Mitochondrial-nuclear communication is vital for maintaining cellular homeostasis. This communication begins with mitochondria sensing environmental cues and transmitting signals to the nucleus through the retrograde cascade, involving metabolic signals such as substrates for epigenetic modifications, ATP and AMP levels, calcium flux, etc. These signals inform the nucleus about the cell's metabolic state, remodel epigenome and regulate gene expression, and modulate mitochondrial function and dynamics through the anterograde feedback cascade to control cell fate and physiology. Disruption of this communication can lead to cellular dysfunction and disease progression, particularly in cancer. The Warburg effect is the metabolic hallmark of cancer, characterized by disruption of mitochondrial respiration and increased lactate generation from glycolysis. This metabolic reprogramming rewires retrograde signaling, leading to epigenetic changes and dedifferentiation, further reprogramming mitochondrial function and promoting carcinogenesis. Understanding these processes and their link to tumorigenesis is crucial for uncovering tumorigenesis mechanisms. Therapeutic strategies targeting these disrupted pathways, including metabolic and epigenetic components, provide promising avenues for cancer treatment.

The dominant chemotherapeutic agent, cisplatin (CP), is widely used to manage various cancer types. Despite its effectiveness, CP use is associated with severe hepatotoxicity. Cilostazol (CSZ), a selective phosphodiesterase III inhibitor, has recently demonstrated remarkable anti-inflammatory and anti-apoptotic properties in different diseases. Additionally, it exhibits hepatoprotective effects against various forms of liver injury. Hence, this study aimed to assess the potential hepatoprotective and ameliorative effects of CSZ on CP-induced acute liver injury (ALI) and to elucidate the underlying molecular mechanisms. To achieve this, ALI was induced by a single injection of CP (20 mg/kg; i.p.) in male Wistar rats pretreated with CSZ (5 or 10 mg/kg) administered orally for one week. The findings revealed that CSZ effectively reversed CP-induced hepatic dysfunction, as evidenced by notable liver function tests and improvements in histological examination. Additionally, CSZ protected against CP-mediated liver oxidative stress by decreasing MDA levels while increasing GSH and GPx levels and enhancing SOD activity. Furthermore, CSZ exhibited a potent anti-inflammatory effect, reducing the expression of pro-inflammatory cytokines, including NF-κB, IL-1β, and TNF-α. Regarding hepatocyte apoptosis, CSZ suppressed Bax immunoexpression and caspase-3 and caspase-9 levels while enhancing Bcl-2 expression, thereby mitigating hepatic cell death. The hepatoprotective effects of CSZ could be attributed to the regulation of the miRNA-34a/AMPK/SIRT1/PGC-1α signaling pathway, leading to the activation of the Nrf2/HO-1-mediated antioxidative defense mechanism. In conclusion, CSZ could be a promising therapeutic agent for preventing CP-induced ALI, potentially improving the quality of life for cancer patients.

Myocardial ischemia/reperfusion (I/R) injury has high morbidity and mortality rates, posing a significant burden on society. There is an urgent need to understand its pathogenesis and develop effective treatments. Reactive oxygen species (ROS) are crucial for the development of myocardial I/R injury, and inhibiting ROS overproduction is one of the most critical ways to delay myocardial I/R injury. Sirtuins are a group of nicotinic adenine dinucleotide ( +)-dependent histone deacetylases whose members can regulate ROS by modulating various biological processes. Numerous studies have shown that Sirtuins play an essential role in the progression of myocardial I/R injury by regulating ROS. This study focuses on the relationship between myocardial I/R injury and ROS, Sirtuins and ROS, discusses the role of Sirtuins in regulating ROS in myocardial I/R, and summarizes the therapeutic modalities aimed at targeting Sirtuins to modulate ROS in myocardial I/R injury, thereby guiding future research endeavors.

Lipids, which are indispensable for cellular architecture and energy storage, predominantly consist of triglycerides (TGs), phospholipids, cholesterol, and their derivatives. These hydrophobic entities are housed within dynamic lipid droplets (LDs), which expand and contract in response to nutrient availability. Historically perceived as a cellular waste disposal mechanism, autophagy has now been recognized as a crucial regulator of metabolism. Within this framework, lipophagy, the selective degradation of LDs, plays a fundamental role in maintaining lipid homeostasis. Dysregulated lipid metabolism and autophagy are frequently associated with metabolic disorders such as obesity and atherosclerosis. In this context, peroxisome proliferator-activated receptors (PPARs), particularly PPAR-γ, serve as intracellular lipid sensors and master regulators of gene expression. Their regulatory influence extends to both autophagy and lipid metabolism, indicating a complex interplay between these processes. This review explores the hypothesis that PPARs may directly modulate autophagy within the realm of lipid metabolism, thereby contributing to the pathogenesis of metabolic diseases. By elucidating the underlying molecular mechanisms, we aim to provide a comprehensive understanding of the intricate regulatory network that connects PPARs, autophagy, and lipid homeostasis. The crosstalk between PPARs and other signaling pathways underscores the complexity of their regulatory functions and the potential for therapeutic interventions targeting these pathways. The intricate relationships among PPARs, autophagy, and lipid metabolism represent a pivotal area of research with significant implications for understanding and treating metabolic disorders.

Cardiovascular diseases such as coronary heart disease, heart failure, or stroke are the most common cause of death worldwide and are regularly based on risk factors like diabetes mellitus, hypertension, or obesity. At the same time, both diseases and risk factors are significantly influenced by sex hormones. In order to better understand this influence and also specifically improve the therapy of female patients, medical research has recently focused increasingly on gender-specific differences. The goal is to develop personalized, gender-specific therapy concepts for these diseases to further enhance health outcomes. The enzyme adenosine monophosphate-activated protein kinase (AMPK) is a central regulator of energy metabolism, protecting the cardiovascular system from energy depletion, thereby promoting vascular health and preventing cellular damage. AMPK confers cardioprotective effects by preventing endothelial and vascular dysfunction, and by controlling or regulating oxidative stress and inflammatory processes. For AMPK, sex-specific effects were reported, influencing metabolic and cardiovascular responses. Exercise and metabolic stress generally cause higher AMPK activity in males. At the same time, females exhibit protective mechanisms against insulin resistance or oxidative stress, particularly in conditions like obesity. Additionally, males subject to AMPK deficiency seem to experience greater cardiac and mitochondrial dysfunction. In contrast, females show improvement in cardiovascular function after pharmacological AMPK activation. These differences, influenced by hormones, body composition, and gene expression, highlight the potential to develop personalized, sex-specific AMPK-targeted therapeutic strategies for cardiovascular diseases in the future. Here, we discuss the most actual scientific background, focusing on the protective, gender-specific effects of AMPK, and highlight potential clinical applications.

Butyrate is a four-carbon short-chain fatty acid produced from microbial fermentation of dietary fibers present at high millimolar concentrations in the colonic lumen. However, in an intact epithelium, macrophages residing in the lamina propria are exposed to only micromolar butyrate concentrations. Current studies show anti-inflammatory properties of butyrate and suggest that it might have therapeutic applications in inflammatory bowel disease and colonic cancer. We now show that the effect of butyrate on human macrophages is strongly concentration dependent: 0.1 mM butyrate suppresses LPS-induced production of the pro-inflammatory cytokine tumor necrosis factor (TNF)-α. Experiments with siRNA knockdown and small molecule inhibitors suggest that this is mediated by a mechanism involving PPAR-γ signaling, whereas we observed no or only a minor effect of histone acetylation. In contrast, 10 mM butyrate promotes macrophage cell death, does not inhibit LPS-induced production of TNF-α, and promotes production of IL-1β, while production of anti-inflammatory IL-10 is reduced in a mechanism involving G protein-coupled receptors, the lipid transporter CD36, and the kinase SRC. We propose that butyrate is a signaling molecule for intestinal integrity, since intestinal disruption exposes macrophages to high butyrate concentrations.

Prolonged and intense physical activity can trigger stress response mechanisms across various physiological systems-including the cardiovascular, respiratory, gastrointestinal, musculoskeletal, and neuroendocrine systems-disrupting energy metabolism, immune function, redox balance, and hormonal regulation. Critically, when not accompanied by adequate recovery, such exertion may impair rather than enhance athletic performance. In parallel, there has been growing interest in probiotics as natural, safe, and accessible dietary supplements with the potential to support performance and recovery. Emerging evidence highlights the pivotal role of the gut microbiome in mediating communication along the gut-brain and gut-muscle axes, thereby influencing not only metabolic and immune functions but also neuromuscular adaptation and fatigue resistance. This review explores the mechanisms through which probiotics may enhance exercise performance, mitigate exercise-induced fatigue, and improve physiological adaptation via modulation of inflammation, oxidative stress, and metabolic signaling pathways. Framed within the context of predictive, preventive, and personalized medicine (3P medicine), this paper emphasizes the diagnostic and therapeutic potential of personalized probiotic strategies in optimizing athletic performance through the qualitative and quantitative assessment of microbiota and host responses.

Mitochondria supply most of the energy for cellular functions and coordinate numerous cellular pathways. Their dynamic nature allows them to adjust to stress and cellular metabolic demands, thus ensuring the preservation of cellular homeostasis. Loss of normal mitochondrial function compromises cell survival and has been implicated in the development of many diseases and in aging. Although exposure to continuous or severe stress has adverse effects on cells, mild mitochondrial stress enhances mitochondrial function and potentially extends health span through mitochondrial adaptive responses. Over the past few decades, sestrin2 (SESN2) has emerged as a pivotal regulator of stress responses. For instance, SESN2 responds to genotoxic, oxidative, and metabolic stress, promoting cellular defense against stress-associated damage. Here, we focus on recent findings that establish SESN2 as an orchestrator of mitochondrial stress adaptation, which is supported by its involvement in the integrated stress response, mitochondrial biogenesis, and mitophagy. Additionally, we discuss the integral role of SESN2 in mediating the health benefits of exercise as well as its impact on skeletal muscle, liver and heart injury, and aging.

Cardiovascular disease remains the leading cause of death globally, and drugs for new targets are urgently needed. Mitochondria are the primary sources of cellular energy, play crucial roles in regulating cellular homeostasis, and are tightly associated with pathological processes in cardiovascular disease. In response to physiological signals and external stimuli in cardiovascular disease, mitochondrial quality control, which mainly includes mitophagy, mitochondrial dynamics, and mitochondrial biogenesis, is initiated to meet cellular requirements and maintain cellular homeostasis. Traditional Chinese Medicine (TCM) has been shown to have pharmacological effects on alleviating cardiac injury in various cardiovascular diseases, including myocardial ischemia/reperfusion, myocardial infarction, and heart failure, by regulating mitochondrial quality control. Recently, several molecular mechanisms of TCM in the treatment of cardiovascular disease have been elucidated. However, mitochondrial quality control by TCM for treating cardiovascular disease has not been investigated. In this review, we aim to decipher the pharmacological effects and molecular mechanisms of TCM in regulating mitochondrial quality in various cardiovascular diseases. We also present our perspectives regarding future research in this field.

Astragali radix is widely used to treat diabetes and Astragalus polysaccharides (APS) is a primary bioactive compound. Previous evidence has demonstrated that APS, when administered, is an effective monomer in the treatment of diabetic nephropathy (DN). In the present systematic review and meta-analysis, the effects and potential underlying mechanisms of APS in the treatment of DN were evaluated. PubMed, Embase, EBSCO, Web of Science and OVID databases were employed to obtain the published studies included in the present meta-analysis up to April 2024. Each article's quality was assessed using the Jadad score assessment scale. The odds ratios of risk factors were pooled using a random-effects meta-analysis model. Heterogeneity was assessed using the Cochrane Q statistics and I-Square (I2) tests, and publication bias was detected using the funnel plot and/or Egger's test. If necessary, the authors of the identified papers were contacted for more information. The primary outcomes were analyzed, including the parameters of creatinine, kidney-to-urine protein, blood urea nitrogen, urine protein and fasting blood glucose. Additionally, APS was found to reduce known risk factors, including kidney weight and total cholesterol levels. Furthermore, it was revealed that the therapeutic effects of APS in DN may be associated with antifibrotic, anti-inflammatory and anti-oxidative stress processes. The findings of the present study have validated the anti-DN effects of APS, and the safety of its use; however, further rigorously designed and well-performed preclinical trials are required in order to fully evaluate the anti-DN effects and safety of APS, and to verify these findings prior to its possible clinical application.

Bangle, a perennial herb belonging to the ginger family with antiinflammatory properties, has been under-researched in ulcerative colitis. This study aimed to investigate the effects of Bangle extract (BaE) on inflammation and autophagy in the colons of mice with dextran sulfate sodium (DSS)-induced colitis. Male C57BL/6J mice were assigned to four groups: control, DSS + 0% BaE, DSS + 1% BaE, and DSS + 3% BaE. The BaE groups were fed BaE diets for 3 weeks, followed by an additional week of BaE diets and 3% DSS in the water. The control group received a standard chow diet and water for 4 weeks. Plasma leucine-rich α2-glycoprotein (LRG) levels, macrophage count, and the levels of nuclear factor kappa B (NFκB) p65, tumor necrosis factor-α (TNF-α), adenosine monophosphate-activated protein kinase (AMPK), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), mechanistic target of rapamycin (mTOR), and autophagy markers were analyzed. In the DSS + 0% BaE group, LRG levels, macrophage count, NFκB p65 protein, and TNF-α mRNA levels were significantly higher compared to the control group. However, in the DSS + 3% BaE group, these levels were significantly reduced. Additionally, PGC-1α and phosphorylated AMPK levels were increased, while phosphorylated mTOR levels decreased, and autophagy marker microtubule-associated protein 1 light chain 3B (LC3B)-II levels were increased in the DSS + 3% BaE group. BaE may ameliorate colonic inflammation and upregulate autophagy via the modulation of the AMPK/mTOR/NFκB pathway in DSS-induced colitis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial disease characterized by hepatic steatosis. Mitochondrial dysfunction resulting in the incomplete digestion of surplus fat is one of the key factors that lead to hepatic steatosis but the reason for this remains unclear. We investigated the role of neurotensin (NTS), a gut hormone, in inducing maladaptive fat metabolism in steatotic liver. We identify CD36 and PGC1α, two critical drivers of MASLD, as direct NTS signaling targets in the liver. NTS upregulates CD36, a free fatty acid receptor, in hepatocytes and promotes long chain lipid uptake. Conversely, NTS inhibits PGC1α, which acts as a lipid sensor and translocates to the nucleus to activate lipid catabolism-related genes in an AMPK-dependent manner. Thus, a high fat diet decreases the fatty acid oxidation and oxidative phosphorylation capacity of the liver and hepatocytes from NTS or NTS receptor 1 (NTSR1) wild type mice; whereas NTS deficiency preserves the lipid metabolism capacity of the liver. NTS signaling is significantly upregulated in MASLD and in metabolic dysfunction-associated steatohepatitis (MASH) human liver samples when compared to normal livers, which correlates with the expression of CD36 and oxidative phosphorylation proteins. These findings provide critical mechanistic insights into the maladaptive fat metabolism noted with steatosis in mice and humans and suggest novel strategies for therapeutic intervention of MASLD, which affects nearly one-quarter of the global population.

Retinitis pigmentosa (RP) is a progressive retinal degenerative disorder characterized by photoreceptor cell death, leading to vision loss. Current treatments are limited, and there is a need for non-invasive interventions. This study evaluates the neuroprotective effects of voluntary exercise in an RP mouse model and explores the role of the adiponectin signaling pathway in mediating these effects. Pregnant Pde6b rd10 (rd10) mice, a transgenic model of RP, and wild-type C57BL/6J mice were divided into sedentary or voluntary running groups (n = 4 per group). Offspring were analyzed at 6 weeks for photoreceptor nuclei counts, outer segment lengths, serum and retinal adiponectin levels, and expression of AMPK and PGC-1α proteins using immunohistochemistry, ELISA, and Western blotting. Voluntary exercise significantly preserved photoreceptor nuclei (97 ± 16 vs. 32 ± 5 in sedentary rd10 mice) and outer segment lengths for rods (13.1 ± 1.2 μ vs. 1.1 ± 0.6 μ) and cones (7 ± 0.9 μ vs. 0.2 ± 0.1 μm) compared to sedentary rd10 mice. Serum adiponectin levels increased significantly in exercised rd10 mice (p < 0.05), while retinal adiponectin levels were elevated in both sedentary and exercised rd10 mice relative to wild-type controls (p < 0.005). No significant changes in AMPK (p = 0.724) and PGC-1α (p = 0.794) protein levels were observed between exercised and sedentary rd10 mice. These findings suggest that voluntary exercise enhances photoreceptor survival in RP by increasing serum adiponectin levels, potentially contributing to neuroprotection. Elevated retinal adiponectin appears linked to RP pathology rather than exercise-induced changes. This study highlights the therapeutic potential of exercise in RP and identifies adiponectin as a promising target for further investigation into neuroprotective mechanisms and treatments.

Diabetes mellitus (DM) is a chronic metabolic disorder marked by sustained hyperglycemia. These disturbances contribute to extensive damage across various tissues and organs, giving rise to severe complications such as vision loss, kidney failure, amputations, and higher morbidity and mortality rates. Furthermore, DM imposes a substantial economic and emotional burden on patients, families, and healthcare systems. Mitophagy, a selective process that targets the clearance of damaged or dysfunctional mitochondria, is pivotal for sustaining cellular homeostasis through mitochondrial turnover and recycling. Emerging evidence indicates that dysfunctional mitophagy acts as a key pathogenic driver in the pathogenesis of DM and its associated complications. Natural small molecules are particularly attractive in this regard, offering advantages such as low toxicity, favorable pharmacokinetic profiles, excellent biocompatibility, and a broad range of biochemical activities. This review systematically evaluates the mechanistic roles of natural small molecules-including ginsenosides, resveratrol, and berberine-in enhancing mitophagy and restoring mitochondrial homeostasis via activation of core signaling pathways (e.g., PINK1/Parkin, BNIP3/NIX, and FUNDC1). These pathways collectively ameliorate pathological hallmarks of DM, such as oxidative stress, chronic inflammation, and insulin resistance. Furthermore, the integration of nanotechnology with these compounds optimizes their bioavailability and tissue-specific targeting, thereby establishing a transformative therapeutic platform for DM management. Current evidence demonstrates that mitophagy modulation by natural small molecules not only offers novel therapeutic strategies for DM and its chronic complications but also advances the mechanistic foundation for future drug development targeting metabolic disorders.

The concept of the gut microbes-muscle axis underscores the impact of intestinal microbiota on the muscular system, an area that is increasingly coming to light. However, current interpretations and applications of this concept remain underdeveloped. In this review, we concluded and discussed factors, such as short-chain fatty acids, amino acids, vitamins, bile acids, antibiotics, cytokines, hormones, and extracellular vesicles that mediate gut microbes-muscle crosstalk and influence the gut microbes-muscle axis. Additionally, we examined how the gut microbes-muscle axis affects muscle mass, muscle strength, muscle metabolism, as well as muscle oxidative and immune status. Furthermore, we reviewed the influence of the microbes-muscle axis on muscle fiber type transition, muscle fat deposition, and meat quality. These insights illuminate the potential mechanisms by which the gut microbes-muscle axis operates in humans and animals. Thus, this review provides a theoretical foundation for future research and offers practical guidance for its application in biomedical and livestock industries.

AMPKα1 and AMPKα2, key kinases in regulating energy homeostasis, have not been previously cloned or characterized in common carp (Cyprinus carpio). This study identified the open reading frame (ORF) sequences of ampkα1 (1722 bp, encoding 573 amino acids) and ampkα2 (1659 bp, encoding 552 amino acids) through homologous cloning. Sequence alignment and phylogenetic analysis showed a high similarity of both genes with fish homologs. Expression analysis revealed that ampkα1 and ampkα2 are widely expressed across tissues in carp, with ampkα1 highly expressed in the gonads and ampkα2 in the heart. Fasting significantly reduced ampkα1 expression in the heart, adipose tissue, and foregut but increased it in the hindgut and white muscle. Similarly, ampkα2 expression decreased in the hypothalamus and muscle during fasting, with an increase in the midgut. Glucose tolerance tests showed dynamic regulation of ampkα1 and ampkα2, with initial downregulation followed by upregulation in the hepatopancreas, red muscle, and brain. High-glucose and high-fat diets significantly increased ampkα1 and ampkα2 expression in multiple tissues. Insulin and glucagon treatment induced time-dependent changes in both genes in hepatocytes, while Aeromonas hydrophila infection, LPS, and Poly (I:C) stimulation upregulated ampkα1 and ampkα2 in immune-related tissues. Knockdown of ampkα2, but not ampkα1, reduced glut1b mRNA levels, while both knockdowns of ampkα1 and ampkα2 promoted the expression of gsk3β, pygm, acc, fas, srebp, cs, and pro-inflammatory cytokines, suggesting their involvement in metabolic and immune regulation in carp.

Endometriosis affects about 10 % of women of reproductive age, leading to a disabling gynecologic condition. Chronic pain, inflammation, and oxidative stress have been identified as the molecular pathways involved in the progression of this disease, although its precise etiology remains uncertain. Although mitochondria are considered crucial organelles for cellular activity, their dysfunction has been linked to the development of this disease. The purpose of this review is to examine the functioning of the mitochondrion in endometriosis: in particular, we focused on the mitochondrial dynamics of biogenesis, fusion, and fission. Since excessive mitochondrial activity is reported to affect cell proliferation, we also considered mitophagy as a mechanism involved in limiting disease development. To better understand mitochondrial activity, we also considered alterations in circadian rhythms, the gut microbiome, and estrogen receptors: indeed, these mechanisms are also involved in the development of endometriosis. In addition, we focused on recent research about the impact of numerous substances on mitochondrial activity; some of them may offer a future breakthrough in endometriosis treatment by acting on mitochondria and inhibiting cell proliferation.

Cancer treatment era has been revolutionized by the novel therapeutic methods such as immunotherapy in recent years. Immunotherapy-based approaches are considered effective and reliable methods that has brought hope to eradicate certain cancers. Nonetheless, there are some issues, considered as critical obstacles in successful cancer immunotherapy. Such issues are attributed to the ability of the tumor cells in providing a tolerant microenvironment that impairs the immune responses, and help the cancer cells evade the immunogenic cell death. It has been suggested that the re-activation and maintenance of effector immune cells may become possible by metabolic reprogramming. Several signaling pathways have been noticed with the possibility of metabolic reprogramming of tumor-specific T cells, to overcome the metabolic restrictions in the tumor microenvironment; and among them, AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptors (PPAR) have been investigated the most as the main energy sensors and regulators of mitochondrial biogenesis. The synergic effects of AMPK activators and/or PPAR agonists in cancer immunotherapy have been reported. In this review, we compare the roles of AMPK activators and PPAR agonists, and the efficacy of their combination in metabolic reprogramming of cytotoxic T cells in favoring cancer immunotherapy.

Adult rat dorsal root ganglion (DRG) sensory neurons express estrogen receptors (ERs) α and β. Estrogen regulates multiple aspects of the nervous system including development, survival, and axonal outgrowth of DRG neurons. While previous studies have established estrogen's neuroprotective role in these neurons, the specific ER subtypes and downstream signaling pathways mediating these effects remain poorly defined. The objective of our study was to investigate the effects of 17 beta-estradiol (E2) on mitochondrial function and axonal regeneration of cultured DRG neurons and explore the pathways by which E2 acts. We observed that E2 treatment upregulated the levels of phosphorylated AMP-activated protein kinase (AMPK). E2 also increased the levels of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and activating transcription factor 3 (ATF3), which are proteins involved in mitochondrial biogenesis and axonal regeneration. The Seahorse assay showed that E2 elevated basal respiration in cultured DRG neurons. Additionally, E2 treatment for 24 h significantly increased total neurite outgrowth of DRG neurons. Pharmacological inhibition of AMPK using Compound C inhibited E2-mediated increases in ATF3 expression and neurite outgrowth. The Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) inhibitor STO-609 blocked E2-mediated AMPK activation. Furthermore, we assessed whether these effects were mediated by ERα or ERβ by using the ERα selective agonist propyl pyrazole triol (PPT) and ERβ selective agonist diarylpropionitrile (DPN). PPT upregulated phosphorylated AMPK levels and increased total neurite outgrowth, whereas DPN was ineffective. The results demonstrate that E2 acts through ERα to promote neurite outgrowth via a pathway involving activation of CaMKKβ/AMPK in adult DRG neurons. Our findings identify ERα-mediated AMPK activation as a therapeutic target for enhancing neuronal regeneration and mitochondrial function in neurodegenerative disorders.

It has been shown that the AMPK signaling pathway helps maintain the structure of nerve cells and prevent damage caused by hypoxia by preserving the energy available in these cells. This signaling pathway is activated by various drugs, including metformin.

In this study, thirty male rats were randomly divided into healthy rats, CCI (chronic constriction injury), CCI + metformin, CCI + dorsomorphin, and CCI + metformin + dorsomorphin groups. Behavioral tests were performed on the third, seventh, and fourteenth days after the induction of CCI. On the last day, the inflammatory cytokines and pathology were investigated after dissecting the spinal cords and sciatic nerves of the animals, respectively.

The results of this study indicated that metformin could improve performance in behavioral tests and reduce the levels of inflammatory cytokines. Histological analyses further revealed that metformin could decrease inflammation and necrosis in sciatic nerve tissue. Notably, this effect was observed despite dorsomorphin injection, which prevented the therapeutic effects of metformin in the fifth group.

The results of this study indicated that stimulation of the AMPK signaling pathway could effectively preserve the structure of the sciatic nerve, reduce inflammation, and improve responses to behavioral tests.

Aging leads to a decline in the mass and function of skeletal muscles, a condition known as sarcopenia. It was previously reported that aging-related alterations in protein degradation, chronic inflammation, and deterioration of mitochondrial metabolism affect the acceleration of muscle atrophy in the elderly. However, the detailed mechanism or substantial causes for age-related muscle loss are still lacking, yet exercise or an increment in dietary protein intake are suggested as effective approaches to mitigate muscle atrophy. This study aims to investigate the regulatory effect of black soybean (Rhynchosia nulubilis) and black rice (Oryza sativa L.) mixture extract (BBME), which are rich in protein and bioactive compounds, in 12-month-old aged mice and L6 myotubes. BBME was orally administered at 300 and 600 mg/kg/day (low and high doses) for 12 weeks, and its effects on systemic glucose homeostasis and skeletal muscle metabolism were evaluated. Consequently, BBME at a high dose marginally ameliorated muscle loss and significantly improved glucose metabolism. BBME also reduced cellular senescence markers and enhanced mitochondrial biogenesis in aged skeletal muscles. Additionally, BBME exerted insulin-like activity by promoting glucose metabolism in L6 myotubes. These findings suggest the potential of BBME as a functional food ingredient in alleviating aging-induced muscle loss by modulating mitochondrial activity and glucose metabolism.

Mammalian sirtuins are class III histone deacetylases involved in the regulation of multiple biological processes including senescence, DNA repair, apoptosis, proliferation, caloric restriction, and metabolism. Among the mammalian sirtuins, SIRT3, SIRT4, and SIRT5 are localized in the mitochondria and collectively termed the mitochondrial sirtuins. Mitochondrial sirtuins are NAD+-dependent deacetylases that play a central role in cellular metabolism and function as epigenetic regulators by performing post-translational modification of cellular proteins. Several studies have identified the role of mitochondrial sirtuins in age-related pathologies and the rewiring of cancer metabolism. Mitochondrial sirtuins regulate cellular functions by contributing to post-translational modifications, including deacetylation, ADP-ribosylation, demalonylation, and desuccinylation of diverse cellular proteins to maintain cellular homeostasis. Here, we review and discuss the structure and function of the mitochondrial sirtuins and their role as metabolic regulators in breast cancer. Altered breast cancer metabolism may promote tumor progression and has been an essential target for therapy. Further, we discuss the potential role of targeting mitochondrial sirtuin and its impact on breast cancer progression using sirtuin inhibitors and activators as anticancer agents.

Heart failure (HF) is a prominent fatal cardiovascular disorder afflicting 3.4% of the adult population despite the advancement of treatment options. Therefore, a better understanding of the pathogenesis of HF is essential for exploring novel therapeutic strategies. Hypertrophy and fibrosis are significant characteristics of pathological cardiac remodeling, contributing to HF. The mechanisms involved in the development of cardiac remodeling and consequent HF are multifactorial, and in this review, the key underlying mechanisms are discussed. These have been divided into the following categories thusly: (i) mitochondrial dysfunction, including defective dynamics, energy production, and oxidative stress; (ii) cardiac lipotoxicity; (iii) maladaptive endoplasmic reticulum (ER) stress; (iv) impaired autophagy; (v) cardiac inflammatory responses; (vi) programmed cell death, including apoptosis, pyroptosis, and ferroptosis; (vii) endothelial dysfunction; and (viii) defective cardiac contractility. Preclinical data suggest that there is merit in targeting the identified pathways; however, their clinical implications and outcomes regarding treating HF need further investigation in the future. Herein, we introduce the molecular mechanisms pivotal in the onset and progression of HF, as well as compounds targeting the related mechanisms and their therapeutic potential in preventing or rescuing HF. This, therefore, offers an avenue for the design and discovery of novel therapies for the treatment of HF.

AMP-activated protein kinase (AMPK) is a central mediator of cellular metabolism and is activated in direct response to low ATP levels. Activated AMPK inhibits anabolic pathways and promotes catabolic activities that generate ATP through the phosphorylation of multiple target substrates. AMPK is a therapeutic target for activation in several chronic metabolic diseases, and there is increasing interest in targeting AMPK activity in cancer where it can act as a tumor suppressor or conversely it can support cancer cell survival. Small molecule AMPK activators and inhibitors have demonstrated some success in suppressing cancer growth, survival, and drug resistance in preclinical cancer models. In this perspective, we summarize the role of AMPK in cancer and drug resistance, the influence of the tumor microenvironment on AMPK activity, and AMPK activator and inhibitor development. In addition, we discuss the potential importance of isoform-selective targeting of AMPK and approaches for selective AMPK targeting in cancer.

Obesity has become a global pandemic. The approaches researched to prevent it include decreasing energy intake and/or enhancing energy expenditure. Therefore, research on brown adipose tissue is of great importance. Brown adipose tissue is characterized by its high mitochondrial content. Mitochondrial uncoupling protein 1 (UCP1) releases energy as heat instead of chemical energy. Thermogenesis increases energy expenditure. Berberine, a phytochemical widely used in Asian countries, has positive effects on body weight control. While the precise mechanisms behind this effect remain unclear, the adenosine monophosphate-activated protein kinase (AMPK) pathway is known to play a crucial role. Berberine activates AMPK through phosphorylation, significantly impacting brown adipose tissue by enhancing lipolytic activity and increasing the expression of UCP1, peroxisome proliferator-activated receptor γ-co-activator-1α (PGC1α), and PR domain containing 16 (PRDM16). While investigating the mechanism of action of berberine, both the AMPK pathway is being examined in more detail and alternative pathways are being explored. One such pathway is growth differentiation factor 15 (GDF15), known for its appetite-suppressing effect. Berberine's low stability and bioavailability, which are the main obstacles to its clinical use, have been improved through the development of nanotechnological methods. This review examines the potential mechanisms of berberine on browning and summarizes the methods developed to enhance its effect.

Mitochondria are metabolic hubs that govern skeletal muscle health. Although exercise has been established as a powerful inducer of quality control processes that ultimately enhance mitochondrial function, there are currently limited pharmaceutical interventions available that emulate exercise-induced mitochondrial adaptations. To investigate a novel candidate for this role, we examined sulforaphane (SFN), a naturally occurring compound found in cruciferous vegetables. SFN has been documented as a potent antioxidant inducer through its activation of the nuclear factor erythroid 2-related factor 2 (Nrf-2) antioxidant response pathway. However, its effects on muscle health have been underexplored. To investigate the interplay between chronic exercise and SFN, C2C12 myotubes were electrically stimulated to model chronic contractile activity (CCA) in the presence or absence of SFN. SFN promoted Nrf-2 nuclear translocation, enhanced mitochondrial respiration, and upregulated key antioxidant proteins including catalase and glutathione reductase. These adaptations were accompanied by reductions in cellular and mitochondrial reactive oxygen species (ROS) emission. Signaling toward biogenesis was enhanced, demonstrated by increases in mitochondrial transcription factor A (TFAM), peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α nuclear translocation, PGC-1α promoter activity, mitochondrial content, and organelle branching, suggestive of a larger, more interconnected mitochondrial pool. These mitochondrial adaptations were accompanied by an increase in lysosomal proteins, suggesting coordinated regulation. There was no difference in mitochondrial and antioxidant-related proteins between CCA and non-CCA SFN-treated cells. Our data suggest that SFN activates signaling cascades that are common to those produced by contractile activity, indicating that SFN-centered therapeutic strategies may improve the mitochondrial phenotype in skeletal muscle.NEW & NOTEWORTHY Nrf-2 is a transcription factor that has been implicated in mitigating oxidative stress and regulating mitochondrial homeostasis. However, limited research has demonstrated how Nrf-2-mediated adaptations compare with those produced by exercise. To investigate this, we treated myotubes with Sulforaphane, a well-established Nrf-2 activator, and combined this with stimulation-induced chronic contractile activity to model exercise training. Our work is the first to establish that sulforaphane mimics training-induced mitochondrial adaptations, including enhancements in respiration, biogenesis, and dynamics.

The regulatory effect of breastfeeding on offspring metabolism has garnered significant attention as an effective strategy in combating childhood obesity. However, the underlying mechanism remains largely unknown. Through integrated analysis of multiple human milk peptide databases and functional screening, MDPAO1 (milk-derived peptide associated with obesity 1) was identified as having potential activity in promoting the expression of thermogenic genes. In lactating mice, intervention with MDPAO1 enhanced the thermogenic phenotype of brown adipose tissue (BAT) and overall metabolic activity. Moreover, MDPAO1 intervention led to reduced body weight gain, increased brown fat mass, and improved glucose tolerance and insulin sensitivity in a mouse model of high-fat diet (HFD)-induced obesity. RNA-seq analysis of BAT post-MDPAO1 intervention revealed close association with mitochondrial oxidative respiratory chain and mitophagy. Subsequent in vitro experiments conducted on primary brown adipocytes confirmed that MDPAO1 inhibited mitophagy, increased mitochondrial mass, and elevated levels of mitochondrial respiratory chain complexes. In conclusion, this study underscores the potential of MDPAO1, a peptide enriched in breast milk, in activating the thermogenic phenotype of brown adipose tissue and mitigating obesity, thus offering novel insights into the mechanisms underlying breastfeeding's role in preventing childhood obesity.

Eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, which regulates all 3 unfolded protein response pathways, helps maintain cellular homeostasis and overcome endoplasmic reticulum (ER) stress through transcriptional and translational reprogramming. However, transcriptional regulation of mitochondrial homeostasis by eIF2α phosphorylation during ER stress is not fully understood. Here, we report that the eIF2α phosphorylation-activating transcription factor 4 (ATF4) axis is required for the expression of multiple transcription factors, including nuclear factor erythroid 2-related factor 2 and its target genes responsible for mitochondrial homeostasis during ER stress. eIF2α phosphorylation-deficient (A/A) cells displayed dysregulated mitochondrial dynamics and mitochondrial DNA replication, decreased expression of oxidative phosphorylation complex proteins, and impaired mitochondrial functions during ER stress. ATF4 overexpression suppressed impairment of mitochondrial homeostasis in A/A cells during ER stress by promoting the expression of downstream transcription factors and their target genes. Our findings underscore the importance of the eIF2α phosphorylation-ATF4 axis for maintaining mitochondrial homeostasis through transcriptional reprogramming during ER stress.

Sarcopenia frequently occurs with aging and leads to major adverse impacts in elderly individuals. The protective effects of omega-3 polyunsaturated fatty acids against aging-related sarcopenia have been demonstrated; however, the effect and underlying mechanism of EPA or DHA alone remain inconclusive. Hence, the present study was aimed to clarify the differential effects and possible mechanisms of EPA and DHA on aging-related sarcopenia. In this study, two-month-old and eighteen-month-old male C57BL/6J mice were fed with an AIN-93M diet and an AIN-93M diet containing 1% EPA or 1% DHA for 24 weeks, respectively. The results revealed that EPA and DHA supplementation effectively alleviated the decline in grip strength, skeletal muscle mass, and myofiber cross-sectional areas in aged mice, with EPA exhibiting a better effect against aging-related sarcopenia than DHA. The ROS scavenging role of EPA in aged skeletal muscle was also superior to that of DHA. Additionally, EPA showed a stronger role in improving protein turnover and myogenesis in aged skeletal muscle, as evidenced by suppressing the activation of FoxO3a and NF-κB, blunting the expression levels of muscle atrophy markers MAFbx and MuRF1, activating the PI3K/Akt/mTOR signaling pathway, and elevating MyoD expression. Moreover, EPA also revealed a better effect on inhibiting mitochondria- and endoplasmic reticulum stress-mediated apoptosis in aged skeletal muscle. Furthermore, EPA manifested a more pronounced effect on improving mitochondrial damage of aged skeletal muscle than DHA, and the reason might be due to its superior capability of regulating mitochondrial quality control, as clearly shown by enhancing mitochondrial biogenesis through the AMPK/PGC-1α-dependent pathway, restraining the loss of mitochondrial fusion and fission proteins including Opa1, Mfn2, and Fis1, and promoting mitophagy via the PINK1/Parkin-dependent pathway.

Lipid droplets (LDs), serving as the convergence point of energy metabolism and multiple signaling pathways, have garnered increasing attention in recent years. Different cell types within the central nervous system (CNS) can regulate energy metabolism to generate or degrade LDs in response to diverse pathological stimuli. This article provides a comprehensive review on the composition of LDs in CNS, their generation and degradation processes, their interaction mechanisms with mitochondria, the distribution among different cell types, and the roles played by these cells-particularly microglia and astrocytes-in various prevalent neurological disorders. Additionally, we also emphasize the paradoxical role of LDs in post-cerebral ischemia inflammation and explore potential underlying mechanisms, aiming to identify novel therapeutic targets for this disease.

Type 2 diabetes mellitus (T2DM), a serious metabolic disorder, is a worldwide health problem due to the alarming rise in prevalence and elevated morbidity and mortality. Chronic hyperglycemia, insulin resistance, and ineffective insulin effect and secretion are hallmarks of T2DM, leading to many serious secondary complications. These include, in particular, cardiovascular disorders, diabetic neuropathy, nephropathy and retinopathy, diabetic foot, osteoporosis, liver damage, susceptibility to infections and some cancers. Polyphenols such as flavonoids, phenolic acids, stilbenes, tannins, and lignans constitute an extensive and heterogeneous group of phytochemicals in fresh fruits, vegetables and their products. Various in vitro studies, animal model studies and available clinical trials revealed that flavonoids (e.g., quercetin, kaempferol, rutin, epicatechin, genistein, daidzein, anthocyanins), phenolic acids (e.g., chlorogenic, caffeic, ellagic, gallic acids, curcumin), stilbenes (e.g., resveratrol), tannins (e.g., procyanidin B2, seaweed phlorotannins), lignans (e.g., pinoresinol) have the ability to lower hyperglycemia, enhance insulin sensitivity and improve insulin secretion, scavenge reactive oxygen species, reduce chronic inflammation, modulate gut microbiota, and alleviate secondary complications of T2DM. The interaction between polyphenols and conventional antidiabetic drugs offers a promising strategy in the management and treatment of T2DM, especially in advanced disease stages. Synergistic effects of polyphenols with antidiabetic drugs have been documented, but also antagonistic interactions that may impair drug efficacy. Therefore, additional research is required to clarify mutual interactions in order to use the knowledge in clinical applications. Nevertheless, dietary polyphenols can be successfully applied as part of supportive treatment for T2DM, as they reduce both obvious clinical symptoms and secondary complications.

Doxorubicin (DOX), a potent chemotherapy drug, is limited by its cardiotoxic effects, which can lead to heart damage. This study explores the cardioprotective potential of Phosphocreatine (PCr) in vitro and in vivo models, focusing on its impact on the AMPK and PGC-1α pathways, apoptosis reduction, and mitochondrial function preservation. Advanced methodologies, including high-resolution respirometry (HRR), were employed to assess mitochondrial bioenergetics, AMPK activity, and apoptotic rates in cardiomyocytes. Electrocardiography (ECG) and echocardiography (echo) were used to monitor cardiac function in vivo. Results showed that PCr significantly activated the AMPK and PGC-1α pathways, reduced apoptosis, and stabilized mitochondrial function in cardiomyocytes exposed to DOX. There was an upregulation of AMPK and PGC-1α target genes, stabilization of mitochondrial membranes, and improvements in cellular energy production and antioxidant defenses. PCr also markedly reduced apoptotic markers, enhancing cardiomyocyte viability. ECG and echocardiography revealed that PCr preserved cardiac function, indicated by improved heart rate variability, reduced QT interval prolongation, and enhanced ejection fraction. These findings highlight PCr's potential in mitigating DOX-induced cardiotoxicity by enhancing mitochondrial function and reducing apoptosis. The study underscores the promise of PCr as an agent to reduce chemotherapy-related cardiac injuries, paving the way for further research to improve patient outcomes in cancer treatment.

Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) plays a crucial role in regulation of metabolic homeostasis. To understand the role of the catalytic α2 subunit of AMPK in skeletal muscle energy metabolism, myotube cultures were established from AMPKα2+/+ and AMPKα2-/- mice. Myotubes from AMPKα2-/- mice had lower basal oleic acid and glucose oxidation compared to myotubes from AMPKα2+/+ mice. However, the relative response to mitochondrial uncoupling was increased for oleic acid oxidation. Incorporation of acetate into lipids was also lower in myotubes from AMPKα2-/- mice. Proteomics analysis revealed that AMPKα2-/- myotubes had upregulated pathways related to mitochondrial function and fatty acid oxidation, and decreased pathways related to fatty acid biosynthesis. In conclusion, ablation of AMPKα2 catalytic subunit in skeletal muscle cells resulted in reduced basal oxidation of glucose and fatty acids, however upregulated pathways related to mitochondrial function and fatty acid oxidation and reduced lipid formation.

Resveratrol (RES), a natural polyphenolic compound, has shown promise in enhancing skeletal muscle regeneration and metabolic function. This study aims to explore the impact of RES on muscle regeneration after injury through the regulation of antioxidant capacity and mitochondrial biogenesis. RES treatment significantly increased the ratio of tibialis anterior muscle mass to body weight, alongside reduced fasting glucose levels. Following cardiotoxin-induced injury, RES treatment improved muscle regeneration, characterized by greater formation of new fibers and better structural repair compared to the control. Notably, gene expression analyses demonstrated that RES-treated mice exhibited elevated levels of myogenic markers, such as paired box 7 (Pax7), myogenic factor 5 (Myf5), myoblast determination protein (MyoD), and Myogenin (MyoG). Concurrently, yes-associated protein (YAP) increased, underscoring its role in regulating satellite cell activity. Transcriptomic analysis identified enriched pathways related to muscle regeneration and mitochondrial biogenesis, with increased expression of mitochondrial transcription factors and higher mitochondrial DNA content in RES-treated mice. Furthermore, RES enhanced antioxidant capacity via the Kelch-like ECH-associated protein 1 (KEAP-1)/nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) signaling pathway, as indicated by elevated activities of total antioxidant capacity, Glutathione peroxidase (GSH-PX), and superoxidase dismutase (SOD). Collectively, these findings suggest that RES not only promotes muscle regeneration but also supports mitochondrial function and antioxidant defenses, positioning it as a food-derived pharmaceutical for targeting muscle repair after injury.

Chronic obstructive pulmonary disease (COPD) is a prevalent chronic respiratory disease worldwide. Mitochondrial quality control mechanisms encompass processes such as mitochondrial biogenesis, fusion, fission, and autophagy, which collectively maintain the quantity, morphology, and function of mitochondria, ensuring cellular energy supply and the progression of normal physiological activities. However, in COPD, due to the persistent stimulation of harmful factors such as smoking and air pollution, mitochondrial quality control mechanisms often become deregulated, leading to mitochondrial dysfunction. Mitochondrial dysfunction plays a pivotal role in the pathogenesis of COPD, contributing toinflammatory response, oxidative stress, cellular senescence. However, therapeutic strategies targeting mitochondria remain underexplored. This review highlights recent advances in mitochondrial dysfunction in COPD, focusing on the role of mitochondrial quality control mechanisms and their dysregulation in disease progression. We emphasize the significance of mitochondria in the pathophysiological processes of COPD and explore potential strategies to regulate mitochondrial quality and improve mitochondrial function through mitochondrial interventions, aiming to treat COPD effectively. Additionally, we analyze the limitations and challenges of existing therapeutic strategies, aiming to provide new insights and methods for COPD treatment.

Immunotherapy has transformed current cancer management, and it has achieved significant progress over last decades. However, an immunosuppressive tumor microenvironment (TME) diminishes the effectiveness of immunotherapy by suppressing the activity of immune cells and facilitating tumor immune-evasion. Adenosine monophosphate-activated protein kinase (AMPK), a key modulator of cellular energy metabolism and homeostasis, has gained growing attention in anti-tumor immunity. Metformin is usually considered as a cornerstone in diabetes management, and its role in activating the AMPK pathway has also been extensively explored in cancer therapy although the findings on its role remain inconsistent. Metformin in a nanomedicine formulation has been found to hold potential in reprogramming the immunosuppressive TME through immunometabolic modulation of both tumor and immune cells. This review elaborates the foundation and progress of immunometabolic reprogramming of the TME via metformin-based nanomedicines, offering valuable insights for the next generation of cancer therapy.

As the final stage of disease-related tissue injury and repair, fibrosis is characterized by excessive accumulation of the extracellular matrix. Unrestricted accumulation of stromal cells and matrix during fibrosis impairs the structure and function of organs, ultimately leading to organ failure. The major etiology of fibrosis is an injury caused by genetic heterogeneity, trauma, virus infection, alcohol, mechanical stimuli, and drug. Persistent abnormal activation of "quiescent" fibroblasts that interact with or do not interact with the immune system via complicated signaling cascades, in which parenchymal cells are also triggered, is identified as the main mechanism involved in the initiation and progression of fibrosis. Although the mechanisms of fibrosis are still largely unknown, multiple therapeutic strategies targeting identified molecular mechanisms have greatly attenuated fibrotic lesions in clinical trials. In this review, the organ-specific molecular mechanisms of fibrosis is systematically summarized, including cardiac fibrosis, hepatic fibrosis, renal fibrosis, and pulmonary fibrosis. Some important signaling pathways associated with fibrosis are also introduced. Finally, the current antifibrotic strategies based on therapeutic targets and clinical trials are discussed. A comprehensive interpretation of the current mechanisms and therapeutic strategies targeting fibrosis will provide the fundamental theoretical basis not only for fibrosis but also for the development of antifibrotic therapies.

Regulatory T cells (Tregs) play a critical role in maintaining immune homeostasis and preventing autoimmune diseases. Recent advances in immunometabolism have revealed the pivotal role of mitochondrial dynamics and metabolism in shaping Treg functionality. Tregs depend on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) to support their suppressive functions and long-term survival. Mitochondrial processes such as fusion and fission significantly influence Treg activity, with mitochondrial fusion enhancing bioenergetic efficiency and reducing reactive oxygen species (ROS) production, thereby promoting Treg stability. In contrast, excessive mitochondrial fission disrupts ATP synthesis and elevates ROS levels, impairing Treg suppressive capacity. Furthermore, mitochondrial ROS act as critical signaling molecules in Treg regulation, where controlled levels stabilize FoxP3 expression, but excessive ROS leads to mitochondrial dysfunction and immune dysregulation. Mitophagy, as part of mitochondrial quality control, also plays an essential role in preserving Treg function. Understanding the intricate interplay between mitochondrial dynamics and Treg metabolism provides valuable insights for developing novel therapeutic strategies to treat autoimmune disorders and enhance immunotherapy in cancer.

The molecular mechanisms underlying the maintenance and adaptability of the neuromuscular junction (NMJ) remain poorly understood. This study aimed to investigate the role of AMP-activated protein kinase (AMPK) as a key regulator of NMJ stability and plasticity.

A comprehensive, multifaceted approach was employed, integrating genetic, physiological, and pharmacological methodologies to elucidate the role of skeletal muscle AMPK in modulating the neuromuscular synapse.

Our findings reveal an increased abundance of AMPK transcripts within the NMJ and an age-associated decline in AMPK activity and synapse-specific mitochondrial gene expression. Young mice null for skeletal muscle AMPK displayed a neuromuscular phenotype akin to aged animals. Pharmacological AMPK stimulation facilitated its localization in subsynaptic myonuclei, preceded the induction of several NMJ-related transcripts, and enhanced myotube acetylcholine receptor clustering. Exercise-induced AMPK activation in mouse muscle elicited a broad NMJ-related gene response, consistent with human exercise data.

These findings highlight a critical role for AMPK in the maintenance and remodeling of the NMJ, highlighting its potential as a therapeutic target for age-related and neuromuscular disorders.

AMP-activated protein kinase (AMPK) is an energy-sensing serine/threonine kinase involved in metabolic regulation. It is phosphorylated by the upstream liver kinase B1 (LKB1) or calcium/calmodulin-dependent kinase kinase 2 (CaMKKβ). In cultured cells, AMPK activation correlates with LKB1 activity. The phosphorylation activates AMPK, shifting metabolism toward catabolism and promoting mitogenesis. In muscles, inactivity reduces AMPK activation, shifting the phenotype of oxidative muscles toward a more glycolytic profile. Here, we compared the basal level of AMPK activation in glycolytic and oxidative muscles and analyzed whether this relates to LKB1 or CaMKKβ. Using Western blotting, we assessed AMPK expression and phosphorylation in soleus, gastrocnemius (GAST), extensor digitorum longus (EDL), and heart from C57BL6J mice. We also assessed LKB1 and CaMKKβ expression, and CaMKKβ activity in tissue homogenates. AMPK activation was higher in oxidative (soleus and heart) than in glycolytic muscles (gastrocnemius and EDL). This correlated with AMPK α1-isoform expression, but not LKB1 and CaMKKβ. LKB1 expression was sex dependent and lower in male than female muscles. CaMKKβ expression was very low in skeletal muscles and did not phosphorylate AMPK in muscle lysates. The higher AMPK activation in oxidative muscles is in line with the fact that activated AMPK maintains an oxidative phenotype. However, this could not be explained by LKB1 and CaMKKβ. These results suggest that the regulation of AMPK activation is more complex in muscle than in cultured cells. As AMPK has been proposed as a therapeutic target for several diseases, future research should consider AMPK isoform expression and localization, and energetic compartmentalization.NEW & NOTEWORTHY It is important to understand how AMP-activated kinase, AMPK, is regulated, as it is a potential therapeutic target for several diseases. AMPK is activated by liver kinase B1, LKB1, and calcium/calmodulin-dependent kinase kinase 2, CaMKKβ. In cultured cells, AMPK activation correlates with LKB1 expression. In contrast, we show that AMPK-activation was higher in oxidative than glycolytic muscle, without correlating with LKB1 or CaMKKβ expression. Thus, AMPK regulation is more complex in highly compartmentalized muscle cells.

Heart disease (HD) is a general term for various diseases affecting the heart. An increasing body of evidence suggests that the pathogenesis of HD is closely related to mitochondrial dysfunction. Peroxisome proliferator‑activated receptor γ coactivator‑1α (PGC‑1α) is a transcriptional coactivator that plays an important role in mitochondrial function by regulating mitochondrial biogenesis, energy metabolism and oxidative stress. The present review shows that PGC‑1α expression and activity in the heart are controlled by multiple signaling pathways, including adenosine monophosphate‑activated protein kinase, sirtuin 1/3 and nuclear factor κB. These can mediate the activation or inhibition of transcription and post‑translational modifications (such as phosphorylation and acetylation) of PGC‑1α. Furthermore, it highlighted the recent progress of PGC‑1α in HD, including heart failure, coronary heart disease, diabetic cardiomyopathy, drug‑induced cardiotoxicity and arrhythmia. Understanding the mechanisms underlying PGC‑1α in response to pathological stimulation may prove to be beneficial in developing new ideas and strategies for preventing and treating HDs. Meanwhile, the present review explored why the opposite results occurred when PGC‑1α was used as a target therapy.