Muscle PGC-1α Research Articles

Alterations in FoxO3a, NF-κB, and MuRF1 Expression in the Soleus Muscle of Male Rats Following High-Intensity Interval Training and Detraining.

Activation of the transcription factors FoxO3a and NF-κB is necessary for muscle atrophy, which occurs during cancer cachexia and detraining. It is not known how high-intensity interval training (HIIT) and detraining affect activation of these pathways. Two-month-old male Sprague-Dawley rats were assigned to sedentary control (SC) (n = 6) and HIIT (HIIT) (n = 18) groups. The HIIT group was divided into three subgroups: HIIT (n = 6), HIIT + 7-day detraining (n = 6), and HIIT + 14-day detraining (n = 6). The expression of FoxO3a, NF-κB, MuRF1, and PGC-1α in the soleus muscle was examined by RT-PCR using CYBR Green. The 2-Ct, Livak method was used to calculate the changes in data expression. The soleus muscle mass increased after HIIT (35.10%) and decreased after 7- and 14-day of detraining (15 and 21%, respectively). The mRNA expression levels of NF-κB, MuRF1, and PGC1α in the soleus muscle were upregulated, and FoxO3a levels were significantly lower in the HIIT group compare to the SC group (p = 0.001). Taken together, the activity of the FoxO3a/MuRF1 pathway, but not NF-κB /MuRF1, can promote atrophy due to detraining, and MuRF1 is not always a good marker of atrophy.

Endurance exercise-induced histone methylation modification involved in skeletal muscle fiber type transition and mitochondrial biogenesis

Skeletal muscle is a highly heterogeneous tissue, and its contractile proteins are composed of different isoforms, forming various types of muscle fiber, each of which has its own metabolic characteristics. It has been demonstrated that endurance exercise induces the transition of muscle fibers from fast-twitch to slow-twitch muscle fiber type. Herein, we discover a novel epigenetic mechanism for muscle contractile property tightly coupled to its metabolic capacity during muscle fiber type transition with exercise training. Our results show that an 8-week endurance exercise induces histone methylation remodeling of PGC-1α and myosin heavy chain (MHC) isoforms in the rat gastrocnemius muscle, accompanied by increased mitochondrial biogenesis and an elevated ratio of slow-twitch to fast-twitch fibers. Furthermore, to verify the roles of reactive oxygen species (ROS) and AMPK in exercise-regulated epigenetic modifications and muscle fiber type transitions, mouse C2C12 myotubes were used. It was shown that rotenone activates ROS/AMPK pathway and histone methylation enzymes, which then promote mitochondrial biogenesis and MHC slow isoform expression. Mitoquinone (MitoQ) partially blocking rotenone-treated model confirms the role of ROS in coupling mitochondrial biogenesis with muscle fiber type. In conclusion, endurance exercise couples mitochondrial biogenesis with MHC slow isoform by remodeling histone methylation, which in turn promotes the transition of fast-twitch to slow-twitch muscle fibers. The ROS/AMPK pathway may be involved in the regulation of histone methylation enzymes by endurance exercise.

Hypomethylation in promoters of PGC-1α involved in exercise-driven skeletal muscular alterations in old age.

Exercise training can significantly improve skeletal muscle mitochondrial function and has been proven to be highly relevant to alterations in skeletal muscle DNA methylation. However, it remains unclear whether late-in-life exercise has an effect on promoter methylation of PGC-1α, a key regulator of mitochondrial biogenesis. Here we employed two distinct exercise modalities, constant medium intensity exercise training (CMIT) and high-intensity interval exercise training (HIIT), to investigate their impacts on PGC-1α expression and methylation regulation in skeletal muscle of aged mice. The results revealed a notable decrease in PGC-1α expression in skeletal muscle of aged mice, accompanied by elevated methylation levels of the PGC-1α promoter, and increased DNA methyltransferase (DNMT) protein expressions. However, both forms of exercise training significantly corrected PGC-1α epigenetic changes, increased PGC-1α expression, and ameliorated skeletal muscle reduction. Furthermore, exercise training led to elevated expression of proteins related to mitochondrial biogenesis and energy metabolism in skeletal muscle, improving mitochondrial structure and function. In conclusion, late-in-life exercise improved skeletal muscle function, morphology, and mitochondria biogenesis, which may be associated with hypomethylation in promoters of PGC-1α and increased content of skeletal muscle PGC-1α. Notably, there was no clear difference between HIIT and CMIT in PGC-1α expression and skeletal muscle function.

PGC1α in Skeletal Muscle Mediates Anti-Obesity Effects of Soy Isoflavones.

Obesity, a factor increasing the risk of metabolic diseases such as type 2 diabetes, dyslipidemia, and hypertension, can be reduced by the intake of soy isoflavones. In this study, we investigated whether skeletal muscle PGC1α, a transcriptional activator known to promote a variety of exercise-related metabolic processes, is involved in the anti-obesity effects of soy isoflavones using skeletal muscle-specific PGC1α knockout mice. The results showed that the intake of soy isoflavones reduced white adipose tissue weight and increased expression of energy metabolism-related genes such as mitochondrial function, lipolysis, and fatty acid oxidation in skeletal muscle. However, these effects were not observed in skeletal muscle-specific PGC1α knockout mice. In C2C12 myoblasts with overexpressing PGC1α, soy isoflavone treatment increased energy-metabolism related genes. Therefore, PGC1α of skeletal muscle is likely to be involved in the anti-obesity effects of soy isoflavones.

Exercise following joint distraction inhibits muscle wasting and delays the progression of post-traumatic osteoarthritis in rabbits by activating PGC-1α in skeletal muscle

ObjectiveMuscle wasting frequently occurs following joint trauma. Previous research has demonstrated that joint distraction in combination with treadmill exercise (TRE) can mitigate intra-articular inflammation and cartilage damage, consequently delaying the advancement of post-traumatic osteoarthritis (PTOA). However, the precise mechanism underlying this phenomenon remains unclear. Hence, the purpose of this study was to examine whether the mechanism by which TRE following joint distraction delays the progression of PTOA involves the activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), as well as its impact on muscle wasting.MethodsQuadriceps samples were collected from patients with osteoarthritis (OA) and normal patients with distal femoral fractures, and the expression of PGC-1α was measured. The hinged external fixator was implanted in the rabbit PTOA model. One week after surgery, a PGC-1α agonist or inhibitor was administered for 4 weeks prior to TRE. Western blot analysis was performed to detect the expression of PGC-1α and Muscle atrophy gene 1 (Atrogin-1). We employed the enzyme-linked immunosorbent assay (ELISA) technique to examine pro-inflammatory factors. Additionally, we utilized quantitative real-time polymerase chain reaction (qRT-PCR) to analyze genes associated with cartilage regeneration. Synovial inflammation and cartilage damage were evaluated through hematoxylin-eosin staining. Furthermore, we employed Masson’s trichrome staining and Alcian blue staining to analyze cartilage damage.ResultsThe decreased expression of PGC-1α in skeletal muscle in patients with OA is correlated with the severity of OA. In the rabbit PTOA model, TRE following joint distraction inhibited the expressions of muscle wasting genes, including Atrogin-1 and muscle ring finger 1 (MuRF1), as well as inflammatory factors such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in skeletal muscle, potentially through the activation of PGC-1α. Concurrently, the production of IL-1β, IL-6, TNF-α, nitric oxide (NO), and malondialdehyde (MDA) in the synovial fluid was down-regulated, while the expression of type II collagen (Col2a1), Aggrecan (AGN), SRY-box 9 (SOX9) in the cartilage, and superoxide dismutase (SOD) in the synovial fluid was up-regulated. Additionally, histological staining results demonstrated that TRE after joint distraction reduced cartilage degeneration, leading to a significant decrease in OARSI scores.TRE following joint distraction could activate PGC-1α, inhibit Atrogin-1 expression in skeletal muscle, and reduce C-telopeptides of type II collagen (CTX-II) in the blood compared to joint distraction alone.ConclusionFollowing joint distraction, TRE might promote the activation of PGC-1α in skeletal muscle during PTOA progression to exert anti-inflammatory effects in skeletal muscle and joint cavity, thereby inhibiting muscle wasting and promoting cartilage regeneration, making it a potential therapeutic intervention for treating PTOA.

Skeletal muscle PGC-1α remodels mitochondrial phospholipidome but does not alter energy efficiency for ATP synthesis.

Exercise training is thought to improve the mitochondrial energy efficiency of skeletal muscle. Some studies suggest exercise training increases the efficiency for ATP synthesis by oxidative phosphorylation (OXPHOS), but the molecular mechanisms are unclear. We have previously shown that exercise remodels the lipid composition of mitochondrial membranes, and some of these changes could contribute to improved OXPHOS efficiency (ATP produced by O2 consumed or P/O). Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a transcriptional co-activator that coordinately regulates exercise-induced adaptations including mitochondria. We hypothesized that increased PGC-1α activity is sufficient to remodel mitochondrial membrane lipids and promote energy efficiency. Mice with skeletal muscle-specific overexpression of PGC-1α (MCK-PGC-1α) and their wildtype littermates were used for this study. Lipid mass spectrometry and quantitative PCR were used to assess muscle mitochondrial lipid composition and their biosynthesis pathway. The abundance of OXPHOS enzymes was determined by western blot assay. High-resolution respirometry and fluorometry analysis were used to characterize mitochondrial bioenergetics (ATP production, O2 consumption, and P/O) for permeabilized fibers and isolated mitochondria. Lipidomic analyses of skeletal muscle mitochondria from wildtype and MCK-PGC-1α mice revealed that PGC-1α increases the concentrations of cone-shaped lipids such as phosphatidylethanolamine (PE), cardiolipin (CL), and lysophospholipids, while decreases the concentrations of phosphatidylcholine (PC), phosphatidylinositol (PI) and phosphatidic acid (PA). However, while PGC-1α overexpression increased the abundance of OXPHOS enzymes in skeletal muscle and the rate of O2 consumption (JO2), P/O values were unaffected with PGC-1α in permeabilized fibers or isolated mitochondria. Collectively, overexpression of PGC-1α promotes the biosynthesis of mitochondrial PE and CL but neither PGC-1α nor the mitochondrial membrane lipid remodeling induced in MCK-PGC-1α mice is sufficient to increase the efficiency for mitochondrial ATP synthesis. These findings suggest that exercise training may increase OXPHOS efficiency by a PGC-1α-independent mechanism, and question the hypothesis that mitochondrial lipids directly affect OXPHOS enzymes to improve efficiency for ATP synthesis.

Muscle Psn gene combined with exercise contribute to healthy aging of skeletal muscle and lifespan by adaptively regulating Sirt1/PGC-1α and arm pathway.

The Presenilin (Psn) gene is closely related to aging, but it is still unclear the role of Psn genes in skeletal muscle. Here, the Psn-UAS/Mhc-GAL4 system in Drosophila was used to regulate muscle Psn overexpression(MPO) and muscle Psn knockdown(MPK). Drosophila were subjected to endurance exercise from 4 weeks to 5 weeks old. The results showed that MPO and exercise significantly increased climbing speed, climbing endurance, lifespan, muscle SOD activity, Psn expression, Sirt1 expression, PGC-1α expression, and armadillo (arm) expression in aged Drosophila, and they significantly decreased muscle malondialdehyde levels. Interestingly, when the Psn gene is knockdown by 0.78 times, the PGC-1α expression and arm expression were also down-regulated, but the exercise capacity and lifespan were increased. Furthermore, exercise combined with MPO further improved the exercise capacity and lifespan. MPK combined with exercise further improves the exercise capacity and lifespan. Thus, current results confirmed that the muscle Psn gene was a vital gene that contributed to the healthy aging of skeletal muscle since whether it was overexpressed or knocked down, the aging progress of skeletal muscle structure and function was slowed down by regulating the activity homeostasis of Sirt1/PGC-1α pathway and Psn/arm pathway. Exercise enhanced the function of the Psn gene to delay skeletal muscle aging by up regulating the activity of the Sirt1/PGC-1α pathway and Psn/arm pathway.

Carbon monoxide-loaded cell therapy as an exercise mimetic for sarcopenia treatment

Sarcopenia is characterized by loss of muscle strength and muscle mass with aging. The growing number of sarcopenia patients as a result of the aging population has no viable treatment. Exercise maintains muscle strength and mass by increasing peroxisome growth factor activating receptor γ-conjugating factor-1α (PGC-1α) and Akt signaling in skeletal muscle. The present study focused on the carbon monoxide (CO), endogenous activator of PGC-1α and Akt, and investigated the therapeutic potential of CO-loaded red blood cells (CO-RBCs), which is bioinspired from in vivo CO delivery system, as an exercise mimetic for the treatment of sarcopenia. Treatment of C2C12 myoblasts with the CO-donor increased the protein levels of PGC-1α which enhanced mitochondrial biogenesis and energy production. The CO-donor treatment also activated Akt, indicating that CO promotes muscle synthesis. CO levels were significantly elevated in the skeletal muscle of normal mice after intravenous administration of CO-RBCs. Furthermore, CO-RBCs restored the mRNA expression levels of PGC-1α in the skeletal muscle of two experimental sarcopenia mouse models, denervated (Den) and hindlimb unloading (HU) models. CO-RBCs also restored muscle mass in Den mice by activating Akt signaling and suppressing the muscle atrophy factors myostatin and atrogin-1, and oxidative stress. Treadmill tests further showed that the reduced running distance in HU mice was significantly restored by CO-RBC administration. These findings suggest that CO-RBCs have potential as an exercise mimetic for sarcopenia treatment.

Gracilaria chorda attenuates obesity-related muscle wasting through activation of SIRT1/PGC1α in skeletal muscle of mice.

Gracilaria chorda (GC) is a red algal species that is primarily consumed in Asia. Here, we investigated the effect of GC on obesity-related skeletal muscle wasting. Furthermore, elucidating its impact on the activation of sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) constituted a critical aspect in understanding the underlying mechanism of action. In this study, 6-week-old male C57BL/6 mice were fed a high-fat diet (HFD) for 8 weeks to induce obesity, then continued on the HFD for another 8 weeks while orally administered GC. GC decreased ectopic fat accumulation in skeletal muscle and increased muscle weight, size, and function in obese mice. Furthermore, GC reduced skeletal muscle atrophy and increased hypertrophy in mice. We hypothesized that the activation of SIRT1/PGC1α by GC regulates skeletal muscle atrophy and hypertrophy. We observed that GC increased the expression of SIRT1 and PGC1α in skeletal muscle of mice and in C2C12 cells, which increased mitochondrial function and biogenesis. In addition, when C2C12 cells were treated with the SIRT1-specific inhibitor EX-527, no changes were observed in the protein levels of SIRT1 and PGC1α in the GC-treated C2C12 cells. Therefore, GC attenuated obesity-related muscle wasting by improving mitochondrial function and biogenesis through the activation of SIRT1/PGC1α in the skeletal muscle of mice.

Naringenin promotes the expression of oxidized myofibers via the PKA signaling pathway in C57BL/6J mice and C2C12 cells

Naringenin, a citrus-derived flavonoid, has been reported to positively exert skeletal muscle function. The study designed to explore the potential role and mechanisms of naringenin on regulating the expression of oxidized myofibrils in mice and C2C12 myotubes. In this study, we found that naringenin supplementation significantly improved exercise endurance and oxygen consumption of mice, and also increased aerobic enzyme activity and oxidative myofibers expression in skeletal muscle and C2C12 cells. Meanwhile, naringenin activated the expression of p-PKA/PKA, p-LKB1/LKB1, p-AMPK/AMPK and PGC-1α in skeletal muscle. Furthermore, in vitro studies shown that inhibition of PKA, LKB1 and AMPK could attenuate naringenin-regulated increase in slow muscle fiber proteins. This study suggests that naringenin supplementation can enhance slow myofiber expression by activating the PKA signaling pathway in C57BL/6J mice and C2C12 myotubes. These findings provide a new application of naringenin as a natural candidate to regulate oxidized fiber types and endurance of skeletal muscle.

Comparison of Eight Weeks of Moderate-intensity Continuous Training (MICT) and High-intensity Intermittent Training (HIIT) with Sodium Citrate Supplementation on PGC-1α Expression

Introduction: Sports activity increases the expression of PGC-1α, the regulatory factor of mitochondrial biogenesis. This study aimed to investigate the effect of eight weeks of Moderate-intensity Continuous Training (MICT) and High-intensity Intermittent Training (HIIT), along with sodium citrate supplementation, on PGC-1α expression in male Wistar rats. Method: Forty rats were placed in the following five groups: Control, MICT, MICT+sodium citrate, HIIT, and HIIT+sodium citrate. The continuous training group ran for eight weeks and five sessions per week with an average intensity of 70% of the maximum running speed for 15-30 minutes. The interval training group ran for 12 minutes with an intensity range of 50% and 90%. In addition to exercise, the exercise+supplement groups received 15 mmol/l sodium citrate supplement daily. The expression of PGC-1α in the soleus muscle was measured by the western blot method. Data analysis was done using one-way analysis of variance and Tukey's post hoc test. Results: The PGC-1α protein expression increased in both the training groups and the training+supplement groups compared to the control group (P=0.001). Furthermore, adding sodium citrate could significantly increase the PGC-1α expression in the MICTgroup+supplement compared to the MICT group (P=0.005). However, the HIIT had a higher effect on PGC-1α expression than the MICT group. Conclusion: Despite the effectiveness of both training methods, sodium citrate supplementation before HIIT could have more synergistic effects in increasing the expression of PGC-1α.

Muscle-specific overexpression of Atg2 gene and endurance exercise delay age-related deteriorations of skeletal muscle and heart function via activating the AMPK/Sirt1/PGC-1α pathway in male Drosophila.

Atg2 is a key gene in autophagy formation and plays an important role in regulating aging progress. Exercise is an important tool to resist oxidative stress in cells and delay muscle aging. However, the relationship between exercise and the muscle Atg2 gene in regulating skeletal muscle aging remains unclear. Here, overexpression or knockdown of muscle Atg2 gene was achieved by constructing the AtgUAS/MhcGal4 system in Drosophila, and these flies were also subjected to an exercise intervention for 2 weeks. The results showed that both overexpression of Atg2 and exercise significantly increased the climbing speed, climbing endurance, cardiac function, and lifespan of aging flies. They also significantly up-regulated the expression of muscle Atg2, AMPK, Sirt1, and PGC-1α genes, and they significantly reduced muscle malondialdehyde and triglyceride. These positive benefits were even more pronounced when the two were combined. However, the effects of Atg2 knockdown on skeletal muscle, heart, and lifespan were reversed compared to its overexpression. Importantly, exercise ameliorated age-related changes induced by Atg2 knockdown. Therefore, current results confirmed that both overexpression of muscle Atg2 and exercise delayed age-related deteriorations of skeletal muscle, the heart function, and lifespan, and exercise could also reverse age-related changes induced by Atg2 knockdown. The molecular mechanism is related to the overexpression of the Atg2 gene and exercise, which increase the activity of the AMPK/Sirt1/PGC-1α pathway, oxidation and antioxidant balance, and lipid metabolism in aging muscle.

Downregulation of PGC-1α during cisplatin-induced muscle atrophy in murine skeletal muscle

This study aimed to investigate the effects of cisplatin on adenosine triphosphate (ATP) levels, expressions of genes related to mitochondrial oxidative phosphorylation (OXPHOS), and the factors related to mitochondrial biosynthesis in skeletal muscle. Systemic cisplatin administration decreased skeletal muscle mass, skeletal muscle strength, and endurance. The mitochondrial DNA /nuclear DNA ratio was also reduced after treatment with cisplatin. Moreover, among the factors related to mitochondrial biogenesis and function, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) was significantly downregulated in the cisplatin-treated group. Downregulation of PGC-1α in the skeletal muscle may contribute to muscle weakness during cisplatin-induced muscle atrophy.

VMHdm/cSF-1 neuronal circuits regulate skeletal muscle PGC1-α via the sympathoadrenal drive

ObjectiveTo adapt to metabolically challenging environments, the central nervous system (CNS) orchestrates metabolism of peripheral organs including skeletal muscle. The organ-communication between the CNS and skeletal muscle has been investigated, yet our understanding of the neuronal pathway from the CNS to skeletal muscle is still limited. Neurons in the dorsomedial and central parts of the ventromedial hypothalamic nucleus (VMHdm/c) expressing steroidogenic factor-1 (VMHdm/cSF-1 neurons) are key for metabolic adaptations to exercise, including increased basal metabolic rate and skeletal muscle mass in mice. However, the mechanisms by which VMHdm/cSF-1 neurons regulate skeletal muscle function remain unclear. Here, we show that VMHdm/cSF-1 neurons increase the sympathoadrenal activity and regulate skeletal muscle peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) in mice via multiple downstream nodes. MethodsOptogenetics was used to specifically manipulate VMHdm/cSF-1 neurons combined with genetically-engineered mice and surgical manipulation of the sympathoadrenal activity. ResultsOptogenetic activation of VMHdm/cSF-1 neurons dramatically elevates mRNA levels of skeletal muscle Pgc-1α, which regulates a spectrum of skeletal muscle function including protein synthesis and metabolism. Mechanistically, the sympathoadrenal drive coupled with β2 adrenergic receptor (β2AdR) is essential for VMHdm/cSF-1 neurons-mediated increases in skeletal muscle PGC1-α. Specifically, both adrenalectomy and β2AdR knockout block augmented skeletal muscle PGC1-α by VMHdm/cSF-1 neuronal activation. Optogenetic functional mapping reveals that downstream nodes of VMHdm/cSF-1 neurons are functionally redundant to increase circulating epinephrine and skeletal muscle PGC1-α. ConclusionsCollectively, we propose that VMHdm/cSF-1 neurons-skeletal muscle pathway, VMHdm/cSF-1 neurons→multiple downstream nodes→the adrenal gland→skeletal muscle β2AdR, underlies augmented skeletal muscle function for metabolic adaptations.

Anti-fatigue activities of γ-aminobutyric acid-enriched soymilk in an acute exercise-treated mouse model via regulating AMPK/PGC-1α pathway

Gamma-aminobutyric acid (GABA), a four carbon non-protein amino acid, is extensively distributed in nature and shows various biological functions. In the present study, Lactobacillus brevis ATCC 367 and Lactobacillus plantarum ASCC 276, two producers with high GABA production capacity, were selected to ferment soymilk and their optimal culture conditions were investigated. Then, the anti-fatigue ability of GABA-enriched soy protein isolate (SPI) fermented milk was assessed by the weight-loaded forced swimming test and the related biochemical parameters were recorded to find possible reasons. Results demonstrated that soymilk added with glucose was capable of yielding the highest GABA content when used Streptococcus thermophilus 1303 and Lactobacillus brevis ATCC 367 as starter bacteria, and exhibited the high anti-fatigue effect in mice, mainly manifested in extending the forced swimming time, suppressing the blood lactic acid, urea nitrogen and lactate dehydrogenase content, and promoting the level of liver glycogen, muscle glycogen and muscle ATP. More importantly, SPI fermented milk beverages decreased reactive oxygen species levels via improving the concentrations of superoxide dismutase and glutathione peroxidase and inhibiting the content of malondialdehyd and promoted energy reserves by stimulating the expression of AMPK and PGC-1α in muscle, thus showing its fatigue-alleviating effect. Our study disclosed that there was a positive correlation between GABA content and anti-fatigue-related indicators of SPI fermented milk, which will be of interest for developing fermented milk with high anti-fatigue activity.

PPARβ/δ Agonism with GW501516 Increases Myotube PGC-1α Content and Reduces BCAA Media Content Independent of Changes in BCAA Catabolic Enzyme Expression.

Type 2 diabetes is characterized by reduced insulin sensitivity, elevated blood metabolites, and reduced mitochondrial metabolism with reduced expression of genes governing metabolism such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). PGC-1α regulates the expression of branched-chain amino acid (BCAA) metabolism, and thus, increased circulating BCAA in diabetics may be partially explained by reduced PGC-1α expression. PGC-1α functions in-part through interactions with peroxisome proliferator-activated receptor β/δ (PPARβ/δ). The present report examined the effects of the PPARβ/δ agonism on cell metabolism and related gene/protein expression of cultured myotubes, with a primary emphasis on determining the effects of GW on BCAA disposal and catabolic enzyme expression. C2C12 myotubes were treated with GW501516 (GW) for up to 24 hours. Mitochondrial and glycolytic metabolism were measured via oxygen consumption and extracellular acidification rate, respectively. Metabolic gene and protein expression were assessed via quantitative real-time polymerase chain reaction (qRT-PCR) and western blot, respectively. Media BCAA content was assessed via liquid chromatography-mass spectrometry (LC/MS). GW significantly increased PGC-1α protein expression, mitochondrial content, and mitochondrial function. GW also significantly reduced BCAA content within culture media following 24-hour treatment; however, expression of BCAA catabolic enzymes/transporter was unchanged. These data confirm the ability of GW to increase muscle PGC-1α content and decrease BCAA media content without affecting BCAA catabolic enzymes/transporter. These findings suggest heightened BCAA uptake (and possibly metabolism) may occur without substantial changes in the protein levels of related cell machinery.

Aerobic exercise training-induced alteration of gut microbiota composition affects endurance capacity.

This study aimed to clarify whether aerobic exercise training-induced alterations in the gut microbiota affect physiological adaptation with endurance exercise capacity. In study 1, ICR mice were randomly divided into three groups: vehicle intake + sedentary (V+S), vehicle intake + exercise training (V+Ex) and antibiotic intake + exercise training (AB+Ex). In the exercise training groups, treadmill running was performed for 8weeks. During the exercise training intervention, the antibiotic-intake group freely drank water containing antibiotics. In study 2, ICR mice were randomly divided into three groups: Sham, transplantation of caecum microbiota from sedentary mice (Sed-CMT) and exercise training mice (Ex-CMT). In study 1, the treadmill running time to exhaustion, an index of maximal aerobic capacity, after aerobic exercise training in the V+Ex group was significantly longer than that in the V+S and AB+Ex groups. Gastrocnemius muscle citrate synthase (CS) activity and PGC-1α protein levels in the V+Ex group were significantly higher than in the V+S and AB+Ex groups. The bacterial Erysipelotrichaceae and Alcaligenaceae families were positively correlated with treadmill running time to exhaustion. In study 2, the treadmill running time to exhaustion after transplantation was significantly higher in the Ex-CMT group than in the Sham and Sed-CMT groups. Furthermore, CS activity and PGC-1α protein levels in the gastrocnemius muscle were significantly higher in the Ex-CMT group than in the Sham and Sed-CMT groups. Thus, gut microbiota altered by aerobic exercise training may be involved in the augmentation of endurance capacity and muscle mitochondrial energy metabolism. KEY POINTS: Aerobic exercise training changes gut microbiota composition, and the Erysipelotrichaceae and Alcaligenaceae families were among the altered gut bacteria. The gut microbiota was associated with endurance performance and metabolic regulator levels in skeletal muscle after aerobic exercise training. Continuous antibiotic treatment attenuated the increase in endurance performance, citrate synthase activity and PGC-1α levels in skeletal muscle induced by aerobic exercise training. Gut microbiota transplantation from exercise-trained mice improved endurance performance and metabolic regulator levels in recipient skeletal muscle, despite the absence of aerobic exercise training.

Chronic voluntary wheel running exercise ameliorates metabolic dysfunction via PGC-1α expression independently of FNDC5/irisin pathway in high fat diet-induced obese mice

Exercise is an effective intervention to ameliorate metabolic diseases including obesity and insulin resistance, but the mechanisms involved in the metabolic amelioration have not yet been fully elucidated. This study aimed to determine whether AMPK–SIRT1–PGC-1α–FNDC5/Irisin-UCP1 expression is activated and whether metabolic dysfunction is ameliorated by chronic voluntary wheel running (VWR) in high-fat diet (HFD) induced obese mice. C57BL6J mice were randomly assigned into three groups at the age of 7 weeks for 10 weeks: normal chow diet (CON) group, HFD group, and HFD + VWR group. Chronic VWR ameliorates metabolic parameters and leads to increases in the expression of PGC-1α in the gastrocnemius muscle in HFD-induced obese mice. In contrast, the expression of AMPKα, SIRT1, and FNDC5, or circulating irisin levels did not lead to alteration. Improvement of metabolic health was partly mediated via PGC-1α expression by chronic VWR, but not FNDC5/Irisin pathway in HFD-induced obese mice.

Peptides obtained by enzymatic decomposition of mackerel induce recovery from physical fatigue by enhancing the SIRT1-mediated antioxidant effect in the soleus muscle of mice

Fatigue is a serious health problem, and long-term fatigue can lead to mental illnesses and accelerated aging. Oxidative stress, which causes excessive production of reactive oxygen species, is generally thought to increase during exercise and is an indicator of fatigue. Peptides obtained by enzymatic decomposition of mackerel (EMP) contain selenoneine, a strong antioxidant. Although antioxidants increase endurance, the effects of EMP on physical fatigue are unknown. The present study aimed to clarify this aspect. We investigated the effects of EMP on changes in locomotor activity, expression levels of silent mating type information regulation 2 homolog peroxisome 1 (SIRT1), proliferator-activated receptor-γ coactivator-1α (PGC1α), and antioxidative-related proteins including superoxide dismutase 1 (SOD1), SOD2, glutathione peroxidase 1, and catalase in the soleus muscle following EMP treatment before and/or after forced walking. Treatment with EMP before and after forced walking, and not only at one or another time point, improved the subsequent decrease in the locomotor activity and enhanced the levels of SIRT1, PGC1α, SOD1, and catalase expression in the soleus muscle of mice. Moreover, EX-527, a SIRT1 inhibitor, abolished these effects of EMP. Thus, we suggest that EMP combats fatigue by modulating the SIRT1/PGC1α/SOD1-catalase pathway.

Effect of Cold Exposure and Exercise on Insulin Sensitivity and Serum Free Fatty Acids in Obese Rats.

This study aimed to explore the effect of exercise and cold exposure on insulin sensitivity and the level of serum free fatty acids (FFA) in diet-induced obese rats. Sixty-four diet-induced obese rats were randomly assigned to eight groups: room temperature-sedentary, room temperature-exercise, acute cold exposure-sedentary, acute cold exposure-exercise, intermittent cold exposure-sedentary, intermittent cold exposure-exercise, sustained cold exposure-sedentary, and sustained cold exposure-exercise. After the interventions, the homeostatic model assessment for insulin resistance (HOMA-IR) values, the level of serum FFA, subcutaneous fat ratio (SFR) and visceral fat ratio, enzyme activities of adipose triglyceride lipase, and lipoprotein lipase (LPL) in inguinal adipose tissue, and protein expression of PGC1-α and p38 MAPK in skeletal muscle were investigated. We found that exercise ( P = 0.0136) and cold exposure ( P < 0.0001) reduced HOMA-IR values independently. Exercise reduced serum FFA ( P = 0.0041), whereas cold exposure did not affect them. Moreover, the HOMA-IR values were positively correlated with the serum FFA levels ( r = 0.32, P = 0.01). SFR or visceral fat ratio was coordinately reduced by the interaction (for SFR, P = 0.0015) or opposing main effects between or of cold exposure and exercise, supporting the reduction of serum FFA. However, cold exposure or exercise increased the activity of adipose triglyceride lipase and LPL independently or interactively (for LPL, P = 0.0143), suggesting an increase in serum FFA. Finally, cold exposure and exercise enhanced protein expression of PGC1-α and p38 MAPK independently or interactively (for p38 MAPK, P = 0.0226), suggesting increased uptake and oxidation of serum FFA in muscle. These results suggest that the combination of exercise and cold exposure may result in more serum FFA utilization than production and thus lead to reduced serum FFA and increased insulin sensitivity.