Peroxisome Proliferator-activated Receptor-γ Coactivator-1α Research Articles

ZiBuPiYin recipe ameliorates diabetes-associated cognitive decline by improving neuronal mitochondrial function in chronic psychologically stressed zucker diabetic fatty rats

Ethnopharmacological relevanceZibu Piyin Recipe (ZBPYR) is a traditional Chinese medicine compound composed of 12 kinds of Chinese herbal medicines including red ginseng and yam. Long-term basic and clinical applications have proved that ZBPYR can prevent and treat cognitive dysfunction. Previous studies showed that chronic psychological stress can increase the risk of type 2 diabetes mellitus (T2DM), and lead to cognitive decline. Mitochondrial dysfunction plays a key role in chronic psychological stress-induced diabetes mellitus. While the mechanism of mitochondrial dysfunction and insulin resistance in diabetes-associated cognitive decline (DACD) is unclear. Aim of the studyOur previous research found that a ZiBuPiYin recipe (ZBPYR) has significant pharmacological effects against DACD. The present study investigated changes in mitochondrial dysfunction in the brain and the mechanism of insulin resistance and mitochondrial damage to explore the relationship between neuronal mitochondrial dysfunction and insulin resistance in chronic psychologically stressed DACD rats. Materials and methodsZucker diabetic fatty (ZDF) rats with spontaneous T2DM and rats with diabetic cognitive impairment that was induced by chronic psychological stress were used in in vivo experiments. PC12 cells that were damaged by rotenone were used for the in vitro experiment. ResultsThe findings indicated that the number of mitochondria decreased, morphology and membrane potential were damaged, and reactive oxygen species increased in the cortex and hippocampus in psychologically stressed DACD rats. Protein kinase Cβ2 (PKCβ2) activation and insulin resistance were markedly induced by chronic psychological stress, together with decreases in peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and mitochondrial fusion protein 2 (Mfn2). Furthermore, ZBPYR exerted protective effects both in in vivo and in vitro. ConclusionMitochondrial damage and insulin resistance were observed in the brain in chronic psychologically stressed DACD rats. The ZBPYR significantly improved brain mitochondrial damage and insulin resistance in chronic psychologically stressed DACD rats. These results provide novel insights for the development of ZBPYR as a traditional Chinese medicine for the treatment of chronic psychological stress and DACD.

Lasmiditan promotes recovery from acute kidney injury through induction of mitochondrial biogenesis.

Acute kidney injury (AKI) involves rapid loss of renal function and occurs in 8-16% of hospitalized patients. AKI can be induced by drugs, sepsis, and ischemia-reperfusion (I/R). Hallmarks of AKI include mitochondrial and microvasculature dysfunction as well as renal tubular injury. There is currently no available therapeutic for AKI. Previously, our group identified that serotonin (5-HT)1F receptor agonism with lasmiditan accelerated endothelial cell recovery and induced mitochondrial biogenesis (MB) in vitro. We hypothesized that lasmiditan, a Federal Drug Administration-approved drug, would induce MB and improve microvascular and renal function in a mouse model of AKI. Male mice were subjected to renal I/R and treated with lasmiditan (0.3 mg/kg) or vehicle beginning 24 h after injury and then daily until euthanasia at 6 or 12 days. Serum creatinine was measured to estimate glomerular filtration rate. The renal cortex was assessed for mitochondrial density, vascular permeability and integrity, tubular damage, and interstitial fibrosis. Lasmiditan increased mitochondrial number (1.4-fold) in renal cortices. At 6 days, serum creatinine decreased 41% in the I/R group and 72% with lasmiditan. At 6 or 12 days, kidney injury molecule-1 increased in the I/R group and decreased 50% with lasmiditan. At 12 days, interstitial fibrosis decreased with lasmiditan by 50% and collagen type 1 by 38%. Evan's blue dye leakage increased 2.5-fold in the I/R group and was restored with lasmiditan. The tight junction proteins zonula occludens-1, claudin-2, and claudin-5 decreased in the I/R group and recovered with lasmiditan. At 6 or 12 days, peroxisome proliferator-activated receptor-γ coactivator-1α and electron transport chain complexes increased only with lasmiditan. In conclusion, lasmiditan treatment beginning AKI induces MB, attenuated vascular and tubular injury, decreased interstitial fibrosis, and lowered serum creatinine. Given that lasmiditan is a Federal Drug Administration-approved drug, these preclinical data support repurposing lasmiditan as a therapeutic for AKI.NEW & NOTEWORTHY AKI pathology involves a rapid decline in kidney function and occurs in 8-16% of hospitalized patients. There is currently no therapeutic for AKI. AKI results in mitochondria dysfunction, microvasculature injury, and loss of renal tubular function. In an I/R-induced AKI mouse model, treatment with the FDA-approved 5-HT1F receptor-selective agonist lasmiditan induced mitochondrial biogenesis, improved vascular integrity, reduced fibrosis, and reduced proximal tubule damage. These data support repurposing lasmiditan for the treatment of AKI.

Resveratrol improves diabetic cardiomyopathy by preventing asymmetric dimethylarginine-caused peroxisome proliferator-activated receptor-γ coactivator-1α acetylation

ObjectivesCardiac protection of resveratrol is related to the improvement of mitochondrial function through sirtuin1 (SIRT1) activation and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) deacetylation. Asymmetric dimethylarginine (ADMA) as an endogenous inhibitor of nitric oxide synthases is associated with diabetic cardiovascular complications and has a cross-talk with lysine acetylation. This study was to determine whether resveratrol reverses ADMA's pathogenic role in diabetic cardiomyopathy and elucidate the underlying mechanisms in type 2 diabetic (T2DM) rats and cardiomyocytes. MethodsT2DM Rats were induced by high-fat diet plus small-dose streptozotocin injection (35 mg/kg). Resveratrol was given by gavage (50 mg/kg/d) to some rats for 16w. Cardiac function was measured by echocardiography, and PGC-1α acetylation was detected by immunoprecipitation. Mitochondrial DNA and ATP contents were analyzed to evaluate mitochondrial biogenesis and function. ResultsEndogenous ADMA accumulation and its signal disorders were associated with cardiac and mitochondrial dysfunctions in accompany with increased PGC-1α acetylation and decreased PGC-1α expression in the myocardium of T2DM rats compared with control rats. Resveratrol treatment attenuated ADMA accumulation, cardiac and mitochondrial dysfunctions in parallel with reversing altered PGC-1α expression and acetylation in the myocardium of T2DM rats. Exogenous ADMA not only reproduced mitochondrial dysfunction and cardiac hypertrophy but also reduced PGC-1α expression and enhanced PGC-1α acetylation in accompany of down-regulating SIRT1 and up-regulating acetyltransferase expression, all of which could be prevented by resveratrol pretreatment in cardiomyocytes. ConclusionsThese results indicate that ADMA promotes PGC-1α acetylation as a potential therapeutic target for resveratrol of management diabetic cardiomyopathy in T2DM rats.

The diagnostic value of peroxisome proliferator-activated receptor-γ coactivator-1α in identifying different chronic heart failure phenotypes.

BackgroundDespite advances in diagnosing and treating chronic heart failure (HF), the underlying mechanisms in different HF phenotypes remain unclear. Mitochondrial energy metabolism is crucial in HF etiology. Our study aimed to explore the value of metabolic-associated biomarker peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) in identifying different HF phenotypes.MethodsA total of 172 participants were enrolled in the Affiliated Hospital of Xuzhou Medical University and were subsequently divided into four groups based on the European Society of Cardiology HF management guideline: the non-HF control (Control, N = 46), heart failure with reduced ejection fraction (HFrEF, N = 54), heart failure with mildly reduced ejection fraction (HFmrEF, N = 22), and heart failure with preserved ejection fraction (HFpEF, N = 50) groups. Each participant’s baseline data were recorded, blood samples were taken, and echocardiography was conducted. The level of PGC1α expression was determined using an enzyme-linked immunosorbent assay (ELISA) kit. The receiver operative characteristics (ROC) curve was further established in the four groups to assess the diagnostic value for overall HF and each HF phenotype with the calculation of the area under the curve (AUC) and 95% confidence interval (CI).ResultsPGC1α expression was significantly increased in HF patients (315.0 ± 69.58 nmol/L) compared to non-HF participants (233.3 ± 32.69 nmol/L). Considering different HF phenotypes, PGC1α expression was considerably higher in the HFmrEF group (401.6 ± 45.1 nmol/L)than in the other two phenotypes (299.5 ± 62.27 nmol/L for HFrEF and 293.5 ± 56.37 nmol/L for HFpEF, respectively).Furthermore, the AUCs of PGC1α in overall HF and each HF phenotype were all over 0.8, showing the ideal diagnostic value. Additionally, we provided the cut-off criteria for clinical use, which needs further validation. There was no significant correlation between PGC1α and N-terminal (NT)-prohormone B-type natriuretic peptide (BNP)/blood glucose, suggesting that PGC1α might exert a unique function in HF yet in a different pattern.ConclusionWe discovered that PGC1α could be used as a potential biomarker for differentiating HF patients from those without HF and for distinguishing HFmrEF from HFrEF and HFpEF.

Morinda officinalis polysaccharide attenuates osteoporosis in rats underwent bilateral ovariectomy by suppressing the PGC-1α/PPARγ pathway.

Osteoporosis (OP) is a widespread disease that causes risks of spine and hip fractures. Morinda officinalis polysaccharide (MOP) shows therapeutic potential in OP. This article intended to understand the mechanism by which MOP impacts bone mineral density (BMD) and serum trace elements in OP rats. OP rat models were established by bilateral ovariectomy (OVX). Rats were intragastrically administered with MOP or ZLN005 [the activator of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)] since the first day after operation for 8 weeks. Microstructural changes in OP rats were analyzed using micro-computed tomography system. Contents of serum Zn, Cu, Fe, and Mg in rats were measured. Levels of serum superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), GSH, and malondialdehyde (MDA) in rats were determined by Enzyme-linked immunosorbent assay. Protein levels of PGC-1α and peroxisome proliferator-activated receptor γ (PPARγ) in cartilage tissues of rats were determined via Western blotting. MOP enhanced BMD, bone volume per trabecular volume (BV/TV), Tb.N, and Tb.Th and reduced Tb.Sp in the distal femur of OVX rats, elevated levels of serum Cu, Fe, and Mg and contents of SOD, GSH, and GSH-PX and decreased MDA content. Moreover, MOP suppressed the PGC-1α/PPARγ pathway. Activation of PGC-1α partially abolished the action of MOP on ameliorating OP in OVX rats and strengthening anti-oxidation ability. MOP mitigated OP in OVX rats by inhibiting the PGC-1α/PPARγ pathway.

Dysregulated myokines and signaling pathways in skeletal muscle dysfunction in a cigarette smoke-induced model of chronic obstructive pulmonary disease.

Skeletal muscle dysfunction is an important extrapulmonary comorbidity of chronic obstructive pulmonary disease (COPD). Muscle-derived cytokines (myokines) play important roles in skeletal muscle growth and function, but their contributions to skeletal muscle dysfunction in COPD have not been fully understood. In the current study, by using a well-established mouse model of COPD with skeletal muscle dysfunction, we found that the expressions of Fndc5 (fibronectin type III domain-containing protein 5, the precursor of irisin) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) were decreased, while myostatin (Mstn), phosphorylated extracellular regulated kinase (p-Erk1/2), and p-Smad3 expressions were upregulated in skeletal muscles from cigarette smoke-exposed mice and in cigarette smoke extract (CSE)-stimulated C2C12 myotubes. Treatment with Smad3 or Erk1/2 inhibitors partially restored the expression of Fndc5 in CSE-stimulated C2C12 myotubes. Taken together, CSE exposure, by upregulation of p-Erk1/2, promoted the expression of Mstn, which further inhibited Fndc5 expression by the p-Smad3/PGC-1α pathway, revealing a novel regulating mechanism of myokines in the pathogenesis of skeletal muscle comorbidities of COPD.

The Critical Role of AMPKα1 in Regulating Autophagy and Mitochondrial Respiration in IL-15-Stimulated mTORC1Weak Signal-Induced T Cell Memory: An Interplay between Yin (AMPKα1) and Yang (mTORC1) Energy Sensors in T Cell Differentiation.

Two common γ-chain family cytokines IL-2 and IL-15 stimulate the same mammalian target of rapamycin complex-1 (mTORC1) signaling yet induce effector T (TE) and memory T (TM) cell differentiation via a poorly understood mechanism(s). Here, we prepared in vitro IL-2-stimulated TE (IL-2/TE) and IL-15-stimulated TM (IL-15/TM) cells for characterization by flow cytometry, Western blotting, confocal microscopy and Seahorse-assay analyses. We demonstrate that IL-2 and IL-15 stimulate strong and weak mTORC1 signals, respectively, which lead to the formation of CD62 ligand (CD62L)− killer cell lectin-like receptor subfamily G member-1 (KLRG)+ IL-2/TE and CD62L+KLRG− IL-15/TM cells with short- and long-term survival following their adoptive transfer into mice. The IL-15/mTORC1Weak signal activates the forkhead box-O-1 (FOXO1), T cell factor-1 (TCF1) and Eomes transcriptional network and the metabolic adenosine monophosphate-activated protein kinase-α-1 (AMPKα1), Unc-51-like autophagy-activating kinase-1 (ULK1) and autophagy-related gene-7 (ATG7) axis, increasing the expression of mitochondrial regulators aquaporin-9 (AQP9), mitochondrial transcription factor-A (TFAM), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), carnitine palmitoyl transferase-1 (CPT1α), microtubule-associated protein light chain-3 II (LC3II), Complex I and ortic atrophy-1 (OPA1), leading to promoting mitochondrial biogenesis and fatty-acid oxidation (FAO). Interestingly, AMPKα1 deficiency abrogates these downstream responses to IL-15/mTORC1Weak signaling, leading to the upregulation of mTORC1 and hypoxia-inducible factor-1α (HIF-1α), a metabolic switch from FAO to glycolysis and reduced cell survival. Taken together, our data demonstrate that IL-15/mTORC1Weak signaling controls T-cell memory via activation of the transcriptional FOXO1-TCF1-Eomes and metabolic AMPKα1-ULK1-ATG7 pathways, a finding that may greatly impact the development of efficient vaccines and immunotherapies for the treatment of cancer and infectious diseases.

Novel prognostic model predicts overall survival in colon cancer based on RNA splicing regulation gene expression

Colon cancer is the third most common cancer and the second leading cause of cancer‐related death worldwide. Dysregulated RNA splicing factors have been reported to be associated with tumorigenesis and development in colon cancer. In this study, we interrogated clinical and RNA expression data of colon cancer patients from The Cancer Genome Atlas (TCGA) dataset and the Gene Expression Omnibus (GEO) database. Genes regulating RNA splicing correlated with survival in colon cancer were identified and a risk score model was constructed using Cox regression analyses. In the risk model, RNA splicing factor peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PPARGC1) is correlated with a good survival outcome, whereas Cdc2‐like kinase 1(CLK1), CLK2, and A‐kinase anchor protein 8‐like (AKAP8L) with a bad survival outcome. The risk model has a good performance for clinical prognostic prediction both in the TCGA cohort and the other two validation cohorts. In the tumor microenvironment (TME) analysis, the immune score was higher in the low‐risk group, and TME‐related pathway gene expression was also higher in low‐risk group. We further verified the mRNA and protein expression levels of these four genes in the adjacent nontumor, tumor, and liver metastasis tissues of colon cancer patients, which were consistent with bioinformatics analysis. In addition, knockdown of AKAP8L can suppress the proliferation and migration of colon cancer cells. Animal studies have also shown that AKAP8L knockdown can inhibit tumor growth in colon cancer in vivo. We established a prognostic risk model for colon cancer based on genes related to RNA splicing regulation and uncovered the role of AKAP8L in promoting colon cancer progression.

Supplementation of Dimethylglycine Sodium Salt in Sow Milk Reverses Skeletal Muscle Redox Status Imbalance and Mitochondrial Dysfunction of Intrauterine Growth Restriction Newborns.

The current study sought to understand the mechanism underlying skeletal muscle dysfunction brought on by intrauterine growth restriction (IUGR) and to explore the treatment benefits of applying dimethylglycine sodium salt (DMG-Na) in sow milk to newborns during the suckling period. Each of the 10 sows delivered one newborn with a normal birth weight (NBW) and one with an IUGR. Additionally, two NBW and two IUGR newborns were collected per litter of another 10 sows. The 20 NBW newborns were divided between the N (sow milk) and ND (sow milk + 0.1% DMG-Na) groups, while 20 IUGR newborns were divided between the I (sow milk) and ID (sow milk + 0.1% DMG-Na) groups. The skeletal muscle histomorphology, redox status, and levels of gene and protein expression were worse (p < 0.05) in the I group than in the N group. In addition, supplementation with DMG-Na (ND and ID groups) improved (p < 0.05) those parameters compared to the unsupplemented groups (N and I groups). Inhibited nuclear factor erythroid 2-related factor 2 (Nrf2)/sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptorγcoactivator-1α (PGC-1α) activity resulted in decreased redox status, skeletal muscle structural damage, skeletal muscle mitochondrial function impairment, and decreased performance in IUGR newborns. Supplementation of DMG-Na in sow milk activated the Nrf2/SIRT1/PGC-1α in IUGR newborns, thereby improving their skeletal muscle performance.

Caloric restriction alters galanin and its receptor in hypothalamus of wistar rats

Caloric restriction (CR) reverses obesity and insulin resistance, yet the detailed mechanism underlying its beneficial effects is poorly understood. The galanin system is closely associated with energy metabolism. It is yet unclear whether this effect of CR is operating through the regulation of the galanin system. To test this effect, we subjected rats to either 60% or 40% calorie restriction for one week. After the one-week's experiment, galanin and many genes associated with the function of metabolism were examined. The present findings showed that 7 days of 60% or 40% calorie restriction lowered body weight and plasma glucose concentration in rats, suggesting that rats under CR have improved weight loss and systemic glucose metabolism. Besides, the lower plasma glucose was associated with an increase in muscle glucose uptake resulting from elevations of both glucose transporter 4 (GLUT4) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression in skeletal muscles. Moreover, the levels of galanin and its receptors (GALR1-3) mRNA markedly increased in the hypothalamus of CR rats. Taken together, these results supported that non-pharmacological activation of the galanin/GALR signaling with CR regimen led to activation of the PGC-1α/GLUT4 axis in skeletal muscles which can enhance energy metabolism. The current findings provide additional evidence that galanin is a critical factor for CR-induced weight loss and metabolic changes. CR regimen may be recognized as a non-pharmacological intervention that could prevent obesity and its associated metabolic disorders.

Ellagic Acid Alters Muscle Fiber-Type Composition and Promotes Mitochondrial Biogenesis through the AMPK Signaling Pathway in Healthy Pigs.

Ellagic acid (EA), because of its remarkable health-promoting ability, has aroused widespread interest in the fields of nutrition and medicine. However, no reports showed that EA regulates mitochondrial biogenesis as well as muscle fiber-type composition in pigs. Our study found that dietary 75 and 150 mg/kg EA obviously augmented the slow myosin heavy chain (MyHC) protein level, the number of slow-twitch muscle fibers, and the activity of malate dehydrogenase (MDH) in the longissimus thoracis (LT) muscle of growing-finishing pigs. In contrast, dietary 75 and 150 mg/kg EA decreased the fast MyHC level, the number of fast-twitch muscle fibers, and the activity of lactate dehydrogenase (LDH) in the LT muscle. In addition, our further study found that dietary 75 and 150 mg/kg EA promoted the mitochondrial DNA (mtDNA) content, the mRNA expressions of ATP synthase (ATP5G), mtDNA transcription factor A (TFAM), AMP-activated protein kinase α1 (AMPKα1), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and sirtuin 1 (Sirt1), and the level of phospho-LKB1 (P-LKB1), phospho-AMPK (P-AMPK), Sirt1, and PGC-1α in the LT muscle. In vitro, 5, 10, and 20 μmol/L EA treatment upregulated the level of slow MyHC, but only 10 μmol/L EA treatment decreased fast MyHC protein expression in porcine skeletal muscle satellite cells (PSCs). In addition, our data again found that 10 μmol/L EA treatment promoted the mtDNA content, the mRNA levels of ATP5G, mitochondrial transcription factor b1 (TFB1M), citrate synthase (Cs), AMPKα1, PGC-1α, and Sirt1, and the protein expressions of P-AMPK, P-LKB1, PGC-1α, and Sirt1 in PSCs. What is more, inhibition of the AMPK signaling pathway by AMPKα1 siRNA significantly eliminated the improvement of EA on muscle fiber-type composition as well as the mtDNA content in PSCs. In conclusion, EA altered muscle fiber-type composition and promoted mitochondrial biogenesis through the AMPK signaling pathway.

Physical exercise improves mitochondrial function in ovariectomized rats.

Estrogen deficiency causes metabolic disorders in humans and rodents, including in part due to changes in energy expenditure. We have shown previously that skeletal muscle mitochondrial function is compromised in ovariectomized (Ovx) rats. Since physical exercise is a powerful strategy to improve skeletal muscle mitochondrial content and function, we hypothesize that exercise training would counteract the deficiency-induced skeletal muscle mitochondrial dysfunction in Ovx rats. We report that exercised Ovx rats, at 60-65% of maximal exercise capacity for 8 weeks, exhibited less fat accumulation and body weight gain compared with sedentary controls. Treadmill exercise training decreased muscle lactate production, indicating a shift to mitochondrial oxidative metabolism. Furthermore, reduced soleus muscle mitochondrial oxygen consumption confirmed that estrogen deficiency is detrimental to mitochondrial function. However, exercise restored mitochondrial oxygen consumption in Ovx rats, achieving similar levels as in exercised control rats. Exercise-induced skeletal muscle peroxisome proliferator-activated receptor-γ coactivator-1α expression was similar in both groups. Therefore, the mechanisms by which exercise improves mitochondrial oxygen consumption appears to be different in Ovx-exercised and sham-exercised rats. While there was an increase in mitochondrial content in sham-exercised rats, demonstrated by a greater citrate synthase activity, no induction was observed in Ovx-exercised rats. Normalizing mitochondrial respiratory capacity by citrate synthase activity indicates a better oxidative phosphorylation efficiency in the Ovx-exercised group. In conclusion, physical exercise sustains mitochondrial function in ovarian hormone-deficient rats through a non-conventional mitochondrial content-independent manner.

Differential Immunometabolic Effects of High-Fat Diets Containing Coconut, Sunflower, and Extra Virgin Olive Oils in Female Mice.

To compare the effects of three high-fat diets (HFDs) based on coconut, sunflower, or extra virgin olive oils (EVOOs) on adipose tissue, metabolism, and inflammation. Mice are fed for 16weeks on their respective HFD. HFD based on coconut oil produces significantly lower body weight than EVOO- or sunflower oil-based HFDs. Furthermore, the coconut oil HFD leads to metabolic disturbances such as reduction of circulating leptin and adiponectin concentrations, hypertriglyceridemia, hepatomegaly, and liver triglyceride accumulation. Likewise, this diet produces an increase in serum pro-inflammatory cytokines (interleukin 6 [IL-6] and tumor necrosis factor-α [TNF-α]). In white (WAT) and brown (BAT) adipose tissue, the HFD based on coconut oil does not cause significant changes in the expression of studied proteins related to thermogenesis (uncoupling protein 1 [UCP-1]), mitochondrial biogenesis, and browning (peroxisome proliferator-activated receptor-γ coactivator 1α [PGC-1α] and nuclear factor E2-related factor 2 [Nrf2]). However, the HFD based on EVOO induces upregulation of UCP-1, PGC-1α, and Nrf2 expression in BAT, increases the expression of UCP-1 and PGC-1α in inguinal WAT, and enhances the expression of PGC-1α in epididymal WAT. An HFD based on coconut oil could reduce circulating leptin and adiponectin concentrations, increase the liver fat content, raise serum triglycerides, and promote inflammation by increasing circulating pro-inflammatory cytokines, while an EVOO-based HFD could increase thermogenic activity.

Effects of PGC-1α overexpression on the myogenic response during skeletal muscle regeneration

The ability of skeletal muscle to regenerate from injury is crucial for locomotion, metabolic health, and quality of life. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1A) is a transcriptional coactivator required for mitochondrial biogenesis. Increased mitochondrial biogenesis is associated with improved muscle cell differentiation, however PGC1A's role in skeletal muscle regeneration following damage requires further investigation. The purpose of this study was to investigate the role of skeletal muscle-specific PGC1A overexpression during regeneration following damage. 22 C57BL/6J (WT) and 26 PGC1A muscle transgenic (A1) mice were injected with either phosphate-buffered saline (PBS, uninjured control) or Bupivacaine (MAR, injured) into their tibialis anterior (TA) muscle to induce skeletal muscle damage. TA muscles were extracted 3- or 28-days post-injury and analyzed for markers of regenerative myogenesis and protein turnover. Pgc1a mRNA was ∼10–20 fold greater in A1 mice. Markers of protein synthesis, AKT and 4EBP1, displayed decreases in A1 mice compared to WT at both timepoints indicating a decreased protein synthetic response. Myod mRNA was ∼75% lower compared to WT 3 days post-injection. WT mice exhibited decreased cross-sectional area of the TA muscle at 28 days post-injection with bupivacaine compared to all other groups. PGC1A overexpression modifies the myogenic response during regeneration.

Ciclopirox inhibits NLRP3 inflammasome activation via protecting mitochondria and ameliorates imiquimod-induced psoriatic inflammation in mice

The maturation and secretion of interleukin-1β (IL-1β) mediated by NLRP3 inflammasome activation plays an important role in the progression of many inflammatory diseases. Inhibition of NLRP3 inflammasome activation may be a promising strategy to treat these inflammation-driven diseases, such as psoriasis. As a broad-spectrum antifungal agent, ciclopirox (CPX) is widely used in the treatment of dermatomycosis. Although CPX has been reported to have anti-inflammatory effects in many studies, there has been little research into its underlying mechanisms. In our study, CPX reduced lipopolysaccharide (LPS)/nigericin-induced NLRP3 inflammasome activation (IC50: 1.684 μM). Mechanistically, CPX upregulated peroxisome proliferator-activated receptor-γ coactivator-1α expression (by 82.7% at 5 μM and 87.5% at 10 μM) to protect mitochondria. Our studies showed that CPX reduced mitochondrial reactive oxygen species production, increased mitochondrial membrane potential, elevated mitochondrial biosynthesis, and up-regulated intracellular adenosine triphosphate level. Furthermore, treatment with CPX promoted the up-regulation of mRNA expression, which involved mitochondrial biosynthesis (NRF1, NRF2, TFAM) and antioxidation (SOD1 and CAT). In addition, CPX ameliorated inflammatory response in imiquimod-induced psoriasis mice. This study provides a potential pharmacological mechanism for CPX to treat psoriasis and other NLRP3-driven inflammatory diseases.

Mechanisms of mitochondrial respiratory adaptation.

Mitochondrial energetic adaptations encompass a plethora of conserved processes that maintain cell and organismal fitness and survival in the changing environment by adjusting the respiratory capacity of mitochondria. These mitochondrial responses are governed by general principles of regulatory biology exemplified by changes in gene expression, protein translation, protein complex formation, transmembrane transport, enzymatic activities and metabolite levels. These changes can promote mitochondrial biogenesis and membrane dynamics that in turn support mitochondrial respiration. The main regulatory components of mitochondrial energetic adaptation include: the transcription coactivator peroxisome proliferator-activated receptor-γ (PPARγ) coactivator 1α (PGC1α) and associated transcription factors; mTOR and endoplasmic reticulum stress signalling; TOM70-dependent mitochondrial protein import; the cristae remodelling factors, including mitochondrial contact site and cristae organizing system (MICOS) and OPA1; lipid remodelling; and the assembly and metabolite-dependent regulation of respiratory complexes. These adaptive molecular and structural mechanisms increase respiration to maintain basic processes specific to cell types and tissues. Failure to execute these regulatory responses causes cell damage and inflammation or senescence, compromising cell survival and the ability to adapt to energetically demanding conditions. Thus, mitochondrial adaptive cellular processes are important for physiological responses, including to nutrient availability, temperature and physical activity, and their failure leads to diseases associated with mitochondrial dysfunction such as metabolic and age-associated diseases and cancer.

Lactate promotes metastasis of normoxic colorectal cancer stem cells through PGC-1α-mediated oxidative phosphorylation

Uneven oxygen supply in solid tumors leads to hypoxic and normoxic regions. Hypoxic cells exhibit increased secretion of lactate, which creates an acidic tumor microenvironment (TME). This acidic TME is positively associated with tumor metastasis. Despite the increased metastatic capacity of hypoxic cells, they are located relatively further away from the blood vessels and have limited access to the circulatory system. Studies have shown that cancer stem cells (CSCs) are enriched for tumor metastasis-initiating cells and generally undergo aerobic respiration, which could be enhanced by lactate. We therefore hypothesized that TME-derived lactate may promote the metastasis of normoxic CSCs. In the present study, the abundance of hypoxic and normoxic CSCs was analyzed in primary CRC tumors. It was found that the proportion of normoxic CSCs was positively associated with tumor stage. Using two human CRC cell lines, LoVo and SW480, and a patient-derived xenograft (XhCRC), it was found that treatment with lactate promoted normoxic CSC metastasis. Metabolism analysis indicated that, upon treatment with lactate, oxidative phosphorylation (OXPHOS) activity in normoxic CSCs was enhanced, whereas hypoxic CSCs were rarely altered. At the molecular level, the expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a master regulator of lactate oxidation, was found to be elevated in normoxic CSCs. Furthermore, PGC-1α knockdown markedly reduced the metastatic potential of normoxic CSCs. Notably, both the PGC-1α-mediated OXPHOS activity and metastatic potential were impaired when hypoxia-inducible factor-1α (HIF-1α) was activated in normoxic CSCs. Together, these findings provide a therapeutic strategy against tumor metastasis through the targeting of PGC-1α and, thus, the suppression of lactate-feeding OXPHOS in normoxic CSCs may improve the therapeutic benefit of patients with cancer, particularly CRC.

Metformin mitigates gas explosion‑induced blast lung injuries through AMPK‑mediated energy metabolism and NOX2‑related oxidation pathway in rats

Gas explosions are a recurrent event in coal mining that cause severe pulmonary damage due to shock waves, and there is currently no effective targeted treatment. To illustrate the mechanism of gas explosion-induced lung injury and to explore strategies for blast lung injury (BLI) treatment, the present study used a BLI rat model and supplementation with metformin (MET), an AMP-activated protein kinase (AMPK) activator, at a dose of 10 mg/kg body weight by intraperitoneal injection. Protein expression levels were detected by western blotting. Significantly decreased expression of phosphorylated (p)-AMPK, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) and metabolic activity were observed in the BLI group compared with those in the control group. However, the mitochondrial stability, metabolic activity and expression of p-AMPK and PGC1α were elevated following MET treatment. These results suggested that MET could attenuate gas explosion-induced BLI by improving mitochondrial homeostasis. Meanwhile, high expression of nicotinamide adenine dinucleotide phosphate oxidase (NOX2) and low expression of catalase (CAT) were observed in the BLI group. The expression levels of NOX2 and CAT were restored in the BLI + MET group relative to changes in the BLI group, and the accumulation of oxidative stress was successfully reversed following MET treatment. Overall, these findings revealed that MET could alleviate BLI by activating the AMPK/PGC1α pathway and inhibiting oxidative stress caused by NOX2 activation.

Pentamethylquercetin Regulates Lipid Metabolism by Modulating Skeletal Muscle-Adipose Tissue Crosstalk in Obese Mice.

Irisin is an exercise-induced hormone that regulates lipid metabolism. The present study investigates whether the anti-obesity effect of the natural flavonoid pentamethylquercetin (PMQ) is related to irisin secretion from skeletal muscle in whole animals and cultured cells. Obese mice induced by monosodium glutamate were administered oral PMQ to determine blood irisin level and in vivo parameters of lipid metabolism, and cultured mouse C2C12 myoblasts and 3T3-L1 preadipocytes were employed to investigate the related molecular identities. PMQ increased circulating irisin and decreased bodyweight, insulin, and lipid levels accompanied with increasing brown-like adipocyte formation in obese mice. The brown adipocyte marker uncoupling protein 1 (UCP-1) and other brown-like adipocyte-specific genes and/or markers were increased in mouse white fat tissue, while PMQ treatment reversed the above changes. PMQ also dose-dependently increased the reduced levels of AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and fibronectin type III domain-containing 5 (FNDC5) signal molecules in obese mice. Interestingly, the irisin level was increased in the culture medium of C2C12 cells treated with PMQ, and the conditioned medium stimulated the brown-like transition of 3T3-L1 preadipocytes with the increased expression of PGC-1α, FNDC5, UCP-1, and other brown-like adipocyte-specific genes. The effects of conditioned culture medium were abolished in C2C12 cells with silenced PGC-1α. On the other hand, PMQ-induced upregulation of PGC-1α and FNDC5 expression was reduced by AMPK inhibitor Compound C in C2C12 cells. Our results demonstrate the novel information that PMQ-induced irisin secretion from skeletal muscle involves the improvement of metabolic dysfunction in obese mice via activating the AMPK/PGC-1α/FNDC5 signal pathway, suggesting that PMQ modulates skeletal muscle-adipose tissue crosstalk and may be a promising drug candidate for treating obesity and obesity-related metabolic diseases.

Effect of dietary L-theanine supplementation on skeletal muscle fiber type transformation in weaning piglets

The aim of this study was to explore the effect of dietary L-theanine (LT) supplementation on skeletal muscle fiber type transformation in weaning piglets. Our data showed that LT significantly increased the slow-twitch fiber-related genes expression and the percentage of slow oxidative fiber, and decreased the MyHC IIb mRNA expression and the percentage of fast glycolytic fiber. In addition, LT significantly increased the succinic dehydrogenase (SDH) and malate dehydrogenase (MDH) activities and increased the LDH activities. In addition, LT significantly affected mitochondrial biogenesis and function and antioxidative related genes expression, and increased the protein expression of p-adenosine monophosphate (AMP)-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), nuclear factor E2-related factor 2 (Nrf2), NADPH quinone oxidoreductase-1 (NQO1) and heme oxygenase-1 (HO-1) and decreased the Keap1 protein levels. Furthermore, our data indicated that LT significantly increased the mRNA and protein expression of prospero-related homeobox 1 (Prox1), calcineurin A (CnA), and NFATc1, suggesting that dietary LT supplementation promoted skeletal muscle fiber transition from types II to I might be via activation of calcineurin signaling pathway. Taken together, these findings suggested that LT promoted the transformation of muscle fiber types from slow oxidative to fast glycolytic by increasing antioxidant capacity and improving mitochondrial biogenesis and function and activation of calcineurin signaling pathway.