Expression of FET-1 related transcripts during chicken embryogenesis suggests a role in muscle development.

The genetic basis of somatic cell identity in avian sex determination is still unknown. FET1, an endogenous retrovirus, has previously been demonstrated to be expressed during gonad development. Here, we report expression of FET1 related transcripts in non-gonadal tissue during chicken development. Both the forward and reverse FET1 related transcripts were seen in various developing muscle tissues. Both the "full-length" and partial FET1 transcripts were expressed; the latter however showed a more ubiquitous expression pattern. Female-specific gonadal expression of both sense and antisense transcripts was also confirmed. An anti-FET1 antibody, however, failed to distinguish between the predicted FET1 protein and other endogenous retroviral proteins expressed at E6.5. Our data suggest a possible role for FET1 related transcripts in sex-specific differences in muscle size and growth rate in the chickens.

Spatial metabolomics, LC-MS and RNA-Seq reveal the effect of red and white muscle on rabbit meat flavor.

Meat quality is a key factor influencing consumer purchasing decisions. Muscle composition consists of various types of myofibers (type I and type IIa, IIb, IIx myofibers), and the relative composition of fiber types has a significant impact on the overall biochemical properties and flavor of fresh meat. However, the relationship between biochemical changes in myofibers and their impact on meat quality remains underexplored. In this study, we compared the differences in meat quality by examining different muscles in rabbits, each containing different muscle fiber types. We focused on the adductor (ADD) and semitendinosus (ST) as our research subjects and investigated skeletal muscle metabolism at the individual myofibers level using Spatial metabolomics. Additionally, we utilized LC-MS and RNA-Seq to explore the molecular mechanisms underlying the metabolic differences between red and white muscle fibers. Our findings demonstrated that variations in myofiber composition significantly influenced meat color, pH, water content, and drip loss. Spatial metabolomics analysis identified 22 unique red and white muscle fingerprint metabolites, while LC-MS analysis revealed 123 differential metabolites, and these differential metabolites were mainly enriched in the pathways of ABC transporters, Biosynthesis of amino acids, glutathione metabolism, and arginine biosynthesis. To further elucidate the molecular mechanism of differential metabolism in ADD and ST, we identified 2248 differentially expressed genes (DEGs) by RNA-Seq and then combined DEGs with DMs for joint analysis. We found that red muscle exhibited higher levels of metabolites such as L-glutamic acid, glutathione, ascorbate, ornithine, oxidized glutathione, gamma-L-glutamyl-L-cysteine, cysteinylglycine, fumaric acid, gamma-aminobutyric acid. Additionally, related metabolic genes such as MGST1, ODC1, MGST3 and PRDX6 were highly expressed in ST muscle. These metabolites and genes were enriched in the glutathione and nicotinamide pathways, and had significant effects on meat color and drip loss. Moreover, red muscle contained more flavor compounds and nutrients, including adenosine monophosphate (AMP), ornithine, citrulline, taurine, acetyl phosphate, L-glutamic acid metabolites, as well as taurine and hypotaurine metabolites. Our results demonstrate that fresh meat with a higher proportion of red muscle fibers exhibited superior meat quality, enhanced flavor, and higher nutrient content. Furthermore, red muscle contains more antioxidant metabolites that can effectively prevent meat oxidation during the production process.

Influence of lipid and metabolite profiles of mitochondrial fraction on pH and color stability of longissimus lumborum muscle with different ultimate beef pH.

This study aimed to explore the differences in the lipidome and mitochondrial fraction metabolome of Nellore cattle meat in different ranges of ultimate pH (pHu) normal (≤5.79), intermediate (5.80 to 6.19) and high (≥ 6.20) after 3- and 21-d postmortem. Instrumental color, myoglobin redox state, oxygen consumption, and metmyoglobin-reducing activity were measured during storage. A total of 472 lipids and 22 mitochondrial fraction metabolites were identified. Beef with high pHu showed positive regulation of ceramides involved in apoptosis and negative regulation of lipid classes related to membrane permeability and stability. In addition, lower carnitine content was noted in high-pHu beef than in normal-pHu beef. Acylcarnitines, phosphatidylinositol, and IMP showed upregulation in beef with intermediate pHu, indicating changes mainly related to energy, purine and pyruvate metabolism. Aging time impacted on the lipid content and metabolites involved in different metabolic pathways. These results provided new insights into beef's mitochondrial fraction lipid and metabolic profile with different pHu. In addition, beef with intermediate pHu differs from beef with high pHu due to changes in energy metabolism.

The importance of including metmyoglobin levels in reflectance-based oxygen consumption measurements.

Reflectance-based oxygen consumption measurement utilizes changes in oxymyoglobin levels between bloomed and vacuum-packaged meat, assuming that oxymyoglobin is converted to deoxymyoglobin. However, the interconversion of oxymyoglobin to deoxymyoglobin depends on the age of the meat and the length of display; hence, oxygen consumption calculations might yield inaccurate interpretations if deoxymyoglobin is not the final form. The objective was to evaluate the effectiveness of determining metmyoglobin levels during oxygen consumption analysis and its relationship to beef color stability. Seven psoas major (color labile) and longissimus (color stable) were displayed in retail for 6 d and evaluated for oxygen consumption on the retail (oxygen exposed) and interior (non­oxygen exposed) surfaces. The retail surface had greater (P < 0.05) metmyoglobin formed during oxygen consumption than the interior surface on d 6 of the display. Furthermore, the psoas major muscle exhibited greater (P < 0.05) metmyoglobin content during oxygen consumption than the longissimus on the retail surface paralleling with the decline in color stability. Therefore, the study indicates that sampling location and including metmyoglobin content in oxygen consumption calculations, along with changes in oxymyoglobin, will better explain meat color stability.

Unveiling the link: exploring muscle oxygen saturation in fibromyalgia and its implications for symptomatology and therapeutic strategies.

Fibromyalgia, characterized as a complex chronic pain syndrome, presents with symptoms of pervasive musculoskeletal pain, significant fatigue, and pronounced sensitivity at specific anatomical sites. Despite extensive research efforts, the origins of fibromyalgia remain enigmatic. This narrative review explores the intricate relationship between muscle oxygen saturation and fibromyalgia, positing that disruptions in the oxygenation processes within muscle tissues markedly influence the symptom profile of this disorder. Muscle oxygen saturation, crucial for muscle function, has been meticulously investigated in fibromyalgia patients through non-invasive techniques such as near-infrared spectroscopy and magnetic resonance imaging. The body of evidence consistently indicates substantial alterations in oxygen utilization within muscle fibers, manifesting as reduced efficiency in oxygen uptake during both rest and physical activity. These anomalies play a significant role in fibromyalgia's symptomatology, especially in terms of chronic pain and severe fatigue, potentially creating conditions that heighten pain sensitivity and accumulate metabolic byproducts. Hypothesized mechanisms for these findings encompass dysfunctions in microcirculation, mitochondrial irregularities, and autonomic nervous system disturbances, all meriting further research. Understanding the dynamics of muscle oxygen saturation in fibromyalgia is of paramount clinical importance, offering the potential for tailored therapeutic approaches to alleviate symptoms and improve the quality of life for sufferers. This investigation not only opens new avenues for innovative research but also fosters hope for more effective treatment strategies and improved outcomes for individuals with fibromyalgia.

Denervation­induced NRG3 aggravates muscle heterotopic ossification via the ErbB4/PI3K/Akt signaling pathway.

Peripheral nerve injury exacerbates progression of muscle heterotopic ossification (HO) and induces changes in expression of local cytokines in muscle tissue. The objective of the present study was to assess the impact of peripheral nerve injury on muscle HO development and the mechanism of cytokine modulation. A mouse model of gastrocnemius muscle HO was established and the sciatic nerve cut to simulate peripheral nerve injury. To evaluate the underlying factors contributing to the exacerbation of muscle HO resulting from denervation, fresh muscle tissue was collected and micro­computed tomography, histochemical staining, RNA­sequencing, reverse transcription­quantitative PCR, Western blot, muscle tissue chip array were performed to analyze the molecular mechanisms. Sciatic nerve injury exacerbated HO in the gastrocnemius muscle of mice. Moreover the osteogenic differentiation of nerve­injured muscle tissue­derived fibro­adipogenic progenitors (FAPs) increased in vitro. The expression of neuregulin 3 (NRG3) was demonstrated to be increased after nerve injury by muscle tissue chip array. Subsequent transcriptome sequencing analysis of muscle tissue revealed an enrichment of the PI3K/Akt pathway following nerve injury and an inhibitor of the PI3K/Akt pathway reduced the osteogenic differentiation of FAPs. Mechanistically, in vitro, peripheral nerve injury increased secretion of NRG3, which, following binding to ErbB4 on the cell surface of FAPs, promoted expression of osteogenesis­associated genes via the PI3K/Akt signaling pathway, thus contributing to osteogenic differentiation of FAPs. In vivo, inhibition of the PI3K/Akt pathway effectively protected against muscle HO induced by peripheral nerve injury in mice. The present study demonstrated that the regulatory roles of NRG3 and the PI3K/Akt pathway in peripheral nerve injury exacerbated muscle HO and highlights a potential therapeutic intervention for treatment of peripheral nerve injury­induced muscle HO.

PTPN1/2 inhibition promotes muscle stem cell differentiation in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a lethal disease caused by mutations in the DMD gene that encodes dystrophin. Dystrophin deficiency also impacts muscle stem cells (MuSCs), resulting in impaired asymmetric stem cell division and myogenic commitment. Using MuSCs from DMD patients and the DMD mouse model mdx, we found that PTPN1 phosphatase expression is up-regulated and STAT3 phosphorylation is concomitantly down-regulated in DMD MuSCs. To restore STAT3-mediated myogenic signaling, we examined the effect of K884, a novel PTPN1/2 inhibitor, on DMD MuSCs. Treatment with K884 enhanced STAT3 phosphorylation and promoted myogenic differentiation of DMD patient-derived MuSCs. In MuSCs from mdx mice, K884 treatment increased the number of asymmetric cell divisions, correlating with enhanced myogenic differentiation. Interestingly, the pro-myogenic effect of K884 is specific to human and murine DMD MuSCs and is absent from control MuSCs. Moreover, PTPN1/2 loss-of-function experiments indicate that the pro-myogenic impact of K884 is mediated mainly through PTPN1. We propose that PTPN1/2 inhibition may serve as a therapeutic strategy to restore the myogenic function of MuSCs in DMD.

Characterization of Age-Dependent Changes in Skeletal Muscle Repair and Regeneration Using a Mouse Model of Acute Muscle Injury.

Acute skeletal muscle injury initiates a process of necrosis, debris clearance, and ultimately tissue regeneration via myogenesis. While skeletal muscle stem cells (MuSCs) are responsible for populating the proliferative myogenic progenitor pool to fuel muscle repair, recruited and resident immune cells have a central role in the regulation of muscle regeneration via the execution of phagocytosis and release of soluble factors that act directly on MuSCs to regulate myogenic differentiation. Therefore, the timing of MuSC proliferation and differentiation is closely linked to the populations and behaviors of immune cells present within skeletal muscle. This has important implications for aging and muscle repair, as systemic changes in immune system function contribute to a decline in muscle regenerative capacity. Here, we present adapted protocols for the isolation of mononuclear cells from skeletal muscles for the quantification of immune cell populations using flow cytometry. We also describe a cardiotoxin skeletal muscle injury protocol and detail the expected outcomes including immune cell infiltration to the injured sites and formation of new myocytes. As immune cell function is substantially influenced by aging, we extend these approaches and outcomes to aged mice.

Temporal variation in p38-mediated regulation of DUX4 in facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is a degenerative muscle disease caused by loss of epigenetic silencing and ectopic reactivation of the embryonic double homeobox protein 4 gene (DUX4) in skeletal muscle. The p38 MAP kinase inhibitor losmapimod is currently being tested in FSHD clinical trials due to the finding that p38 inhibition suppresses DUX4 expression in preclinical models. However, the role of p38 in regulating DUX4 at different myogenic stages has not been investigated. We used genetic and pharmacologic tools in FSHD patient-derived myoblasts/myocytes to explore the temporal role of p38 in differentiation-induced DUX4 expression. Deletion of MAPK14/11 or inhibition of p38α/ß caused a significant reduction in early differentiation-dependent increases in DUX4 and DUX4 target gene expression. However, in MAPK14/11 knockout cells, there remains a differentiation-associated increase in DUX4 and DUX4 target gene expression later in differentiation. Furthermore, pharmacologic inhibition of p38α/ß only partially decreased DUX4 and DUX4 target gene expression in late differentiating myotubes. In xenograft studies, p38α/ß inhibition by losmapimod failed to suppress DUX4 target gene expression in late FSHD xenografts. Our results show that while p38 is critical for DUX4 expression during early myogenesis, later in myogenesis a significant level of DUX4 expression is independent of p38α/ß activity.

Sex dimorphism and tissue specificity of gene expression changes in aging mice.

BACKGROUND: Aging is a complex process that involves all tissues in an organism and shows sex dimorphism. While transcriptional changes in aging have been well characterized, the majority of studies have focused on a single sex and sex differences in gene expression in aging are poorly understood. In this study, we explore sex dimorphism in gene expression in aging mice across three tissues. METHODS: We collected gastrocnemius muscle, liver and white adipose tissue from young (6 months, n = 14) and old (24 months, n = 14) female and male C57BL/6NIA mice and performed RNA-seq. To investigate sex dimorphism in aging, we considered two levels of comparisons: (a) differentially expressed genes between females and males in the old age group and (b) comparisons between females and males across the aging process. We utilized differential expression analysis and gene feature selection to investigate candidate genes. Gene set enrichment analysis was performed to identify candidate molecular pathways. Furthermore, we performed a co-expression network analysis and chose the gene module(s) associated with aging independent of sex or tissue-type. RESULTS: We identified both tissue-specific and tissue-independent genes associated with sex dimorphism in aged mice. Unique differentially expressed genes between old males and females across tissues were mainly enriched for pathways related to specific tissue function. We found similar results when exploring sex differences in the aging process, with the exception that in the liver genes enriched for lipid metabolism and digestive system were identified in both females and males. Combining enriched pathways across analyses, we identified amino acid metabolism, digestive system, and lipid metabolism as the core mechanisms of sex dimorphism in aging. Although the vast majority of age-related genes were sex and tissue specific, we identified 127 hub genes contributing to aging independent of sex and tissue that were enriched for the immune system and signal transduction. CONCLUSIONS: There are clear sex differences in gene expression in aging across liver, muscle and white adipose. Core pathways, including amino acid metabolism, digestive system and lipid metabolism, contribute to sex differences in aging.

Aging is a complex process that occurs differently across tissues, and in men compared to women. However, the mechanisms that cause sex differences are not well understood. Using naturally aging mouse models we compared how specific genes were differently expressed in muscle, liver and fat of old and young female and male mice. We found that the vast majority of genes that were changed with age were only changed in one sex and specific tissues. Overall, sex differences in aging across tissues were related to genes involved in amino acid metabolism, digestive system and lipid metabolism. Notably, lipid metabolism is important in aging females across all tissues. We also identified a set of genes associated with aging independent of sex and tissue-type involved in immune pathways and signaling. These results enhance our understanding of sex differences in aging.

Therapeutic potential of omaveloxolone in counteracting muscle atrophy post-denervation: a multi-omics approach.

BACKGROUND: Muscle atrophy caused by denervation is common in neuromuscular diseases, leading to loss of muscle mass and function. However, a comprehensive understanding of the overall molecular network changes during muscle denervation atrophy is still deficient, hindering the development of effective treatments. METHOD: In this study, a sciatic nerve transection model was employed in male C57BL/6 J mice to induce muscle denervation atrophy. Gastrocnemius muscles were harvested at 3 days, 2 weeks, and 4 weeks post-denervation for transcriptomic and proteomic analysis. An integrative multi-omics approach was utilized to identify key genes essential for disease progression. Targeted proteomics using PRM was then employed to validate the differential expression of central genes. Combine single-nucleus sequencing results to observe the expression levels of PRM-validated genes in different cell types within muscle tissue.Through upstream regulatory analysis, NRF2 was identified as a potential therapeutic target. The therapeutic potential of the NRF2-targeting drug Omaveloxolone was evaluated in the mouse model. RESULT: This research examined the temporal alterations in transcripts and proteins during muscle atrophy subsequent to denervation. A comprehensive analysis identified 54,534 transcripts and 3,218 proteins, of which 23,282 transcripts and 1,852 proteins exhibited statistically significant changes at 3 days, 2 weeks, and 4 weeks post-denervation. Utilizing multi-omics approaches, 30 hubgenes were selected, and PRM validation confirmed significant expression variances in 23 genes. The findings highlighted the involvement of mitochondrial dysfunction, oxidative stress, and metabolic disturbances in the pathogenesis of muscle atrophy, with a pronounced impact on type II muscle fibers, particularly type IIb fibers. The potential therapeutic benefits of Omaveloxolone in mitigating oxidative stress and preserving mitochondrial morphology were confirmed, thereby presenting novel strategies for addressing muscle atrophy induced by denervation. GSEA analysis results show that Autophagy, glutathione metabolism, and PPAR signaling pathways are significantly upregulated, while inflammation-related and neurodegenerative disease-related pathways are significantly inhibited in the Omaveloxolone group.GSR expression and the GSH/GSSG ratio were significantly higher in the Omaveloxolone group compared to the control group, while MuSK expression was significantly lower than in the control group. CONCLUSION: In our study, we revealed the crucial role of oxidative stress, glucose metabolism, and mitochondrial dysfunction in denervation-induced muscle atrophy, identifying NRF2 as a potential therapeutic target. Omaveloxolone was shown to stabilize mitochondrial function, enhance antioxidant capacity, and protect neuromuscular junctions, thereby offering promising therapeutic potential for treating denervation-induced muscle atrophy.

Assessment of Urolithin A effects on muscle endurance, strength, inflammation, oxidative stress, and protein metabolism in male athletes with resistance training: an 8-week randomized, double-blind, placebo-controlled study.

BACKGROUND: This study aimed to investigate the impact of Urolithin A (UA) on muscle endurance, muscle strength, inflammatory levels, oxidative stress, and protein metabolism status in resistance-trained male athletes. METHOD: An 8-week randomized, double-blind, placebo-controlled study was conducted with twenty resistance-trained male athletes. Participants were supplemented with 1 g of UA daily. Muscle strength and muscle endurance measures were assessed, and fasting venous blood samples and morning urine samples were collected to evaluate their oxidative stress levels, inflammatory markers, and protein metabolism status. RESULTS: There were no significant differences observed in terms of dietary energy intake and composition between the two assessments conducted within a 24-hour period. After 8 weeks of UA supplementation, compared to baseline measurements, the UA group exhibited increases in 1RM bench press and squat, although these changes were not statistically significant (Δ = 3.00 ± 0.17 kg, p = 0.051, Δ = 1.35 ± 2.73 kg, p = 0.499). However, significant improvements were noted in Maximum Voluntary Isometric Contraction (MVIC) and repetitions to failure (RTF) performance (Δ = 36.10 ± 0.62 NM, p = 0.000; Δ = 2.00 ± 0.56, p = 0.001). When compared to the placebo group, the UA supplementation for 8 weeks led to an increase in 1RM bench press and squat, although statistical significance was not reached (Δ = 3.50 ± 0.79 kg, p = 0.462; Δ = 2.55 ± 1.36 kg, p = 0.710). Furthermore, the group receiving UA supplementation, compared to the placebo group, showed significant improvements in MVIC and RTF (Δ = 43.50 ± 0.77 NM, p = 0.048; Δ = 2.00 ± 1.22, p = 0.011), indicating that the UA group exhibited superior performance enhancements in these metrics compared to the placebo group. After 8 weeks of UA supplementation, the UA group showed a significant decrease in 3-methylhistidine (3-MH) compared to baseline measurement (Δ=-2.38 ± 1.96 µmol/L, p = 0.049). Additionally, the UA group exhibited a significant increase in C-reactive protein (CRP) compared to baseline (Δ = 0.71 ± 0.21 mg/L, p = 0.001). However, there was no significant changes observed in Interleukin-6 (IL-6) (Δ=-1.00 ± 1.01 pg/mL, p = 0.076), or superoxide dismutase (SOD) (Δ=-0.004 ± 0.72 U/mL, p = 0.996) compared to baseline in the UA group. When compared to the placebo group, there was no significant difference observed in 3-MH in the UA group (Δ=-3.20 ± 0.31 µmol/L, p = 0.36). In terms of inflammation markers, the UA group exhibited a significant decrease in CRP (Δ=-0.79 ± 0.38 mg/L, p = 0.032) compared to the placebo group, whereas there was a decrease in IL-6 without statistical significance (Δ=-1.75 ± 0.45 pg/mL, p = 0.215). Furthermore, the UA group showed a significant decrease in SOD compared to the placebo group (Δ=-4.32 ± 0.90 U/mL, p = 0.041). CONCLUSIONS: After 8 weeks of UA supplementation at 1 g/day, resistance-trained male athletes showed improvements in muscle strength and endurance. Additionally, UA supplementation was also associated with reduced oxidative stress levels and a decrease in inflammation response levels.

[The Structural Features of Skeletal Muscle Titin Aggregates].

Titin is a multidomain protein of striated and smooth muscles of vertebrates. The protein consists of repeating immunoglobulin-like (Ig) and fibronectin-like (FnIII) domains, which are ß-sandwiches with a predominant ß-structure, and also contains disordered regions. In this work, the methods of atomic force microscopy (AFM), X-ray diffraction, and Fourier transform infrared spectroscopy were used to study the morphology and structure of aggregates of rabbit skeletal muscle titin obtained in two different solutions: 0.15 M glycine-KOH, pH 7.0 and 200 mM KCl, 10 mM imidazole, pH 7.0. According to AFM data, skeletal muscle titin formed amorphous aggregates of different morphologies in the above two solutions. Amorphous aggregates of titin formed in a solution containing glycine consisted of much larger particles than aggregates of this protein formed in a solution containing KCl. The "KCl-aggregates" according to AFM data had the form of a "sponge"-like structure, while amorphous "glycine-aggregates" of titin formed "branching" structures. Spectrofluorometry revealed the ability of "glycine-aggregates" of titin to bind to the dye thioflavin T (TT), and X-ray diffraction revealed the presence of one of the elements of the amyloid cross ß-structure, a reflection of ~4.6 Å, in these aggregates. These data indicate that "glycine-aggregates" of titin are amyloid or amyloid-like. No similar structural features were found in "KCl-aggregates" of titin; they also did not show the ability to bind to thioflavin T, indicating the non-amyloid nature of these titin aggregates. Fourier transform infrared spectroscopy revealed differences in the secondary structure of the two types of titin aggregates. The data we obtained demonstrate the features of structural changes during the formation of intermolecular bonds between molecules of the giant titin protein during its aggregation. The data expand the understanding of the process of amyloid protein aggregation.

[Knockout of Hsp70 Genes Modulates Age-Related Transcriptomic Changes in Leg Muscles and Reduces the Locomotion Speed and Lifespan of Drosophila melanogaster].

This study investigated the effect of knockout of six Hsp70 genes (orthologues of the mammalian genes Hspa1a, Hspa1b, Hspa2, and Hspa8) on age-related changes in gene expression in the legs of Drosophila melanogaster, which contain predominantly skeletal muscle bundles. For this, the leg transcriptomic profile was examined in males of the w^(1118) control strain and the Hsp70^(-) strain on the 7th, 23rd and 47th days of life. In w^(1118) flies, an age-related decrease in the locomotion (climbing) speed (a marker of functional state and endurance) was accompanied by a pronounced change in the transcriptomic profile of the leg skeletal muscles, which is conservative in nature. In Hsp70^(-) flies, the median lifespan was shorter and the locomotion speed was significantly lower compared to the control; at the same time, complex changes in the age-related dynamics of the skeletal muscle transcriptome were observed. Mass spectrometry-based quantitative proteomics showed that 47-day-old Hsp70^(-) flies, compared with w^(1118) flies, demonstrated multidirectional changes in the contents of key enzymes of glucose metabolism and fat oxidation (glycolysis, pentose phosphate pathway, Krebs cycle, beta-oxidation, and oxidative phosphorylation). Such dysregulation may be associated with a compensatory increase in the expression of other genes encoding chaperones (small Hsp, Hsp40, 60, and 70), which regulate specific sets of target proteins. Taken together, our data show that knockout of six Hsp70 genes slightly reduced the median lifespan of flies, but significantly reduced the locomotion speed, which may be associated with complex changes in the transcriptome of the leg skeletal muscles and with multidirectional changes in the contents of key enzymes of energy metabolism.

Advancements in Drug Delivery Systems for the Treatment of Sarcopenia: An Updated Overview.

Since sarcopenia is a progressive condition that leads to decreased muscle mass and function, especially in elderly people, it is a public health problem that requires attention from researchers. This review aims to highlight drug delivery systems that have a high and efficient therapeutic potential for sarcopenia. Current as well as future research needs to consider the barriers encountered in the realization of delivery systems, such as the route of administration, the interaction of the systems with the aggressive environment of the human body, the efficient delivery and loading of the systems with therapeutic agents, and the targeted delivery of therapeutic agents into the muscle tissue without creating undesirable adverse effects. Thus, this paper sets the framework of existing drug delivery possibilities for the treatment of sarcopenia, serving as an inception point for future interdisciplinary studies.

Investigating the Causal Effects of Exercise-Induced Genes on Sarcopenia.

Exercise is increasingly recognized as an effective strategy to counteract skeletal muscle aging and conditions such as sarcopenia. However, the specific exercise-induced genes responsible for these protective effects remain unclear. To address this, we conducted an eight-week aerobic exercise regimen on late-middle-aged mice and developed an integrated approach that combines mouse exercise-induced genes with human GWAS datasets to identify causal genes for sarcopenia. This approach led to significant improvements in the skeletal muscle phenotype of the mice and the identification of exercise-induced genes and miRNAs. By constructing a miRNA regulatory network enriched with transcription factors and GWAS signals related to muscle function and traits, we focused on 896 exercise-induced genes. Using human skeletal muscle cis-eQTLs as instrumental variables, 250 of these exercise-induced genes underwent two-sample Mendelian randomization analysis, identifying 40, 68, and 62 causal genes associated with sarcopenia and its clinical indicators-appendicular lean mass (ALM) and hand grip strength (HGS), respectively. Sensitivity analyses and cross-phenotype validation confirmed the robustness of our findings. Consistently across the three outcomes, RXRA, MDM1, RBL2, KCNJ2, and ADHFE1 were identified as risk factors, while NMB, TECPR2, MGAT3, ECHDC2, and GINM1 were identified as protective factors, all with potential as biomarkers for sarcopenia progression. Biological activity and disease association analyses suggested that exercise exerts its anti-sarcopenia effects primarily through the regulation of fatty acid oxidation. Based on available drug-gene interaction data, 21 of the causal genes are druggable, offering potential therapeutic targets. Our findings highlight key genes and molecular pathways potentially responsible for the anti-sarcopenia benefits of exercise, offering insights into future therapeutic strategies that could mimic the safe and mild protective effects of exercise on age-related skeletal muscle degeneration.

Acetylcholine receptor-ß inhibition by interleukin-6 in skeletal muscles contributes to modulating neuromuscular junction during aging.

BACKGROUND: Aging-related strength decline contributes to physiological deterioration and is a good predictor of poor prognosis. However, the mechanisms underlying neuromuscular junction disorders affecting contraction in aging are not well described. We hypothesized that the autocrine effect of interleukin (IL)-6 secreted by skeletal muscle inhibits acetylcholine receptor (AChR) expression, potentially causing aging-related strength decline. Therefore, we investigated IL-6 and AChR ß-subunit (AChR-ß) expression in the muscles and sera of aging C57BL/6J mice and verified the effect of IL-6 on AChR-ß expression. METHODS: Animal experiments, in vitro studies, bioinformatics, gene manipulation, dual luciferase reporter gene assays, and chromatin immunoprecipitation experiments were used to explore the role of the transcription cofactor peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α) and its interacting transcription factors in the IL-6-mediated regulation of AChR-ß expression. RESULTS: IL-6 expression gradually increased during aging, inhibiting AChR-ß expression, which was reversed by tocilizumab. Both tocilizumab and the PGC1α agonist reversed the inhibiting effect of IL-6 expression on AChR-ß. Compared to inhibition of signal transducer and activator of transcription 3, extracellular signal-regulated kinases 1/2 (ERK1/2) inhibition suppressed the effects of IL-6 on AChR-ß and PGC1α. In aging mouse muscles and myotubes, myocyte enhancer factor 2 C (MEF2C) was recruited by PGC1α, which directly binds to the AChR-ß promoter to regulate its expression. CONCLUSIONS: This study verifies AChR-ß regulation by the IL-6/IL-6R-ERK1/2-PGC1α/MEF2C pathway. Hence, evaluating muscle secretion, myokines, and AChRs at an earlier stage to determine pathological progression is important. Moreover, developing intervention strategies for monitoring, maintaining, and improving muscle structure and function is necessary.

Transcriptional changes of genes encoding sarcoplasmic reticulum calcium binding and up-taking proteins in normal and Duchenne muscular dystrophy dogs.

BACKGROUND: Cytosolic calcium overload contributes to muscle degradation in Duchenne muscular dystrophy (DMD). The sarcoplasmic reticulum (SR) is the primary calcium storage organelle in muscle. The sarco-endoplasmic reticulum ATPase (SERCA) pumps cytosolic calcium to the SR during muscle relaxation. Calcium is kept in the SR by calcium-binding proteins. METHODS: Given the importance of the canine DMD model in translational studies, we examined transcriptional changes of SERCA (SERCA1 and SERCA2a), SERCA regulators (phospholamban, sarcolipin, myoregulin, and dwarf open reading frame), and SR calcium-binding proteins (calreticulin, calsequestrin 1, calsequestrin 2, and sarcalumenin) in skeletal muscle (diaphragm and extensor carpi ulnaris) and heart (left ventricle) in normal and affected male dogs by droplet digital PCR before the onset (≤ 2-m-old), at the active stage (8 to 16-m-old), and at the terminal stage (30 to 50-m-old) of the disease. Since many of these proteins are expressed in a fiber type-specific manner, we also evaluated fiber type composition in skeletal muscle. RESULTS: In affected dog skeletal muscle, SERCA and its regulators were down-regulated at the active stage, but calcium-binding proteins (except for calsequestrin 1) were upregulated at the terminal stage. Surprisingly, nominal differences were detected in the heart. We also examined whether there exists sex-biased expression in 8 to 16-m-old dogs. Multiple transcripts were significantly downregulated in the heart and extensor carpi ulnaris muscle of female dogs. In fiber type analysis, we found significantly more type I fiber in the diaphragm of 8 to 16-m-old affected dogs, and significantly more type II fibers in the extensor carpi ulnaris of 30 to 50-m-old affected dogs. However, no difference was detected between male and female dogs. CONCLUSIONS: Our study adds new knowledge to the understanding of muscle calcium regulation in normal and dystrophic canines.

The Role of Non-Coding RNAs in Regulating Cachexia Muscle Atrophy.

Cachexia is a late consequence of various diseases that is characterized by systemic muscle loss, with or without fat loss, leading to significant mortality. Multiple signaling pathways and molecules that increase catabolism, decrease anabolism, and interfere with muscle regeneration are activated. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play vital roles in cachexia muscle atrophy. This review mainly provides the mechanisms of specific ncRNAs to regulate muscle loss during cachexia and discusses the role of ncRNAs in cachectic biomarkers and novel therapeutic strategies that could offer new insights for clinical practice.

The Top 5 Can't-Miss Sport Supplements.

Background/Objectives: Sports supplements have become popular among fitness enthusiasts for enhancing the adaptive response to exercise. This review analyzes five of the most effective ergogenic aids: creatine, beta-alanine, nitrates, caffeine, and protein. Methods: We conducted a narrative review of the literature with a focus on the sport supplements with the most robust evidence for efficacy and safety. Results: Creatine, one of the most studied ergogenic aids, increases phosphocreatine stores in skeletal muscles, improving ATP production during high-intensity exercises like sprinting and weightlifting. Studies show creatine supplementation enhances skeletal muscle mass, strength/power, and muscular endurance. The typical dosage is 3-5 g per day and is safe for long-term use. Beta-alanine, when combined with the amino acid histidine, elevates intramuscular carnosine, which acts as a buffer in skeletal muscles and delays fatigue during high-intensity exercise by neutralizing hydrogen ions. Individuals usually take 2-6 g daily in divided doses to minimize paresthesia. Research shows significant performance improvements in activities lasting 1-4 min. Nitrates, found in beetroot juice, enhance aerobic performance by increasing oxygen delivery to muscles, enhancing endurance, and reducing oxygen cost during exercise. The recommended dosage is approximately 500 milligrams taken 2-3 h before exercise. Caffeine, a central nervous system stimulant, reduces perceived pain while enhancing focus and alertness. Effective doses range from 3 to 6 milligrams per kilogram of body weight, typically consumed an hour before exercise. Protein supplementation supports muscle repair, growth, and recovery, especially after resistance training. The recommended intake for exercise-trained men and women varies depending on their specific goals. Concluions: In summary, creatine, beta-alanine, nitrates, caffeine, and protein are the best ergogenic aids, with strong evidence supporting their efficacy and safety.