Activation of α7 Nicotinic Acetylcholine Receptor Improves Muscle Endurance by Upregulating Orosomucoid Expression and Glycogen Content in Mice.

There are presently no acknowledged therapeutic targets or official drugs for the treatment of muscle fatigue. The alpha7 nicotinic acetylcholine receptor (α7nAChR) is expressed in skeletal muscle, with an unknown role in muscle endurance. Here, we try to explore whether α7nAChR could act as a potential therapeutic target for the treatment of muscle fatigue. Results showed that nicotine and PNU-282987 (PNU), as nonspecific and specific agonists of α7nAChR, respectively, could both significantly increase C57BL6/J mice treadmill-running time in a time- and dose-dependent manner. The improvement effect of PNU on running time and ex vivo muscle fatigue index disappeared when α7nAChR deletion. RNA sequencing revealed that the differential mRNAs affected by PNU were enriched in glycolysis/gluconeogenesis signaling pathways. Further studies found that PNU treatment significantly elevates glycogen content and ATP level in the muscle tissues of α7nAChR+/+ mice but not α7nAChR-/- mice. α7nAChR activation specifically increased endogenous glycogen-targeting protein orosomucoid (ORM) expression both in vivo skeletal muscle tissues and in vitro C2C12 skeletal muscle cells. In ORM1 deficient mice, the positive effects of PNU on running time, glycogen and ATP content, as well as muscle fatigue index, were abolished. Therefore, the activation of α7nAChR could enhance muscle endurance via elevating endogenous anti-fatigue protein ORM and might act as a promising therapeutic strategy for the treatment of muscle fatigue.

Orosomucoid 2 is an endogenous regulator of neuronal mitochondrial biogenesis and promotes functional recovery post-stroke.

Development of functional recovery therapies is critical to reduce the global impact of stroke as the leading cause of long-term disability. Our previous studies found that acute-phase protein orosomucoid (ORM) could provide an up to 6h therapeutic time window to reduce infarct volume in acute ischemic stroke by improving endothelial function. However, its role in neurons and functional recovery post-stroke remains largely unknown. Here, we showed that exogenous ORM administration with initial injection at 0.5h (early) or 12h (delayed) post-MCAO daily for consecutive 7 days significantly decreased infarct area, improved motor and cognitive functional recovery, and promoted mitochondrial biogenesis after MCAO. While neuron-specific knockout of ORM2, a dominant subtype of ORM in the brain, produced opposite effects which could be rescued by exogenous ORM. In vitro, exogenous ORM protected SH-SY5Y cells from OGD-induced damage and promoted mitochondrial biogenesis, while endogenous ORM2 deficiency worsened these processes. Mechanistically, inactivation of CCR5 or AMPK eliminated the protective effects of ORM on neuronal damage and mitochondrial biogenesis. Taken together, our findings demonstrate that ORM, mainly ORM2, is an endogenous regulator of neuronal mitochondrial biogenesis by activating CCR5/AMPK signaling pathway, and might act as a potential therapeutic target for the functional recovery post-stroke.

A non-antibiotic erythromycin derivative improves muscle endurance by regulating endogenous anti-fatigue protein orosomucoid in mice.

At present, there are no official approved drugs for improving muscle endurance. Our previous research found acute phase protein orosomucoid (ORM) is an endogenous anti-fatigue protein, and macrolides antibiotics erythromycin can elevate ORM level to increase muscle bioenergetics and endurance parameters. Here, we further designed, synthesized and screened a new erythromycin derivative named HMS-01, which lost its antibacterial activity in vitro and in vivo. Data showed that HMS-01 could time- and dose-dependently prolong mice forced-swimming time and running time, and improve fatigue index in isolated soleus muscle. Moreover, HMS-01 treatment could increase the glycogen content, mitochondria number and function in liver and skeletal muscle, as well as ORM level in these tissues and sera. In Orm-deficient mice, the anti-fatigue and glycogen-elevation activity of HMS-01 disappeared. Therefore, HMS-01 might act as a promising small molecule drug targeting ORM to enhance muscle endurance.

The role of arbuscular mycorrhizal fungi in micronutrient homeostasis and cadmium uptake and transfer in rice under different flooding intensities.

Flooding intensity significantly alters the availability of iron (Fe), zinc (Zn), and cadmium (Cd) in paddy soil. However, the influence of arbuscular mycorrhizal fungi (AMF) on the uptake and transfer of Cd and micronutrients (Fe and Zn) under Cd stress in varying flooding conditions is not well understood. A pot experiment was conducted to investigate the micronutrient homeostasis and Cd uptake and transfer in rice cultivated in Cd-contaminated soil with AMF inoculation under continuous and intermittent flooding conditions. Compared to non-inoculation controls, mycorrhizal inoculation decreased Cd concentration in rice plants under continuous and intermittent flooding, and improved grain yield by 39.2 % for early season rice and 21.1 % for late season rice under continuous flooding. Mycorrhizal inoculation balanced the availability of Zn and Fe and decreased the availability of Cd in soil, lowering the ratios of soil-available Cd to both soil-available Zn and soil Fe2+. These changes led to a redistribution of Zn and Fe concentrations in rice, thereby reducing Cd acquisition in a soil-rice system. Structural equation model (SEM) analysis revealed that mycorrhizal inoculation had a strong direct negative effect on the expression of Zn and Fe-related genes OsNRAMP1, OsIRT1, and OsIRT2 in the roots of rice, which in turn directly affected root Cd concentration. Furthermore, mycorrhizal colonization decreased Cd transfer coefficients from leaves to grains under continuous flooding and from nodes and leaves to grains under intermittent flooding. In the nodes, the Fe concentration and the expression of genes OsIRT1 and OsHMA2 were associated with Cd transfer from the nodes to grains. Similarly, in the leaves, the expression of genes OsZIP1 and OsMTP1 corresponded with Cd transfer from leaves to grains. This study provides insights into the role of AMF in affecting micronutrient concentrations and Cd uptake in rice under varying flooding conditions.

Efficient extraction performance and mechanisms of Cd2+ and Pb2+ in water by novel dicationic ionic liquids.

Ten novel hydrophobic dicationic ionic liquids (DILs) were synthesized and applied for the extraction of heavy metals in aqueous solutions. Their physicochemical properties were measured at ambient temperature, and the leaching behaviors of the as-prepared DILs in water were assessed by TOC analysis. Metal extraction experiments were carried out to evaluate the extraction performances of the DILs. It was found that the extraction rates of up to 0.45 and 0.53 mg·(g·min)-1 were achieved with 100 mg DILs for 5 mL of 5 mg/L Cd2+ and Pb2+ solutions. Besides, the extraction efficiencies of Cd2+ and Pb2+ were respectively up to 95.48% and 98.46%, when the volumes of the simulated wastewater were expanded by a factor of 20 at a constant extraction phase ratio (1000 mg DILs for 50 mL of 5 mg/L Cd2+ or Pb2+ solutions). The reusability of the novel DILs was successfully proved by the back-extraction experiments with 0.5 M HNO3. Finally, taking Cd2+ extraction as an example, the extraction mechanism based on FTIR analysis and quantum chemical calculations showed that both S and O atoms in the anions of DILs had physical and quasi-chemical interactions with Cd2+, which were stronger than the electrostatic attraction.

A Hydrogen Evolution Catalyst [Co2O2] Metallacycle Enables Regioselective Allene C(sp2)-H Functionalization.

Selective functionalization of allenic C(sp2)-H is an ideal approach to upgrading simple allenes to synthetically useful allenes, albeit suffering from challenges associated with inert reactivity and inferior selectivity. Inspired by energy chemistry, a catalytic hydrogen evolution reaction (HER) strategy was leveraged to selectively activate weakly acidic allene C(sp2)-H bonds in a reductive mode. An array of [Co2O2] metallacycle complexes were readily devised starting from amino acids, and they were demonstrated as robust HER catalysts, which would selectively break allenic C(sp2)-H bonds to release hydrogen. With the newly developed HER catalyst, regioselective electrochemical functionalization of allenic C(sp2)-H with alcoholic α C(sp3)-H was unprecedentedly achieved. This strategy features excellent regioselectivity, unconventional chemoselectivity, good functional-group tolerance (62 examples), and mild conditions. Mechanism experiments revealed a reactive hydroxy-coordinated cobalt(II) species in the reaction. Density functional theory (DFT) calculations were also conducted to rationalize the regioselectivity observed in the reaction.

Insulin-like Growth Factor 2 (IGF2)-Fused Lysosomal Targeting Chimeras for Degradation of Extracellular and Membrane Proteins.

Targeted degradation of the cell-surface and extracellular proteins via the endogenous lysosomal degradation pathways, such as lysosome-targeting chimeras (LYTACs), has recently emerged as an attractive tool to expand the scope of extracellular chemical biology. Herein, we report a series of recombinant proteins genetically fused to insulin-like growth factor 2 (IGF2), which we termed iLYTACs, that can be conveniently obtained in high yield by standard cloning and bacterial expression in a matter of days. We showed that both type-I iLYTACs, in which IGF2 was fused to a suitable affibody or nanobody capable of binding to a specific protein target, and type-II iLYTAC (or IGF2-Z), in which IGF2 was fused to the IgG-binding Z domain that served as a universal antibody-binding adaptor, could be used for effective lysosomal targeting and degradation of various extracellular and membrane-bound proteins-of-interest. These heterobifunctional iLYTACs are fully genetically encoded and can be produced on a large scale from conventional E. coli expression systems without any form of chemical modification. In the current study, we showed that iLYTACs successfully facilitated the cell uptake, lysosomal localization, and efficient lysosomal degradation of various disease-relevant protein targets from different mammalian cell lines, including EGFR, PD-L1, CD20, and α-synuclein. The antitumor properties of iLYTACs were further validated in a mouse xenograft model. Overall, iLYTACs represent a general and modular strategy for convenient and selective targeted protein degradation, thus expanding the potential applications of current LYTACs and related techniques.

Light availability and plant shade tolerance modify plant-microbial interactions and feedbacks in subtropical trees.

Plant-soil feedbacks (PSFs) are an important mechanism of species coexistence in forest communities. However, evidence remains limited for how light availability regulates PSFs in species with different shade tolerance via changes in plant-microbial interactions. Here we tested in a glasshouse experiment how PSFs changed as a function of light availability and tree shade tolerance. Soil bacterial and fungal communities were profiled using the 16S rRNA and ITS2 gene sequencing, respectively. Under low light, individual PSFs were positively related to shade tolerance, while the least shade-tolerant species produced the most positive PSFs under high light. Pairwise PSFs between species with contrasting shade tolerance were strongly positive under high light but negative under low light, thereby promoting the dominance of less shade-tolerant species in forest gaps and species coexistence under closed canopy, respectively. Under high light, PSFs were related to soil microbial composition and diversity, with the relative abundance of arbuscular mycorrhizal fungi being the primary driver of PSFs. Under low light, none of soil microbial properties were significantly related to PSFs. These findings indicate PSFs and plant shade tolerance interact to promote species coexistence and improve our understanding of how soil microbes contribute to variation in PSFs.

Palladium Catalyzed Annulation of o-Iodo-Anilines with Propargyl Alcohols: Synthesis of Substituted Quinolines.

A palladium catalyzed annulation of o-iodo-anilines with propargyl alcohols for the synthesis of substituted quinolines has been developed. The reaction tolerates diverse functional groups under mild conditions, providing direct access to 2,4-disubstituted quinolines from easily available starting materials. A broad range of 2,4-disubstituted quinolines were efficiently prepared in good to excellent yields.

Neoadjuvant chemotherapy or upfront surgery in hepatoblastoma: A multicenter retrospective study.

BACKGROUND: We retrospectively investigated the role of neoadjuvant chemotherapy in low-risk patients with hepatoblastoma (HB) who underwent curative resection between February 2009 and December 2017. We also verified the feasibility of the risk stratification system to select the optimal patients for upfront surgery. PROCEDURE: We compared 5-year overall survival (OS) and event-free survival (EFS) between the upfront surgery (n = 26) and neoadjuvant chemotherapy (n = 104) groups at three oncology centers in Beijing, China. To reduce the effect of covariate imbalance, propensity score matching (PSM) was used. We explored whether preoperative chemotherapy affected surgical outcomes and identified the risk factors for events and death, including resection margin status, PRETreatment EXTent of disease stages, age, sex, pathology classification, and α-fetoprotein levels. RESULTS: The median follow-up period was 64 (interquartile range 60-72) months. After PSM, 22 pairs of patients were identified, and the patient characteristics were similar for all variables included in PSM. In the upfront surgery group, the 5-year EFS and OS rates were 81.8% and 86.3%, respectively. In the neoadjuvant chemotherapy group, the 5-year EFS and OS rates were 81.8% and 90.9%, respectively. No significant differences in EFS or OS were observed between the groups. Pathological classification was the only risk factor for death, disease progression, tumor recurrence, other tumors found during HB diagnosis, and death from any cause (p = .007 and .032, respectively). CONCLUSIONS: Upfront surgery achieved long-term disease control in low-risk patients with resectable HB, thus reduced the cumulative toxicity of platinum-based chemotherapy drugs.

Histological damage characteristics and quantitive analysis of porcine skin with non-insulated microneedle radiofrequency.

OBJECTIVE: In recent years, the microneedle radiofrequency (MRF) has been widely used for skin rejuvenation, but histological studies on the immediate trauma caused by different parameters of non-insulated RF microneedles METHODS: The skin of three pigs was treated with different needle depths, pulse widths and energy levels of non-insulated microneedle RF. Samples were collected before, immediately, and 2 weeks after treatment. The immediate histological response of each group was assessed and quantified by hematoxylin and eosin staining, Masson staining and Victoria Blue staining. RESULTS: In the treatment of non-insulated microneedle RF, different energy levels affected mainly the range of thermal damage (p = 0.044), and different needle depths affected mainly the depth of the cavity (p = 0.022). But the width of the coagulation zone width was determined by different factors. There was no significant difference in the histology of immediate damage caused by different pulse widths. Reepithelialization of the epidermis and basic wound repair can be completed within 2 weeks. CONCLUSION: Non-insulated RF microneedle therapy is an effective and safe treatment that can stimulate dermal wound healing with less thermal coagulation and a wide range of reversible thermal damage. However, it should be noted that the set needle depth may not correspond to the actual penetration depth, nor to the actual depth of histologic trauma.

Genomic analysis of a novel Aeromonas veronii phage pAEv1810, belonging to the genus Petsuvirus.

Phage-derived therapies are promising treatments in the fight against bacterial diseases as an alternative strategy nowadays. Species of Aeromonas veronii is an important pathogen causing freshwater fish diseases, the findings on genomic sequences of their bacteriophages are limited. In this work, a lytic bacteriophage capable of specifically infecting A. veronii strain AEv1810 was characterized at the gene level and was designated as pAEv1810. Transmission electron microscopic observation revealed that pAEv1810 belongs to the family of Myoviridae. The genome of phage pAEv1810 consists of 235,066 bp with 38.4% G + C content. Twenty-three of 249 putative proteins encoded by this phage have known functions, and four tRNA genes were found in phage genome. Phylogenetic analyses of RNA polymerase and Terminase large subunit revealed that phage pAEv1810 is closing to those phages classified to the genus Petsuvirus.

Corynebacterium kalidii sp. nov, an endophyte from a shoot of the halophyte Kalidium cuspidatum.

A Gram-stain-positive, non-motile, rod-shaped bacterial strain designated LD5P10T was isolated from a root of Kalidium cuspidatum, in Tumd Right Banner, Inner Mongolia, China. The strain grew at 4-40 â„ƒ (optimum 30 â„ƒ), and pH 5.0-10.0 (optimum pH 8.0), and in the presence of 0-16.0% (w/v) NaCl (optimum 2.0%). The strain was positive for catalase, and urease, and negative for nitrate reduction, and oxidase. The phylogenetic trees based on the 16S rRNA gene sequences and the whole genome sequence both revealed that strain LD5P10T clustered tightly with Corynebacterium glyciniphilum AJ 3170T and shared 98.1, 98.1, and < 98.1% of the 16S rRNA gene sequence similarities with strains C. glyciniphilum AJ 3170T, C. variabile DSM 20132T, and all the other current type strains. Strain LD5P10T contained MK-9 as the major respiratory quinone. Its major polar lipids were phosphatidylglycerol, diphosphatidylglycerol, phosphoglycolipid, two unidentified lipids, and two unidentified phospholipids. Its major fatty acids were C16:0 and C18:1 ω9c. The genomic DNA G + C content was 69.0%. The average nucleotide identity based on BLAST (ANIb), amino acid identity (AAI), and digital DNA-DNA hybridization (dDDH) values of strain LD5P10T to C. glyciniphilum AJ 3170T and C. variabile DSM 20132T were 82.9 and 76.4%, 85.3 and 69.4%, and 25.8 and 20.9%, respectively. The phylogenetic, physiological, and phenotypic results allowed the discrimination of strain LD5P10T from its phylogenetic relatives. Corynebacterium kalidii sp. nov. is, therefore, proposed with strain LD5P10T (= CGMCC 1.19144T = JCM 35048T) as the type strain.

Characterization and genomic analysis of the novel Aeromonas veronii phage pAEv1812.

Bacteria of the species Aeromonas veronii are generally ubiquitous in different aquatic environments and are capable of causing a variety of diseases in aquatic animals. In this work, the phage isolate pAEv1812, which is lytic to A. veronii strain 1810, was characterized and sequenced. Morphological analysis revealed that pAEv1812 has a symmetrical head and a long non-contractile tail. A one-step growth curve analysis showed that the latent period and burst period of pAEv1812 were approximately 40 min and 80 min, respectively, with a burst size of 190 PFU/infected cell. The genome of phage pAEv1812 is 61,461 bp in length with a G+C content of 61.4%. Eighteen of the 75 putative proteins encoded by this phage have known functions, and there were no rRNA and tRNA genes in the genome. Phylogenetic analysis based on amino acid sequences of the major capsid protein and terminase large subunit suggested that phage pAEv1812 should be included as a member of the genus Chivirus.

Chemical Modification for the "Off-/On" Regulation of Enzyme Activity.

Enzymes with excellent catalytic performance play important roles in living organisms. Advances in strategies for enzyme chemical modification have enabled powerful strategies for exploring and manipulating enzyme functions and activities. Based on the development of chemical enzyme modifications, incorporating external stimuli-responsive features-for example, responsivity to light, voltage, magnetic force, pH, temperature, redox activity, and small molecules-into a target enzyme to turn "on" and "off" its activity has attracted much attention. The ability to precisely control enzyme activity using different approaches will greatly expand the chemical biology toolbox for clarification and detection of signal transduction and in vivo enzyme function and significantly promote enzyme-based disease therapy. This review summarizes the methods available for chemical enzyme modification mainly for the off-/on control of enzyme activity and particularly highlights the recent progress regarding the applications of this strategy.

The adipokine orosomucoid alleviates adipose tissue fibrosis via the AMPK pathway.

The excess deposition of underlying extracellular matrix (ECM) in adipose tissue is defined as adipose tissue fibrosis that is a major contributor to metabolic disorder such as obesity and type 2 diabetes. Anti-fibrosis therapy has received much attention in the treatment of metabolic disorders. Orosomucoid (ORM) is an acute-phase protein mainly produced by liver, which is also an adipokine. In this study, we investigated the effects of ORM on adipose tissue fibrosis and the potential mechanisms. We showed that ORM1-deficient mice exhibited an obese phenotype, manifested by excessive collagen deposition in adipose tissues and elevated expression of ECM regulators such as metalloproteinases (MMP-2, MMP-13, MMP-14) and tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2, TIMP-3). Administration of exogenous ORM (50 mg· kg-1· d-1, ip) for 7 consecutive days in high-fat diet (HFD)-fed mice and leptin receptor (LepR)-deficient db/db mice attenuated these abnormal expressions. Meanwhile, ORM administration stimulated AMP-activated protein kinase (AMPK) phosphorylation and decreased transforming growth factor-ß1 (TGF-ß1) level in adipose tissues of the mice. In TGF-ß1-treated 3T3-L1 fibroblasts, ORM (10 µg/mL) improved the impaired expression profiles of fibrosis-related genes, whereas a selective AMPK inhibitor dorsomorphin (1 µmol/mL) abolished these effects. Together, our results suggest that ORM exerts a direct anti-fibrosis effect in adipose tissue via AMPK activation. ORM is expected to become a novel target for the treatment of adipose tissue fibrosis.

Ignatzschineria rhizosphaerae sp. nov. Isolated from Rhizosphere Soil of the Halophyte Kalidium cuspidatum.

A Gram-staining negative, non-motile, aerobic, rod-shaped bacterium, designated strain HR5S32T, was isolated from rhizosphere soil of the halophyte Kalidium cuspidatum, in Tumd Right Banner, Inner Mongolia, northern China. Strain HR5S32T grew at 10-40 °C (optimum 30 °C), pH 6.0-10.0 (optimum pH 9.0), and 0-12% (w/v) NaCl (optimum 2%). It was positive for catalase, methyl red test, Voges-Proskauer test, and nitrate reduction, but negative to oxidase, urease and hydrolysis of Tween 80. The phylogenetic trees based on the 16S rRNA gene sequences and whole genome both showed that strain HR5S32T was most closely related to Ignatzschineria indica FFA1T (= KCTC 22643 T). Ubiquinone-8 (Q-8) was the major respiratory quinone. Phosphatidylglycerol, phosphatidylethanolamine, and phospholipid were the major polar lipids. Its major fatty acids were Summed features 8 (C18:1 ω6c and/or C18:1 ω7c), C16:0, Summed features 3 (C16:1ω6c and/or C16:1 ω7c), and C14:0. The genome consisted of a 3,074,733 bp circular chromosome, with a G + C content of 38.8%, predicting 2,763 coding sequence genes, 70 tRNA genes and 6 rRNA. The values of the average nucleotide identities (ANI) and digital DNA-DNA hybridization (dDDH) values of strain HR5S32T to I. indica FFA1T were 74.6% and 22.0%, respectively, hence significantly lower than the thresholds of 95% for ANI and 70% for DDH for species delineation. The results of phenotypic, physiological, genotypic, and phylogenetic tests allowed the differentiation of strain HR5S32T from its closely related species. Ignatzschineria rhizosphaerae sp. nov. is therefore proposed, and the type strain is HR5S32T (= CGMCC 1.19435 T = KCTC 92093 T).

Treatment of exogenous hyperpigmentary disorders following silver ion-related chemical exposure with 1,064nm Q-switched laser: a 10-year follow-up.

1,064 nm Q-switched laser has been commonly used to treat pigmentation. However, there is still a lack of research on the treatment of hyperpigmentation caused by topical exposure to metallic salts-related chemical oxidation. We reported an Asian female patient who developed pigmentation 1 year on the face and neck after the recovery from a chemical explosion injury. 1,064 nm Q-switched laser were utilized to treat for 10 years. The facial pigment improved obviously after 10 sessions of treatment of 1,064 nm Q-switched laser. No recurrence or adverse events occurred during 10 years of treatment and follow-up, while the progression of lesions on the neck was observed.

Hepatoprotective Polysaccharides from Geranium wilfordii: Purification, Structural Characterization, and Their Mechanism.

Traditional Chinese Medicine is generally used as a decoction to guard health. Many active ingredients in the decoction are chemical ingredients that are not usually paid attention to in phytochemical research, such as polysaccharides, etc. Based on research interest in Chinese herbal decoction, crude polysaccharides from G. wilfordii (GCP) were purified to obtain two relatively homogeneous polysaccharides, a neutral polysaccharide (GNP), and an acid polysaccharide (GAP) by various chromatographic separation methods, which were initially characterized by GC-MS, NMR, IR, and methylation analysis. Studies on the hepatoprotective activity of GCP in vivo showed that GCP might be a potential agent for the prevention and treatment of acute liver injury by inhibiting the secretion levels of ALT, AST, IL-6, IL-1ß, TNF-α, and MDA expression levels, increasing SOD, and the GSH-Px activity value. Further, in vitro assays, GNP and GAP, decrease the inflammatory response by inhibiting the secretion of IL-6 and TNF-α, involved in the STAT1/T-bet signaling pathway.

Erythromycin has therapeutic efficacy on muscle fatigue acting specifically on orosomucoid to increase muscle bioenergetics and physiological parameters of endurance.

At present, there are still no official or semi-official recommendations for the treatment of muscle fatigue. We previously reported that acute phase protein orosomucoid (ORM) can enhance muscle endurance and exert anti-fatigue effect. In attempting to seek anti-fatigue drugs that target ORM, we found macrolide antibiotics, particularly erythromycin, were effective. Erythromycin can significantly prolong the time of mice forced-swimming and treadmill running, increase muscle fatigue index, alleviate fatigue-induced tissue damage, and elevate glycogen content, mitochondria function and ATP level in the muscle. Also, erythromycin increases ORM protein expression in a dose- and time- dependent manner both in vitro and in vivo. Further studies found that erythromycin could increase the activity of ORM promoter and the stability of ORM mRNA, which might both be responsible for the ORM up-regulation. ORM knockdown or knockout could abolish the promoting effect of erythromycin in mice forced-swimming time, muscle fatigue index and glycogen level. Furthermore, those effects were also abolished in mice with C-C motif chemokine receptor 5 (CCR5) antagonist administration or AMPKα2 deficiency. Therefore, erythromycin could enhance muscle glycogen and endurance via up-regulating the level of ORM and activating CCR5-AMPK pathway, indicating it might act as a potential drug to treat muscle fatigue.