators, the AMP-activated protein kinase (AMPK) and the peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) signaling pathways play an important role in autophagy, inflammation, and insulin resistance, as well as mutual communication between skeletal muscle, adipose tissue, and the liver. Furthermore, AMPK and PGC-1α signaling pathways are implicated in the gut microbiome–muscle axis. In this review, we describe the pathological link between SOB and its associated complications such as metabolic, cardiovascular, and liver disease, falls and fractures, osteoarthritis, pulmonary disease, and mental health via dysregulated autophagy controlled by AMPK and/or PGC-1α signaling pathways. Here, we propose potential treatments for SOB by modulating autophagy activity and gut dysbiosis based on plausible pathological links.

scholarly journals Hyperhomocysteinemia attenuates angiogenesis through reduction of HIF-1α and PGC-1α levels in muscle fibers during hindlimb ischemia

2014 ◽  
Vol 306 (8) ◽  
pp. H1116-H1127 ◽  
Author(s):  
Sudhakar Veeranki ◽  
Srikanth Givvimani ◽  
Sathnur Pushpakumar ◽  
Suresh C. Tyagi
Keyword(s):  
Skeletal Muscle ◽  
Muscle Function ◽  
Muscle Fibers ◽  
Hypoxia Inducible Factor ◽  
Tissue Perfusion ◽  
Peroxisome Proliferator ◽  
Hindlimb Ischemia ◽  
Skeletal Muscle Function ◽  
Artery Ligation ◽  
Peroxisome Proliferator Activated Receptor

Hyperhomocysteinemia (HHcy) is associated with elderly frailty, skeletal muscle injury and malfunction, reduced vascular integrity and function, and mortality. Although HHcy has been implicated in the impairment of angiogenesis after hindlimb ischemia in murine models, the underlying mechanisms are still unclear. We hypothesized that HHcy compromises skeletal muscle perfusion, collateral formation, and arteriogenesis by diminishing postischemic vasculogenic responses in muscle fibers. To test this hypothesis, we created femoral artery ligation in wild-type and heterozygous cystathionine β-synthase (CBS+/−) mice (a model for HHcy) and assessed tissue perfusion, collateral vessel formation, and skeletal muscle function using laser-Doppler perfusion imaging, barium angiography, and fatigue tests. In addition, we assessed postischemic levels of VEGF and levels of its muscle-specific regulators: hypoxia-inducible factor (HIF)-1α and peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α. The observations indicated dysregulation of VEGF, HIF-1α, and PGC-1α levels in ischemic skeletal muscles of CBS+/− mice. Concomitant with the reduced ischemic angiogenic responses, we also observed diminished leptin expression and attenuated Akt signaling in ischemic muscle fibers of CBS+/− mice. Moreover, there was enhanced atrogene, ubiquitin ligases that conjugate proteins for degradation during muscle atrophy, transcription, and reduced muscle function after ischemia in CBS+/− mice. These results suggest that HHcy adversely affects muscle-specific ischemic responses and contributes to muscle frailty.

scholarly journals Klotho Protein Promotes Adipocyte Differentiation

Endocrinology ◽  
2006 ◽  
Vol 147 (8) ◽  
pp. 3835-3842 ◽  
Author(s):  
Yukana Chihara ◽  
Hiromi Rakugi ◽  
Kazuhiko Ishikawa ◽  
Masashi Ikushima ◽  
Yoshihiro Maekawa ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Adipocyte Differentiation ◽  
Binding Protein ◽  
Early Period ◽  
Peroxisome Proliferator ◽  
Differentiation Markers ◽  
Peroxisome Proliferator Activated Receptor ◽  
Fatty Acid Binding ◽  
Age Related ◽  
Klotho Protein

Mice with homozygous disruption of the klotho exhibit multiple age-related disorders and have barely detectable amounts of white adipose tissue. Although klotho expression in cultured adipocytes has been reported, little is known about its function in adipocytes. In the present study, we investigated the role of klotho on adipocyte differentiation. Adipocyte differentiation was induced by incubation of confluent 3T3-L1 cells with insulin, dexamethasone, and 1-methyl-3-isobutyl-xanthin. Klotho-siRNA and expression vector were produced for klotho suppression and overexpression, respectively. Klotho protein was purified for determination of the hormonal effect of klotho. Klotho mRNA and protein expression increased up to the 3rd d of differentiation. A peroxisome proliferator-activated receptor-γ agonist increased klotho expression during the early period of adipocyte differentiation. The mRNA expression of adipocyte differentiation markers, such as CCAAT/enhancer-binding protein (C/EBP)α, C/EBPβ, C/EBPδ, peroxisome proliferator-activated receptor-γ, and fatty acid binding protein 4, was decreased by klotho suppression, and increased 1.9- to 3.8-fold by klotho overexpression. The results of Oil Red O staining also suggested that klotho overexpression promoted adipocyte differentiation. Klotho protein stimulation resulted in a 2.4- to 4.6-fold increase in mRNA expression of differentiation markers compared with control, and the time course depended on adipocyte induction status. Western blot analysis showed that protein levels of C/EBPα and C/EBPδ were increased by Klotho protein stimulation. These results suggest that klotho works as a hormonal factor to promote adipocyte differentiation in the early days, during the period of transient proliferation in the differentiation process, and that klotho may play an essential role in adipocyte differentiation.

Skeletal muscle aging

2007 ◽  
Vol 17 (1) ◽  
pp. 13-23 ◽  
Author(s):  
Graeme L Close ◽  
Philippa Haggan ◽  
Anne McArdle
Keyword(s):  
Skeletal Muscle ◽  
Life Expectancy ◽  
Muscle Function ◽  
Active Life Expectancy ◽  
Active Life ◽  
Muscle Aging ◽  
Age Related ◽  
Dramatic Rise ◽  
Skeletal Muscle Aging

Average world life expectancy has seen a dramatic rise over the last two centuries although active life expectancy remains relatively unchanged. One reason for this is that aging results in skeletal muscle becoming smaller, weaker and more susceptible to contraction-induced injury. By the age of 70, muscle strength is reduced by around 30–40% and this can have catastrophic effects on quality of life. Despite a vast amount of research into age-related changes in skeletal muscle, the exact mechanisms responsible for this is still unclear and thus treatments to preserve muscle function with aging remain elusive.

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