Stimulation Of Mitochondrial Biogenesis Research Articles

ANESTHESIOLOGY IN THE LIGHT OF THE TRANSFORMATIONS OF THE THEORY OF STRESS AND ADAPTATION. PERSPECTIVE OR SKEPTICISM OF PRACTICAL USE? (literature review)

The article attempts to analyze the main modern transformations of the theory of stress and adaptation and the possibility of implementing anti-stress adaptation reactions of general anesthesia. One of the central non-specific mechanisms of stressor injury has been found to be the stimulation of free-radical processes as a result of the often concomitant hypoxemia / hypoxia and the prooxidant effects of catecholamines. Data on the regulatory and adaptive effect of FR products (AOS and nitrogen) in the regulation of gene expression and increased production of antistress proteins, stimulation of mitochondrial biogenesis and normalization of energy metabolism are presented. The discussions of the "apologists" of adaptology about the "integral" indicators of the type of adaptation and the functional state of the organism are given. Emphasis is placed on the anesthesiologist's understanding that the organism is a relatively open selforganizing and self-structured dissipative system, as well as a critical view of the mathematical method of evaluating adaptation processes in the organism.

Оксидативный стресс как неспецифический фактор патогенеза органных повреждений (обзор литературы и собственных исследований)

В обзоре освещены современные литературные данные и собственные исследования в области клинической медицины и биологии молекулярных механизмов оксидативного стресса, его роль в патогенезе многих заболеваний и органных повреждений. Представлены новые данные об общебиологических закономерностях гибели клетки, органа или организма в целом. Установлено, что одним из центральных неспеци­фических механизмов стрессорного повреждения является стимуляция свободнорадикальных процессов в результате часто сопутствующей гипоксемии/гипоксии и прооксидантных эффектов катехоламинов. Раскрываются причины и механизмы нарушений окислительно-восстановительных реакций в дыхательной цепи митохондрий. Установлено, что окислительно-восстановительные реакции в митохондриальных мембранах четко регулируются генами локально. Разобщение дыхания связывают не только с механическим повреждением мембраны, но и с воздействием целого ряда ядовитых веществ, бактериальных токсинов и лекарственных препаратов на этот процесс. Рассмотрена связь общей скорости дыхания и предела аэробной производительности. Важная роль отводится саморегулирующей, так называемой квазизакрытой системе организма, которая работает против энтропии. В клинических исследованиях установлены пути катастрофического накопления свободных радикалов и цитотоксических метаболитов их катаболизма, триггерные механизмы оксидативного стресса и его роль в развитии апоптоза и тяжелых послеоперационных осложнений. Снижение активности ферментов катаболизма эндогенных альдегидов в тканях и субклеточных фракциях уменьшает адаптационные возможности организма. Определение уровня ферментов катаболизма эндогенных альдегидов может служить одним из критериев тяжести стресса и митохондриального дисгомеостаза в критических состояниях. Указана роль оксидазного и оксигеназного окисления в микросомах при гипоксемии/гипоксии и воздействии ксенобиотиков. Приведены данные о регуляторном и адаптивном влиянии свободнорадикальных продуктов (АФК и азота) на регуляцию экспрессии генов и усиление продукции антистрессорных белков, стимуляцию биогенеза митохондрий и нормализацию энергетического обмена. Обращено внимание на причины недостаточной клинической эффективности применяемых антиоксидантов и пути метаболической адаптации в критических состояниях.

Adaptive optimization of the OXPHOS assembly line partially compensates lrpprc-dependent mitochondrial translation defects in mice

Mouse models of genetic mitochondrial disorders are generally used to understand specific molecular defects and their biochemical consequences, but rarely to map compensatory changes allowing survival. Here we took advantage of the extraordinary mitochondrial resilience of hepatic Lrpprc knockout mice to explore this question using native proteomics profiling and lipidomics. In these mice, low levels of the mtRNA binding protein LRPPRC induce a global mitochondrial translation defect and a severe reduction (>80%) in the assembly and activity of the electron transport chain (ETC) complex IV (CIV). Yet, animals show no signs of overt liver failure and capacity of the ETC is preserved. Beyond stimulation of mitochondrial biogenesis, results show that the abundance of mitoribosomes per unit of mitochondria is increased and proteostatic mechanisms are induced in presence of low LRPPRC levels to preserve a balance in the availability of mitochondrial- vs nuclear-encoded ETC subunits. At the level of individual organelles, a stabilization of residual CIV in supercomplexes (SCs) is observed, pointing to a role of these supramolecular arrangements in preserving ETC function. While the SC assembly factor COX7A2L could not contribute to the stabilization of CIV, important changes in membrane glycerophospholipid (GPL), most notably an increase in SC-stabilizing cardiolipins species (CLs), were observed along with an increased abundance of other supramolecular assemblies known to be stabilized by, and/or participate in CL metabolism. Together these data reveal a complex in vivo network of molecular adjustments involved in preserving mitochondrial integrity in energy consuming organs facing OXPHOS defects, which could be therapeutically exploited.

Acupoint catgut embedding improves senescence in a rat model of ageing by regulating mitophagy via the PINK1 pathway.

Ageing population is a tough task worldwide, and the aggravating trend of ageing population in China brings enormous pressure to healthcare system. Chinese acupuncture has shown definite anti‐ageing effect as arthralgia relief, movement improvement, energy increase and immunity enhancement; however, the mechanisms underlying are far away from illumination. Increasing literature has highlighted the role of alterations in mitochondrial function as a potential central regulator in ageing biology; mitophagy plays a critical role in mitochondrial quality control. In the present study, we demonstrated that acupoint catgut embedding treatment ameliorated ageing‐related alterations in appearance, muscle function and spatial memory in rats, reduced degenerated cells in hippocampus, and maintained relatively normal structures in the hippocampus tissue and neurons. These changes were proved to be associated with the regulation of mitochondrial function and autophagic activity. Furthermore, we investigated part of the molecular mechanisms and demonstrated that the PINK1 other than PINK1–Parkin signalling pathway involved in the effects of acupoint catgut embedding, and the imbalancement between mitochondrial fusion and fission and stimulation of mitochondrial biogenesis may aggravate or compensate for impaired mitochondria. The factors act downstream PINK, and the interaction between them for mitochondrial homeostasis in this process remains to be identified.

How do exercise training variables stimulate processes related to mitochondrial biogenesis in slow and fast trout muscle fibres?

What is the central question of this study? Exercise is known to promote mitochondrial biogenesis in skeletal muscle, but what are the most relevant training protocols to stimulate it? What is the main finding and its importance? As in mammals, training in rainbow trout affects slow and fast muscle fibres differently. Exercise intensity, relative to volume, duration and frequency, is the most relevant training variable to stimulate the processes related to mitochondrial biogenesis in both red and white muscles. This study offers new insights into muscle fibre type-specific transcription and expression of genes involved in mitochondrial adaptations following training. Exercise is known to be a powerful way to improve health through the stimulation of mitochondrial biogenesis in skeletal muscle, which undergoes cellular and molecular adaptations. One of the current challenges in human is to define the optimal training stimulus to improve muscle performance. Fish are relevant models for exercise training physiology studies mainly because of their distinct slow and fast muscle fibres. Using rainbow trout, we investigated the effects of six different training protocols defined by manipulating specific training variables (such as exercise intensity, volume, duration and frequency), on mRNAs and some proteins related to four subsystems (AMP-activated protein kinase-peroxisome proliferator-activated receptor γ coactivator-1α signalling pathway, mitochondrial function, antioxidant defences and lactate dehydrogenase (LDH) metabolism) in both red and white muscles (RM and WM, respectively). In both muscles, high-intensity exercise stimulated more mRNA types and enzymatic activities related to mitochondrial biogenesis than moderate-intensity exercise. For volume, duration and frequency variables, we demonstrated fibre type-specific responses. Indeed, for high-intensity interval training, RM transcript levels are increased by a low training volume, but WM transcript responses are stimulated by a high training volume. Moreover, transcripts and enzymatic activities related to mitochondria and LDH show that WM tends to develop aerobic metabolism with a high training volume. For transcript stimulation, WM requires a greater duration and frequency of exercise than RM, whereas protein adaptations are efficient with a long training duration and a high frequency in both muscles.

Pyrroloquinoline Quinone Modifies Lipid Profile, but Not Insulin Sensitivity, of Palmitic Acid-Treated L6 Myotubes.

Pyrroloquinoline quinone (PQQ) is a novel stimulator of mitochondrial biogenesis and cellular energy metabolism. This is the first study investigating regulatory mechanisms and metabolic responses underlying PQQ’s action in palmitate-exposed L6 myotubes. Particularly, we assessed alterations in lipid content and composition, expression of metabolic enzymes, and changes in glucose transport. The experiments were conducted using muscle cells subjected to short (2 h) and prolonged (24 h) incubation with PQQ in a sequence of pre- and post-palmitic acid (PA) exposure. We demonstrated the opposite effects of 2 and 24 h treatments with PQQ on lipid content, i.e., a decline in the level of free fatty acids and triacylglycerols in response to short-time PQQ incubation as compared to increases in diacylglycerol and triacylglycerol levels observed after 24 h. We did not demonstrate a significant impact of PQQ on fatty acid transport. The analysis of metabolic enzyme expression showed that the vast majority of PQQ-dependent alterations cumulated in the PA/PQQ 24 h group, including elevated protein amount of peroxisome proliferator activated receptor γ co-activator 1α (PGC-1α), sirtuin-1 (SIRT1), phosphorylated 5′AMP-activated protein kinase (pAMPK), carnitine palmitoyltransferase I (CPT1), citrate synthase (CS), fatty acid synthase (FAS), and serine palmitoyltransferase, long chain base subunit 1 (SPT1). In conclusion, the results mentioned above indicate PQQ-dependent activation of both fatty acid oxidation and lipid synthesis in order to adapt cells to palmitic acid-rich medium, although PQQ did not attenuate insulin resistance in muscle cells.

Vascular endothelial growth factor alleviates mitochondrial dysfunction and suppression of mitochondrial biogenesis in models of Alzheimer’s disease

Purpose Mitochondrial dysfunction is a prominent feature of Alzheimer’s disease (AD). As vascular endothelial growth factor (VEGF) has been shown to be protective in AD, the aim of this study was to investigate the effects of VEGF on mitochondrial function in models of AD. Materials and methods Adeno associated virus (AAV)-VEGF was injected into the hippocampus of APP/PS1 mice. Cognitive function was assessed in these mice with use of the Morris water maze (MWM) and β-amyloid (Aβ) levels in the hippocampus were also measured. Cell viability and reactive oxygen species (ROS) levels were determined in the SH-SY5Y cells treated with Aβ25–35 which served as a cell model of AD. Transmission electron microscopy (TEM) was used to evaluate structural changes in mitochondria and mitochondrial DNA (mtDNA) copy number and mitochondrial membrane potential (MMP) were also recorded. Finally, we investigated the effects of VEGF upon mitochondrial biogenesis, autophagy and mitochondrial autophagy (mitophagy) as determined both in vivo and in vitro with western blots. Results VEGF treated mice showed improvements in spatial learning and memory along with reduced Aβ levels. VEGF protected SH-SY5Y cells against Aβ25–35 induced neurotoxicity as demonstrated by increased cell viability and decreased ROS production. Associated with these effects were improvements in mitochondrial structure and function, and increased numbers of mitochondria resulting from stimulation of mitochondrial biogenesis. Conclusions VEGF alleviates Aβ related patholoy in models of AD. In part, these beneficial effects of VEGF result from protection of mitochondria and stimulation of mitochondrial biogenesis.

11-β-hydroxysterols as possible endogenous stimulators of mitochondrial biogenesis as inferred from epicatechin molecular mimicry

Currently, there is great interest in identifying endogenous (i.e. physiological) stimulators of mitochondrial biogenesis (MB), in particular, those that may mediate the effects of exercise. The molecular size of the cacao flavanols (epicatechin and catechin) highly resembles that of sterols and epicatechin has been reported to activate cells surface receptors leading to the stimulation of MB in endothelial and skeletal muscle cells translating into enhanced exercise capacity. We therefore hypothesize, that epicatechin may be acting as a structural mimic of an as yet unknown sterol capable of stimulating MB. We developed a new synthetic process for obtaining enantiomerically pure preparations of (-)-epicatechin and (+)-epicatechin. Applying spatial analytics and molecular modeling, we found that the two isoforms of epicatechin, (-) and (+), have a structural resemblance to 11-β-hydroxypregnenolone, a sterol with no previously described biological activity. As reported in this proof-of-concept study performed in primary cultures of endothelial and muscle cells, 11-β-hydroxypregnenolone is one of the most potent inducers of MB as significant activity can be detected at femtomolar levels. The relative potency of (-)/(+)-epicatechin isoforms and on inducing MB correlates with their degree of spatial homology towards the 11-β-hydroxypregnenolone. On the basis of these results, the detailed in vivo characterization of the potential for these sterols to act as endogenous modulators of MB is warranted.

Short Call Abstracts

Short Call Abstracts

Bitter melon seed oil increases mitochondrial content in gastrocnemius muscle and improves running endurance in sedentary C57BL/6J mice

The α-eleostearic acid (α-ESA) in bitter melon seed oil (BMSO) is efficiently converted by the body into rumenic acid. The objective of this study was to investigate effects of BMSO on skeletal muscle fiber-type switch and endurance capacity in mice, with or without exercise training. In a 3×2 factorial design, C57BL/6J mice were fed a 30% high-fat diet composed of soybean oil, butter or a 1:1 mixture of BMSO and soybean oil, i.e., SB, BT and BM diets, respectively, and were allocated to be sedentary or undergo exercise (Ex). The Ex groups received a 15-min training regimen on a motorized treadmill 5 times a week. After 3-week intervention, endurance capacity was evaluated (total running time and distance until exhaustion). Mice fed a BM diet had significantly less body fat, with increased muscle percentage and improved endurance capacity. Combining sedentary and Ex groups, mice fed a BM diet ran 33% longer and 50% further than those fed SB, or 25% longer and 36% further than those fed BT (P<.01). The BM-diet-increased gastrocnemius cytochrome c protein and mitochondrial DNA content was more prominent in sedentary than in trained mice. Histochemical staining shows sedentary BM-fed mice had a higher succinate dehydrogenase activity among groups. Based on a reporter assay, rumenic acid, rather than α-ESA itself, activated PPARδ ligand binding domain. We concluded that BMSO improved endurance capacity via stimulation of mitochondrial biogenesis and function, potentially influencing muscle metabolism and fiber-type composition in sedentary mice.

The flavanol (−)‐epicatechin improves learning, memory and anxiety behavior in ovariectomized rats

The loss of gonadal function in women during menopause is known to contribute to impaired memory and learning performance. Conversely, menopausal women using estrogen replacement therapy (ERT) can evidence improvements on these endpoints. However, the long-term use of ERT has been show to have important health risks such as increased rates for certain cancers. Supplements, such as phytoestrogens and/or flavonoids have emerged as potential alternative treatments during menopause that may offer safer options. (−)-Epicatechin (Epi), is the most abundant flavonoid present in cacao seeds. Epi is related with a number of healthy cardiometabolic effects in preclinical models and in humans. Such effects include improvements in vascular, cardiac and metabolic function, stimulation of mitochondrial biogenesis and upregulation of enzymatic and non-enzymatic antioxidant systems in tissues such as the heart and skeletal muscle. These effects appear to be related to the binding/stimulation of Epi to the G-protein estrogen receptor (GPER). However, the effects of Epi in postmenopausal female model neurological endpoints including learning, memory and anxiety are poorly understood. In this study we evaluated the effect of Epi (0.01 and 1 mg/kg body weight) on memory, learning and anxiety behavior of ovariectomized (Ovx) rats, an accepted animal model of menopause. For this purpose, Ovx rats were evaluated using two behavioral tests, 1) object recognition task (ORT) (involving short and long term memory; STM, LTM respectively) and, 2) T-maze (anxiety model). As shown in the figure, in the ORT, Ovx rats evidenced significant improvement in short and long term memory with 0.01 mg/Kg of Epi. For anxiety T-maze measures, Epi significantly reduced delayed avoidance latency markedly with the dose of 1.0 mg/Kg and escape latency with both doses of Epi. These data suggest that low dose of Epi improves the recognition memory in Ovx rats and can also reduce anxiety. The underlying mechanisms may be related to the positive effects of Epi on regulators/stimulators of mitochondrial biogenesis and oxidative stress buffering systems which we have reported to occur in senile animals. These results warrant the implementation of future studies in human subjects using Epi. Support or Funding Information DoD 150090 to FV This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

(-)-Epicatechin stimulates mitochondrial biogenesis and cell growth in C2C12 myotubes via the G-protein coupled estrogen receptor

We have reported on the capacity of (-)-epicatechin ((-)-EPI) to stimulate mitochondrial biogenesis (MiB) in mouse skeletal muscle (SkM). However, the mechanisms mediating the effects of (-)-EPI are not fully understood. We previously identified a role of the G-protein coupled estrogen receptor (GPER) in modulating the vascular effects of (-)-EPI. We therefore tested the hypothesis that GPER mediates (at least in part) the stimulatory effects of (-)-EPI on MiB in SkM cells. As an in vitro model, we employed mouse SkM-derived C2C12 myoblasts differentiated into myotubes. Using confocal microscopy, we detected GPER at the cell surface and cytoplasm in C2C12 myotubes. Treatment with (-)-EPI (3 and 10μM) resulted in the stimulation of MiB as per increases in mitochondrial inner (MitoTracker Red FM fluorescence staining) and outer membrane (porin protein levels) markers, transcription factors involved in MiB stimulation (i.e., nuclear respiratory factor-2 [NRF-2] and mitochondrial transcription factor A [TFAM] protein levels) and citrate synthase (CS) activity levels. (-)-EPI-treated myotubes were longer and wider compared to vehicle-treated myotubes. The effects of (-)-EPI on myotube mitochondria and cell size were larger in magnitude to those observed with the GPER agonist G-1. The chemical blockade and down-regulation (siRNA) of GPER evidenced a partial and complete blockade of measured endpoints following (-)-EPI- or G-1-treatment, respectively. Altogether, results indicate that GPER is expressed in muscle cells and appears to mediate to a significant extent, the stimulatory effects of (-)-EPI on MiB. Thus, GPER activation may account for the stimulatory effects of (-)-EPI on SkM structure/function.

Resveratrol-Induced Changes in MicroRNA Expression in Primary Human Fibroblasts Harboring Carnitine-Palmitoyl Transferase-2 Gene Mutation, Leading to Fatty Acid Oxidation Deficiency.

Carnitine palmitoyltransferase-2 (CPT2) is a mitochondrial enzyme involved in long-chain fatty acid entry into mitochondria for their β-oxidation and energy production. Two phenotypes are associated with the extremely reduced CPT2 activity in genetically deficient patients: neonatal lethality or, in milder forms, myopathy. Resveratrol (RSV) is a phytophenol produced by grape plant in response to biotic or abiotic stresses that displays anti-oxidant properties, in particular through AP-1, NFκB, STAT-3, and COX pathways. Some beneficiary effects of RSV are due to its modulation of microRNA (miRNA) expression. RSV can enhance residual CPT2 activities in human fibroblasts derived from CPT2-deficient patients and restores normal fatty acid oxidation rates likely through stimulation of mitochondrial biogenesis. Here, we report changes in miRNA expression linked to CPT2-deficiency, and we identify miRNAs whose expression changed following RSV treatment of control or CPT2-deficient fibroblasts isolated from patients. Our findings suggest that RSV consumption might exert beneficiary effects in patients with CPT2-deficiency.

Targeting Mitochondrial Biogenesis and Mitochondrial Substrate Utilization to Treat Obesity and Insulin Resistance, Respectively - Two Data-Driven Hypotheses.

The mitochondrion plays a critical role in cellular energy metabolism. For this reason it is considered as a plausible target for the treatment of metabolic diseases such as obesity and type-2 diabetes. Although several mitochondrial molecular targets have been suggested and investigated, currently there are no marketed drugs that target the mitochondrion to treat metabolic diseases. Through an investigation of current drugs and investigational compounds, two hypotheses have emerged: 1) inhibition of mitochondrial substrate utilization is associated with increased insulinstimulated glucose uptake; 2) stimulation of mitochondrial biogenesis is related to increased energy expenditure and potentially weight loss. The mode-of-action of both mechanistic hypotheses is currently unknown and potentially controversial since they contradict other experimental findings. However, the fact that both processes are stimulated by different types of compounds with different sites of action supports their potential existence. This review summarizes the data that support these two hypotheses; with the hope that this will stimulate further research and intensify the development of future drugs for the treatment of obesity and type-2 diabetes.

Mesenchymal stem cells sense mitochondria released from damaged cells as danger signals to activate their rescue properties

Mesenchymal stem cells (MSCs) protect tissues against cell death induced by ischemia/reperfusion insults. This therapeutic effect seems to be controlled by physiological cues released by the local microenvironment following injury. Recent lines of evidence indicate that MSC can communicate with their microenvironment through bidirectional exchanges of mitochondria. In particular, in vitro and in vivo studies report that MSCs rescue injured cells through delivery of their own mitochondria. However, the role of mitochondria conveyed from somatic cells to MSC remains unknown. By using a co-culture system consisting of MSC and distressed somatic cells such as cardiomyocytes or endothelial cells, we showed that mitochondria from suffering cells acted as danger-signaling organelles that triggered the anti-apoptotic function of MSC. We demonstrated that foreign somatic-derived mitochondria were engulfed and degraded by MSC, leading to induction of the cytoprotective enzyme heme oxygenase-1 (HO-1) and stimulation of mitochondrial biogenesis. As a result, the capacity of MSC to donate their mitochondria to injured cells to combat oxidative stress injury was enhanced. We found that similar mechanisms – activation of autophagy, HO-1 and mitochondrial biogenesis – occurred after exposure of MSC to exogenous mitochondria isolated from somatic cells, strengthening the idea that somatic mitochondria alert MSC of a danger situation and subsequently promote an adaptive reparative response. In addition, the cascade of events triggered by the transfer of somatic mitochondria into MSC was recapitulated in a model of myocardial infarction in vivo. Specifically, MSC engrafted into infarcted hearts of mice reduced damage, upregulated HO-1 and increased mitochondrial biogenesis, while inhibition of mitophagy or HO-1 failed to protect against cardiac apoptosis. In conclusion, our study reveals a new facet about the role of mitochondria released from dying cells as a key environmental cue that controls the cytoprotective function of MSC and opens novel avenues to improve the effectiveness of MSC-based therapies.

NADPH Oxidase 4 (Nox4) Suppresses Mitochondrial Biogenesis and Bioenergetics in Lung Fibroblasts via a Nuclear Factor Erythroid-derived 2-like 2 (Nrf2)-dependent Pathway

Mitochondrial bioenergetics are critical for cellular homeostasis and stress responses. The reactive oxygen species-generating enzyme, NADPH oxidase 4 (Nox4), regulates a number of physiological and pathological processes, including cellular differentiation, host defense, and tissue fibrosis. In this study we explored the role of constitutive Nox4 activity in regulating mitochondrial function. An increase in mitochondrial oxygen consumption and reserve capacity was observed in murine and human lung fibroblasts with genetic deficiency (or silencing) of Nox4. Inhibition of Nox4 expression/activity by genetic or pharmacological approaches resulted in stimulation of mitochondrial biogenesis, as evidenced by elevated mitochondrial-to-nuclear DNA ratio and increased expression of the mitochondrial markers transcription factor A (TFAM), citrate synthase, voltage-dependent anion channel (VDAC), and cytochrome c oxidase subunit 4 (COX IV). Induction of mitochondrial biogenesis was dependent on TFAM up-regulation but was independent of the activation of the peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α). The enhancement of mitochondrial bioenergetics as well as the increase in mitochondrial proteins in Nox4-deficient lung fibroblasts is inhibited by silencing of nuclear factor erythroid-derived 2-like 2 (Nrf2), supporting a key role for Nrf2 in control of mitochondrial biogenesis. Together, these results indicate a critical role for both Nox4 and Nrf2 in counter-regulation of mitochondrial biogenesis and metabolism.

Carvedilol promotes mitochondrial biogenesis by regulating the PGC-1/TFAM pathway in human umbilical vein endothelial cells (HUVECs)

Carvedilol, a third-generation and nonselective β-adrenoceptor antagonist, is a licensed drug for treating patients suffering from heart failure in clinics. It has been shown that Carvedilol protects cells against mitochondrial dysfunction. However, it's unknown whether Carvedilol affects mitochondrial biogenesis. In this study, we found that treatment with Carvedilol in HUVECs resulted in a significant increase of PGC-1α, NRF1, and TFAM. Notably, Carvedilol significantly increased mtDNA contents and the two mitochondrial proteins, cytochrome C and COX IV. In addition, MitoTracker Red staining results indicated that treatment with Carvedilol increased mitochondria mass. Mechanistically, we found that the effect of Carvedilol on the expression of PGC-1α is mediated by the PKA-CREB pathway. Importantly, our results revealed that stimulation of mitochondrial biogenesis by carvedilol resulted in functional gain of the mitochondria by showing increased oxygen consumption and mitochondrial respiratory rate. The increased expression of PGC-1α and mitochondrial biogenesis induced by Carvedilol might suggest a new mechanism of the therapeutic effects of Carvedilol in heart failure.

Conjugated linoleic acid (CLA) influences muscle metabolism via stimulating mitochondrial biogenesis signaling in adult‐onset inactivity induced obese mice

Recently, conjugated linoleic acid (CLA) has been reported to prevent body weight gain and fat accumulation in part by improving physical activity in mice. The current study was conducted to determine the role of CLA on skeletal muscle metabolism in nescient basic helix‐loop‐helix 2 knock‐out (N2KO) mice, an adult‐onset inactivity induced obese model. Five‐week‐old female N2KO and wild type mice were fed either control or CLA containing diet (0.5%) for 10 wk. Voluntary activity was determined biweekly and markers for muscle metabolisms were determined from the gastrocnemius muscle. CLA fed N2KO animals showed significant increased voluntary movement and gastrocnemius muscle mass compared to control group, whereas in wild type animals, no differences were observed. CLA treatment up‐regulated AMP‐activated protein kinase (AMPK), mitochondria biogenic markers, peroxisome proliferator‐activated receptor‐δ (PPARδ), and mitochondrial transcription factor A (Tfam) compared to control animals. These observations indicate that CLA supplementation activates AMPKα‐PPARδ and/or ‐Tfam signaling cascade for stimulating mitochondria biogenesis. Taken together, these results suggest that CLA may in part activate the underlying biomarkers involved in muscle metabolism via stimulation of mitochondrial biogenesis, resulting in increased voluntary activity and muscle mass, potentially contributing to regulating weight gain.Practical applications: Lack of physical activity is a global public health problem, which induces obesity and its associated pathologies. Approximately, 3.2 million deaths per year are attributable to lack of physical activity. CLA has previously been reported to increase voluntary and endurance activities in mice. However, the exact mode of action is not completely understood. Thus, the purpose of the study was to shed light on positive effects of CLA on physical activity through modulation of molecular targets in skeletal muscle of Nhlh2 knockout mice, which are an adult‐onset inactivity induced obesity model. The current results suggest that CLA acts as a potential exercise‐mimetic, resulting in increased voluntary activity and muscle mass, potentially contributing to regulating weight gain.Conjugated linoleic acid partially improves muscle metabolism via stimulation of mitochondrial biogenesis, resulting in increased voluntary activity.

Mitochondrial Quality Control as a Therapeutic Target.

In addition to oxidative phosphorylation (OXPHOS), mitochondria perform other functions such as heme biosynthesis and oxygen sensing and mediate calcium homeostasis, cell growth, and cell death. They participate in cell communication and regulation of inflammation and are important considerations in aging, drug toxicity, and pathogenesis. The cell's capacity to maintain its mitochondria involves intramitochondrial processes, such as heme and protein turnover, and those involving entire organelles, such as fusion, fission, selective mitochondrial macroautophagy (mitophagy), and mitochondrial biogenesis. The integration of these processes exemplifies mitochondrial quality control (QC), which is also important in cellular disorders ranging from primary mitochondrial genetic diseases to those that involve mitochondria secondarily, such as neurodegenerative, cardiovascular, inflammatory, and metabolic syndromes. Consequently, mitochondrial biology represents a potentially useful, but relatively unexploited area of therapeutic innovation. In patients with genetic OXPHOS disorders, the largest group of inborn errors of metabolism, effective therapies, apart from symptomatic and nutritional measures, are largely lacking. Moreover, the genetic and biochemical heterogeneity of these states is remarkably similar to those of certain acquired diseases characterized by metabolic and oxidative stress and displaying wide variability. This biologic variability reflects cell-specific and repair processes that complicate rational pharmacological approaches to both primary and secondary mitochondrial disorders. However, emerging concepts of mitochondrial turnover and dynamics along with new mitochondrial disease models are providing opportunities to develop and evaluate mitochondrial QC-based therapies. The goals of such therapies extend beyond amelioration of energy insufficiency and tissue loss and entail cell repair, cell replacement, and the prevention of fibrosis. This review summarizes current concepts of mitochondria as disease elements and outlines novel strategies to address mitochondrial dysfunction through the stimulation of mitochondrial biogenesis and quality control.

Muscle wasting in end-stage renal disease promulgates premature death: established, emerging and potential novel treatment strategies

Muscle wasting (or sarcopenia) is a common feature of the uremic phenotype and predisposes this vulnerable patient population to increased risk of comorbid complications, poor quality of life, frailty and premature death. The old age of dialysis patients is in addition a likely contributor to loss of muscle mass. As recent evidence suggests that assessment of muscle strength (i.e. function) is a better predictor of outcome and comorbidities than muscle mass, this opens new screening, assessment and therapeutic opportunities. Among established treatment strategies, the benefit of resistance exercise and endurance training are increasingly recognized among nephrologists as being effective and should be promoted in sedentary chronic kidney disease patients. Testosterone and growth hormone replacement appear as the most promising among emerging treatments strategies for muscle wasting. As treatment of muscle wasting is difficult and seldom successful in this often old, frail, sedentary and exercise-hesitant patient group, novel treatment strategies are urgently needed. In this review, we summarize recent studies on stimulation of mitochondrial biogenesis, myogenic stem (satellite) cells and manipulation of transforming growth factor family members, all of which hold promise for more effective therapies to target muscle mass loss and function in the future.