bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2024–10–20
38 papers selected by
Anna Vainshtein, Craft Science Inc.



  1. Adv Biol (Weinh). 2024 Oct 16. e2400235
      Sarcopenia is a geriatric condition characterized by a decrease in skeletal muscle mass and function, significantly impacting both quality of life and overall health. Mitochondria are the main sites of energy production within the cell, and also produce reactive oxygen species (ROS), which maintain mitochondrial homeostasis-mitophagy (clearing damaged mitochondria); mitochondrial dynamics, which involve fusion and fission to regulate mitochondrial morphology; mitochondrial biogenesis, which ensures the functionality and homeostasis of mitochondria. Sarcopenia is linked to mitochondrial dysfunction, suggesting that muscle mitochondrial function therapy should be investigated. Extrinsic therapies are extensively examined to identify new treatments for muscular illnesses including sarcopenia. Changes in muscle physiology and lifestyle interventions, such as pharmacological treatments and exercise, can modulate mitochondrial activity in older adults. This PubMed review encompasses the most significant mitophagy and sarcopenia research from the past five years. Animal models, cellular models, and human samples are well covered. The review will inform the development of novel mitochondria-targeted therapies aimed at combating age-related muscle atrophy.
    Keywords:  Aging; mechanism; mitochondrial biogenesis; mitochondrial dynamics; mitophagy; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1002/adbi.202400235
  2. Skelet Muscle. 2024 Oct 14. 14(1): 23
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating and incurable neurodegenerative disease. Accumulating evidence strongly suggests that intrinsic muscle defects exist and contribute to disease progression, including imbalances in whole-body metabolic homeostasis. We have previously reported that tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor inducible 14 (Fn14) are significantly upregulated in skeletal muscle of the SOD1G93A ALS mouse model. While antagonising TWEAK did not impact survival, we did observe positive effects in skeletal muscle. Given that Fn14 has been proposed as the main effector of the TWEAK/Fn14 activity and that Fn14 can act independently from TWEAK in muscle, we suggest that manipulating Fn14 instead of TWEAK in the SOD1G93A ALS mice could lead to differential and potentially improved benefits.
    METHODS: We thus investigated the contribution of Fn14 to disease phenotypes in the SOD1G93A ALS mice. To do so, Fn14 knockout mice (Fn14-/-) were crossed onto the SOD1G93A background to generate SOD1G93A;Fn14-/- mice. Investigations were performed on both unexercised and exercised (rotarod and/or grid test) animals (wild type (WT), Fn14-/-, SOD1G93A and SOD1G93A;Fn14-/-).
    RESULTS: Here, we firstly confirm that the TWEAK/Fn14 pathway is dysregulated in skeletal muscle of SOD1G93A mice. We then show that Fn14-depleted SOD1G93A mice display increased lifespan, myofiber size, neuromuscular junction endplate area as well as altered expression of known molecular effectors of the TWEAK/Fn14 pathway, without an impact on motor function. Importantly, we also observe a complex interaction between exercise (rotarod and grid test), genotype, disease state and sex that influences the overall effects of Fn14 deletion on survival, expression of known molecular effectors of the TWEAK/Fn14 pathway, expression of myosin heavy chain isoforms and myofiber size.
    CONCLUSIONS: Our study provides further insights on the different roles of the TWEAK/Fn14 pathway in pathological skeletal muscle and how they can be influenced by age, disease, sex and exercise. This is particularly relevant in the ALS field, where combinatorial therapies that include exercise regimens are currently being explored. As such, a better understanding and consideration of the interactions between treatments, muscle metabolism, sex and exercise will be of importance in future studies.
    Keywords:  Amyotrophic lateral sclerosis; Exercise; Fn14; Metabolism; Sex; Skeletal muscle; TWEAK
    DOI:  https://doi.org/10.1186/s13395-024-00356-0
  3. bioRxiv. 2024 Oct 08. pii: 2024.09.30.615960. [Epub ahead of print]
      Skeletal muscle regeneration is a multistep process involving the activation, proliferation, differentiation, and fusion of muscle stem cells, known as satellite cells. The fusion of s atellite c ell-derived mononucleated m uscle cells (SCMs) is indispensable for the generation of multinucleated, contractile myofibers during muscle repair. However, the molecular and cellular mechanisms underlying SCM fusion during muscle regeneration remain poorly understood. In this study, we uncovered an essential role for branched actin polymerization in SCM fusion. Using conditional knockouts of the Arp2/3 complex and its actin nucleation-promoting factors, N-WASP and WAVE, we demonstrated that branched actin polymerization is required for the SCM fusion, but not for satellite cell proliferation, differentiation, and migration. We showed that the N-WASP and WAVE complexes have partially redundant functions in regulating SCM fusion. Furthermore, we showed that branched actin polymerization is essential for generating invasive protrusions at the fusogenic synapses in SCMs. Taken together, our study has identified new components of the myoblast fusion machinery in skeletal muscle regeneration and demonstrated a critical role for branched actin-propelled invasive protrusions in this process.
    DOI:  https://doi.org/10.1101/2024.09.30.615960
  4. Int J Mol Sci. 2024 Oct 07. pii: 10773. [Epub ahead of print]25(19):
      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.
    Keywords:  exercise; sarcopenia; skeletal muscle aging; transcriptome; two-sample Mendelian randomization
    DOI:  https://doi.org/10.3390/ijms251910773
  5. J Appl Physiol (1985). 2024 Oct 17.
      Skeletal muscle relies on mitochondria to produce energy and support its metabolic flexibility. The function of the mitochondrial pool is regulated by quality control (MQC) processes. The integrated stress response (ISR), a MQC pathway, is activated in response to various cellular stressors. The transcription factor ATF4, the main effector of the ISR, ameliorates cellular stress by upregulating protective genes, such as CHOP and ATF5. Recent literature has shown that the ISR is activated upon mitochondrial stress, however, whether this includes acute exercise-induced stress is poorly defined. To investigate this, a mouse in situ hindlimb protocol was utilized to acutely stimulate muscles at 0.25, 0.5 and 1 tetanic contraction/per second for 9 mins, followed by a 1-hour recovery period. CAMKII and JNK2 were robustly activated 6-fold immediately following the protocol. ISR activation, denoted as the ratio of phosphorylated to total-eIF2a protein levels, was also elevated following recovery. Downstream, contractile activity induced an increase in the nuclear localization of ATF4. Robust 2-fold increases in the mRNA expression of ATF4 and CHOP were also observed following the recovery period. Changes in ATF4 mRNA were independent of transcriptional activation, as assessed using an ATF4 promoter-reporter plasmid. Instead, mRNA decay assays revealed an increase in ATF4 mRNA stability post-contractile activity, as a result of enhanced stabilization by the RNA binding protein, HuR. Thus, acute contractile activity is sufficient to induce mitochondrial stress and activate the ISR, corresponding to the induction of ATF4 with potential consequences for mitochondrial phenotype adaptations in response to repeated exercise.
    Keywords:  Adaptations; Exercise; Mitochondrial Biogenesis; Skeletal Muscle; eIF2α
    DOI:  https://doi.org/10.1152/japplphysiol.00307.2024
  6. Int J Mol Sci. 2024 Sep 24. pii: 10244. [Epub ahead of print]25(19):
      Alzheimer's disease (AD) causes a decline in skeletal muscle function, which can further exacerbate the cognitive dysfunction of patients with AD. It has been widely established that exercise improves AD brain pathology, but the role of skeletal muscle in AD is still poorly understood. In this study, we investigated the effects of treadmill exercise on the exercise ability of APP/PS1 transgenic AD mice and explored potential gene expression changes in their skeletal muscle. The APP/PS1 mice were subjected to a treadmill exercise for 12 weeks, followed by the Morris water maze and the open field test. After behavioral experiments, the changes in morphology, area, collagen fiber deposition, and ultrastructure of the skeletal muscle were determined; the balance of skeletal muscle protein synthesis and decomposition was analyzed; and changes in gene expression were investigated using RNA-Seq. We found that this exercise strategy can promote the learning and memory abilities of AD mice, reduce their anxiety-like behavior, improve their exercise ability, alleviate skeletal muscle atrophy, and optimize the microstructure. It can also enhance skeletal muscle protein synthesis and decomposition and improve several signaling pathways, such as the JAK-STAT, Wnt, and NOD-like receptors while decreasing calcium, cAMP, cGMP-PKG, and other signaling pathways. Six KEGG enrichment signaling pathways were downregulated and five signaling pathways were upregulated in the AD mice compared with wild-type mice, and these pathways were precisely reversed after the treadmill exercise. The expression of transcription factors such as Fosb and Egr1 in the skeletal muscle of AD mice decreased, followed by a decrease in the regulated target genes Socs1, Srrm4, and Il1b, a trend that was reversed following the exercise intervention. After exercise, AD mice exhibited a similar gene expression to that of wild-type mice, indicating enhanced exercise ability. The potential regulatory pathways and related genes identified in this study provide valuable insights for the clinical management and treatment of AD.
    Keywords:  Alzheimer’s disease; exercise; exercise ability; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms251910244
  7. Elife. 2024 Oct 18. pii: RP93312. [Epub ahead of print]13
      Pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic cancer, is a deadly cancer, often diagnosed late and resistant to current therapies. PDAC patients are frequently affected by cachexia characterized by muscle mass and strength loss (sarcopenia) contributing to patient frailty and poor therapeutic response. This study assesses the mechanisms underlying mitochondrial remodeling in the cachectic skeletal muscle, through an integrative exploration combining functional, morphological, and omics-based evaluation of gastrocnemius muscle from KIC genetically engineered mice developing autochthonous pancreatic tumor and cachexia. Cachectic PDAC KIC mice exhibit severe sarcopenia with loss of muscle mass and strength associated with reduced muscle fiber's size and induction of protein degradation processes. Mitochondria in PDAC atrophied muscles show reduced respiratory capacities and structural alterations, associated with deregulation of oxidative phosphorylation and mitochondrial dynamics pathways. Beyond the metabolic pathways known to be altered in sarcopenic muscle (carbohydrates, proteins, and redox), lipid and nucleic acid metabolisms are also affected. Although the number of mitochondria per cell is not altered, mitochondrial mass shows a twofold decrease and the mitochondrial DNA threefold, suggesting a defect in mitochondrial genome homeostasis. In conclusion, this work provides a framework to guide toward the most relevant targets in the clinic to limit PDAC-induced cachexia.
    Keywords:  cachexia; cancer biology; energy metabolism; mitochondria; mouse; muscle wasting; pancreatic cancer
    DOI:  https://doi.org/10.7554/eLife.93312
  8. Eur J Pharmacol. 2024 Oct 10. pii: S0014-2999(24)00745-3. [Epub ahead of print]984 177055
      IL-6 is an important cytokine involved in metabolic, immunological, and cell-fate responses. It is released upon stimulation by skeletal muscle cells through partially characterized mechanisms. In some cell types, IL-6 has been reported to activate a positive feedback loop involving endocytic vesicles, but evidence is mostly based on transcription and signal transduction mechanisms and is very scarce in muscle cells. Our aim was to directly demonstrate the presence of positive feedback in the ATP-induced release of IL-6 into the supernatant of human skeletal muscle cultures. The total release (production) of IL-6 was reduced for higher volumes of supernatant, when the secreted IL-6 molecules are more diluted, and enhanced when the supernatant volume was lower. In addition, secretion was impaired both by tocilizumab, a blocker of human IL-6 receptors, and by the soluble form of the receptor. The secretion in response to ATP was also inhibited by treatment with the endocytosis inhibitor dynasore, and by disruption of the acidic gradient of the endocytic compartment using different methods (chloroquine, NH4Cl or monensin). IL-6 secretion was also impaired by NED-19, a specific inhibitor of the two pore channels receptor mediating Ca2+ release from the endolysosomal compartment. IL-6 and ATP increased IL-6 mRNA levels, an effect blocked by tocilizumab. Altogether, our results demonstrate that ATP-secreted IL-6 activates a positive loop based on IL-6 receptors, endocytosis, two pore channels and IL-6 transcription. Given the importance of muscle IL-6 as a systemic regulator and as an inflammatory mediator, our study can help to understand muscle pathophysiology.
    Keywords:  ATP; Endocytosis; IL-6; IL-6 receptor; Skeletal muscle; Two pore channels
    DOI:  https://doi.org/10.1016/j.ejphar.2024.177055
  9. EMBO J. 2024 Oct 17.
      Tubular aggregate myopathy (TAM) is a heritable myopathy primarily characterized by progressive muscle weakness, elevated levels of creatine kinase (CK), hypocalcemia, exercise intolerance, and the presence of tubular aggregates (TAs). Here, we generated a knock-in mouse model based on a human gain-of-function mutation which results in a severe, early-onset form of TAM, by inducing a glycine-to-serine point mutation in the ORAI1 pore (Orai1G100S/+ or GS mice). By 8 months of age, GS mice exhibited significant muscle weakness, exercise intolerance, elevated CK levels, hypocalcemia, and robust TA presence. Unexpectedly, constitutive Ca2+ entry in mutant mice was observed in muscle only during early development and was abolished in adult skeletal muscle, partly due to reduced ORAI1 expression. Consistent with proteomic results, significant mitochondrial damage and dysfunction was observed in skeletal muscle of GS mice. Thus, GS mice represent a powerful model for investigation of the pathophysiological mechanisms that underlie key TAM symptoms, as well as those compensatory responses that limit the damaging effects of uncontrolled ORAI1-mediated Ca2+ influx.
    Keywords:  Calcium Signaling; Mitochondria; Muscle Disease; ORAI1; Proteomics
    DOI:  https://doi.org/10.1038/s44318-024-00273-4
  10. Cell Metab. 2024 Oct 11. pii: S1550-4131(24)00374-7. [Epub ahead of print]
      Despite the known metabolic benefits of exercise, an integrated metabolic understanding of exercise is lacking. Here, we use in vivo steady-state isotope-labeled infusions to quantify fuel flux and oxidation during exercise in fasted, fed, and exhausted female mice, revealing several novel findings. Exercise strongly promoted glucose fluxes from liver glycogen, lactate, and glycerol, distinct from humans. Several organs spared glucose, a process that broke down in exhausted mice despite concomitant hypoglycemia. Proteolysis increased markedly, also divergent from humans. Fatty acid oxidation dominated during fasted exercise. Ketone production and oxidation rose rapidly, seemingly driven by a hepatic bottleneck caused by gluconeogenesis-induced cataplerotic stress. Altered fuel consumption was observed in organs not directly involved in muscle contraction, including the pancreas and brown fat. Several futile cycles surprisingly persisted during exercise, despite their energy cost. In sum, we provide a comprehensive, integrated, holistic, and quantitative accounting of metabolism during exercise in an intact organism.
    Keywords:  TCA cycle; circulating metabolites; energy metabolism; exercise; in vivo flux quantification; isotope tracing; skeletal muscle
    DOI:  https://doi.org/10.1016/j.cmet.2024.09.010
  11. Molecules. 2024 Sep 24. pii: 4527. [Epub ahead of print]29(19):
      Understanding exercise metabolism and the relationship with volatile organic compounds (VOCs) holds potential in both health care and sports performance. Exercise metabolism can be investigated using whole body exercise testing (in vivo) or through the culture and subsequent electrical pulse stimulation (EPS) of myotubes (in vitro). This research investigates the novel headspace (HS) analysis of EPS skeletal muscle myotubes. An in vitro system was built to investigate the effect of EPS on the volatile constituents in the HS above EPS skeletal muscle. The C2C12 immortalised cell line was chosen. EPS was applied to the system to induce myotube contraction. The in vitro system was applied to the analysis of VOCs using thermal desorption (TD) sampling. Samples were collected under four conditions: environmental samples (enviro), acellular media HS samples (blank), skeletal muscle myotubes without stimulation HS samples (baseline) and EPS of skeletal muscle myotube HS samples (stim). TD sampling combined with gas-chromatography mass spectrometry (GC-MS) detected two compounds that, after multivariate and univariate statistical analysis, were identified as changing due to EPS (p < 0.05). These compounds were tentatively assigned as 1,4-Dioxane-2,5-dione, 3,6-dimethyl- and 1-pentene. The former is a known lactide and the latter has been reported as a marker of oxidative stress. Further research should focus on improvements to the EPS system, including the use of more relevant cell lines, quantification of myotube contractions, and the application of targeted analysis, metabolic assays and media analysis.
    Keywords:  EPS; VOC; gas chromatography; mass spectrometry; skeletal muscle
    DOI:  https://doi.org/10.3390/molecules29194527
  12. Adv Sci (Weinh). 2024 Oct 16. e2406986
      Little is known about if and how circular RNAs (circRNAs) are involved in skeletal muscle atrophy. Here a conserved circular RNA Damage-specific DNA binding protein 1 (circDdb1), derived from the host gene encoding Damage-specific DNA binding protein 1 (DDB1), as a mechanism of muscle atrophy is identified. circDdb1 expression is markedly increased in a variety of muscle atrophy types in vivo and in vitro, and human aging muscle. Both in vivo and in vitro, ectopic expression of circDdb1 causes muscle atrophy. In contrast, multiple forms of muscle atrophy caused by dexamethasone, tumor necrosis factor-alpha (TNF-α), or angiotensin II (Ang II) in myotube cells, as well as by denervation, angiotensin II, and immobility in mice, are prevented by circDdb1 inhibition. Eukaryotic initiation factor 4A3 (EIF4A3) is identified as a regulator of circDdb1 expression in muscle atrophy, whereas circDdb1 encodes a novel protein, circDdb1-867aa. circDdb1-867aa binds with and increases the phosphorylation level of eukaryotic elongation factor 2 (eEF2) at Thr56 to reduce protein translation and promote muscle atrophy. In summary, these findings establish circDdb1 as a shared regulator of muscle atrophy across multiple diseases and a potential therapeutic target.
    Keywords:  circDdb1; eEF2; muscle aging; muscle atrophy; translation
    DOI:  https://doi.org/10.1002/advs.202406986
  13. Nutrients. 2024 Sep 27. pii: 3271. [Epub ahead of print]16(19):
       BACKGROUND: Sarcopenia is characterized by the progressive loss of skeletal muscle mass, strength, and function, significantly impacting overall health and quality of life in older adults. This narrative review explores emerging targets and potential treatments for sarcopenia, aiming to provide a comprehensive overview of current and prospective interventions.
    METHODS: The review synthesizes current literature on sarcopenia treatment, focusing on recent advancements in muscle regeneration, mitochondrial function, nutritional strategies, and the muscle-microbiome axis. Additionally, pharmacological and lifestyle interventions targeting anabolic resistance and neuromuscular junction integrity are discussed.
    RESULTS: Resistance training and adequate protein intake remain the cornerstone of sarcopenia management. Emerging strategies include targeting muscle regeneration through myosatellite cell activation, signaling pathways, and chronic inflammation control. Gene editing, stem cell therapy, and microRNA modulation show promise in enhancing muscle repair. Addressing mitochondrial dysfunction through interventions aimed at improving biogenesis, ATP production, and reducing oxidative stress is also highlighted. Nutritional strategies such as leucine supplementation and anti-inflammatory nutrients, along with dietary modifications and probiotics targeting the muscle-microbiome interplay, are discussed as potential treatment options. Hydration and muscle-water balance are emphasized as critical in maintaining muscle health in older adults.
    CONCLUSIONS: A combination of resistance training, nutrition, and emerging therapeutic interventions holds potential to significantly improve muscle function and overall health in the aging population. This review provides a detailed exploration of both established and novel approaches for the prevention and management of sarcopenia, highlighting the need for further research to optimize these strategies.
    Keywords:  hydration; inflammaging; mitochondrial dysfunction; muscle health; neuromuscular junction; physical performance; satellite cells
    DOI:  https://doi.org/10.3390/nu16193271
  14. Int J Mol Sci. 2024 Sep 27. pii: 10393. [Epub ahead of print]25(19):
      Macrophages are essential to muscle regeneration, as they regulate inflammation, carry out phagocytosis, and facilitate tissue repair. These cells exhibit phenotypic switching from pro-inflammatory (M1) to anti-inflammatory (M2) states during muscle repair, influencing myoblast proliferation, differentiation, and myofiber formation. In Duchenne Muscular Dystrophy (DMD), asynchronous muscle injuries disrupt the normal temporal stages of regeneration, leading to fibrosis and failed regeneration. Altered macrophage activity is associated with DMD progression and physiopathology. Gaining insight into the intricate relationship between macrophages and muscle cells is crucial for creating effective therapies aimed at treating this muscle disorder. This review explores the dynamic functions of macrophages in muscle regeneration and their implications in DMD.
    Keywords:  Duchenne muscular dystrophy; inflammation; macrophages; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms251910393
  15. Adv Healthc Mater. 2024 Oct 17. e2401826
      Muscle atrophy detrimentally impacts health and exacerbates physical disability, leading to increased mortality. In particular, sarcopenia, aging-related degenerative muscle loss, necessitates urgent remedies. Current approaches for treating muscle atrophy include exercise and nutrition, while drug exploration remains in its early stages. Cell therapy, focusing on satellite cells, faces significant challenge due to poor engraftment, safety issue, and high cost. Cell-free approach using extracellular matrix (ECM) shows a regenerative potential, but a lack of mechanical and adhesive properties hinders prolonged efficacy of ECM therapy. Here, durable muscle ECM (MEM) hydrogels for muscle atrophy by fortifying MEM with adhesive phenolic moieties including catechol and pyrogallol are demonstrated. The resultant phenolic MEM hydrogels exhibit enhanced mechanical and adhesive properties and provide sustained muscle-like microenvironments to address muscle atrophy. No local and systemic toxicities are observed after phenolic MEM injection into tibialis anterior muscle. Notably, these engineered MEM hydrogels, devoid of cells or drugs, induce tissue rejuvenation by promoting muscle protein synthesis and facilitating functional muscle recovery in mouse models of disuse- and age-induced atrophy. This study introduces cell-free, ECM-based therapeutics with translational potential for muscle atrophy by reversing muscle loss and restoring function.
    Keywords:  adhesive muscle extracellular matrix; decellularized muscle; muscle atrophy; phenolic hydrogel; sarcopenia
    DOI:  https://doi.org/10.1002/adhm.202401826
  16. Geriatr Gerontol Int. 2024 Oct 14.
      Sarcopenia is an age-related loss of skeletal muscle mass, strength, and function that causes various health problems. In contrast, late-onset primary myopathies, which occur in the older population, are caused by a variety of factors, including genetic mutations, autoimmune processes, and metabolic abnormalities. Although sarcopenia and primary myopathy are two distinct disease processes, their symptoms can overlap, making differentiation challenging. The diagnostic criteria for sarcopenia have evolved over time, and various criteria have been proposed by expert groups. Late-onset primary muscle diseases such as inclusion body myositis, sporadic late-onset nemaline myopathy, muscular dystrophies, distal myopathies, myofibrillar myopathies, metabolic myopathies, and mitochondrial myopathies share common pathogenic mechanisms with sarcopenia, further complicating the diagnostic process. Appropriate clinical evaluation, including detailed history-taking, physical examination, and diagnostic testing, is essential for accurate diagnosis and management. Treatment approaches, including exercise, nutritional support, and disease-specific therapies, must be tailored to the characteristics of each disease. Despite these differences, sarcopenia and primary myopathies require careful consideration in the clinical setting for proper diagnosis and management. This review outlines the evolution of diagnostic criteria and diagnostic items for sarcopenia, late-onset primary myopathies that should be differentiated from sarcopenia, common pathomechanisms, and diagnostic algorithms to properly differentiate primary myopathies. Geriatr Gerontol Int 2024; ••: ••-••.
    Keywords:  inclusion body myositis; late‐onset primary myopathies; muscular dystrophy; sarcopenia; sporadic late‐onset nemaline myopathy
    DOI:  https://doi.org/10.1111/ggi.15000
  17. Int J Mol Sci. 2024 Sep 25. pii: 10302. [Epub ahead of print]25(19):
      The significance of complex I of the electron transport chain (ETC) in the aging process is widely acknowledged; however, its specific impact on the development of sarcopenia in muscle remains poorly understood. This study elucidated the correlation between complex I inhibition and sarcopenia by conducting a comparative analysis of skeletal muscle gene expression in sarcopenia phenotypes from rats, mice, and humans. Our findings reveal a common mechanistic link across species, particularly highlighting the correlation between the suppression of complex I of ETC activity and dysregulated mitochondrial transcription and translation in sarcopenia phenotypes. Additionally, we observed macrophage dysfunction alongside abnormal metabolic processes within skeletal muscle tissues across all species, implicating their pathogenic role in the onset of sarcopenia. These discoveries underscore the importance of understanding the shared mechanisms associated with complex I of ETC in sarcopenia development. The identified correlations provide valuable insights into potential targets for therapeutic interventions aimed at mitigating the impact of sarcopenia, a condition with substantial implications for aging populations.
    Keywords:  aging; electron transport complex I; macrophage; mitochondria; muscle; sarcopenia; skeletal
    DOI:  https://doi.org/10.3390/ijms251910302
  18. Sci China Life Sci. 2024 Oct 12.
      Intramuscular fat (IMF) is a complex adipose tissue within skeletal muscle, appearing specially tissue heterogeneous, and the factors influencing its formation remain unclear. In conditions such as diabetes, aging, and muscle wasting, IMF was deposited in abnormal locations in skeletal muscle, damaged the normal physiological functions of skeletal muscle. Here, we used Longissimus dorsi muscles from pigs with different IMF contents as samples and adopted a method combining spatial transcriptome (ST) and single-nucleus RNA-seq to identify the spatial heterogeneity of IMF. ST revealed that genes involved in TGF-β signaling pathways were specifically highly enriched in IMF. In lean pigs, IMF autocrine produces more TGF-β2, while in obese pigs, IMF received more endothelial-derived TGF-β1. In vitro experiments have proven that porcine endothelial cells in a simulated high-fat environment released more TGF-β1 than TGF-β2. Moreover, under obesity mice, the addition of TGF-β after muscle injury abolished IMF production and slowed muscle repair, whereas TGF-β inhibition accelerated muscle repair. Our findings demonstrate that the TGF-β pathway specifically regulates these processes, suggesting it as a potential therapeutic target for managing muscle atrophy in obese patients and enhancing muscle repair while reducing IMF deposition.
    Keywords:  TGF-β; intramuscular fat; muscle atrophy; single-nucleus RNA-seq; spatial transcriptome
    DOI:  https://doi.org/10.1007/s11427-024-2696-5
  19. Int J Mol Sci. 2024 Oct 05. pii: 10722. [Epub ahead of print]25(19):
      Human skeletal muscle contains different types of tissues with skeletal muscle fibers (SMFs) and intermuscular adipose tissues (IMATs) as the main components. We maintained human skeletal muscle tissues from 12 study participants under native conditions in vitro for 11 days to investigate the dynamics of macrophages that reside in adjacent IMATs and SMFs simultaneously. The samples were subjected to immunohistochemical analysis for macrophage phenotyping and mitochondrial mass assessment before and after maintenance in vitro. Multiplex protein analysis was used to determine cytokine/chemokine expression in tissue extracts. The results revealed significant correlations between donor age or body mass index (BMI) and distinct phenotypes of resident macrophages in SMFs and IMATs. The dynamics of SMF- and IMAT-resident macrophages differed significantly in vitro and exhibited inverse correlations with chemokine/cytokine expression levels and mitochondrial activity. Moreover, the responses of macrophages to saturated and unsaturated fatty acids (FAs) differed substantially between SMFs and IMATs. These findings showed the functional diversity of phenotypically identical macrophages in adjacent niches. Thus, the currently available macrophage markers cannot capture the functional diversity of human tissue-resident macrophages. The model used in the present study may help elucidate how macrophages affect muscle homeostasis and disease in humans.
    Keywords:  adipocytes; chemokines; cytokines; fatty acids; human; mitochondria; skeletal muscle; tissue model; tissue-resident macrophages
    DOI:  https://doi.org/10.3390/ijms251910722
  20. J Physiol Biochem. 2024 Oct 18.
      High-intensity intermittent training (HIIT) in a normobaric hypoxic environment enhances exercise capacity, possibly by increasing the mitochondrial content in skeletal muscle; however, the molecular mechanisms underlying these adaptations are not well understood. Therefore, we investigated whether HIIT under normobaric hypoxia can enhance the expression of proteins involved in mitochondrial biogenesis and dynamics in rat gastrocnemius muscle. Five-week-old male Wistar rats (n = 24) were randomly assigned to the following four groups: (1) sedentary under normoxia (20.9% O2) (NS), (2) training under normoxia (NT), (3) sedentary under normobaric hypoxia (14.5% O2) (HS), and (4) training under normobaric hypoxia (HT). The training groups in both conditions were engaged in HIIT on a treadmill five to six days per week for nine weeks. From the fourth week of the training period, the group assigned to hypoxic conditions was exposed to normobaric hypoxia. Forty-eight hours after completing the final training session, gastrocnemius muscles were surgically removed, and mitochondrial enzyme activity and mitochondrial biogenesis and dynamics regulatory protein levels were determined. Citrate synthase (CS) activity and mitochondrial oxygen phosphorylation (OXPHOS) subunits in the gastrocnemius muscle in the HT significantly exceeded those in the other three groups. Moreover, the levels of a master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and a mitochondrial fusion-related protein, optic atrophy 1 (OPA1), were significantly increased by HIIT under normobaric hypoxia. Our data indicates that HIIT and normobaric hypoxia increase the expression of mitochondrial biogenesis- and dynamics-related proteins in skeletal muscles.
    Keywords:  Autophagy; Hind limb muscle; Mitochondrial fusion and fission; Mitochondrial synthesis; Moderate hypoxia; Treadmill running
    DOI:  https://doi.org/10.1007/s13105-024-01052-9
  21. Nat Protoc. 2024 Oct 18.
      Skeletal myofibers naturally regenerate after damage; however, impaired muscle function can result in cases when a prominent portion of skeletal muscle mass is lost, for example, following traumatic muscle injury. Volumetric muscle loss can be modeled in mice using a surgical model of muscle ablation to study the pathology of volumetric muscle loss and to test experimental treatments, such as the implantation of acellular scaffolds, which promote de novo myogenesis and angiogenesis. Here we provide step-by-step instructions to perform full-thickness surgical ablation, using biopsy punches, and to remove a large volume of the tibialis anterior muscle of the lower limb in mice. This procedure results in a reduction in muscle mass and limited regeneration capacity; the approach is easy to reproduce and can also be applied to larger animal models. For therapeutic applications, we further explain how to implant bioscaffolds into the ablated muscle site. With adequate training and practice, the surgical procedure can be performed within 30 min.
    DOI:  https://doi.org/10.1038/s41596-024-01059-y
  22. Cells. 2024 Sep 27. pii: 1620. [Epub ahead of print]13(19):
      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.
    Keywords:  cachexia; circRNAs; lncRNAs; microRNAs; muscle atrophy; non-coding RNAs
    DOI:  https://doi.org/10.3390/cells13191620
  23. Mol Cell Biol. 2024 Oct 17. 1-13
      Myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by a CTG triplet repeat expansion within the 3' untranslated region of the DMPK gene. Expression of the expanded allele generates RNA containing long tracts of CUG repeats (CUGexp RNA) that form hairpin structures and accumulate in nuclear RNA foci; however, the factors that control DMPK expression and the formation of CUGexp RNA foci remain largely unknown. We performed an unbiased small molecule screen in an immortalized human DM1 skeletal muscle myoblast cell line and identified HSP90 as a modifier of endogenous RNA foci. Small molecule inhibition of HSP90 leads to enhancement of RNA foci and upregulation of DMPK mRNA levels. Knockdown and overexpression of HSP90 in undifferentiated DM1 myoblasts validated the impact of HSP90 with upregulation and downregulation of DMPK mRNA, respectively. Furthermore, we identified p-STAT3 as a downstream mediator of HSP90 impacting levels of DMPK mRNA and RNA foci. Interestingly, differentiated cells exhibited an opposite effect of HSP90 inhibition displaying downregulation of DMPK mRNA through a mechanism independent of p-STAT3 involvement. This study has revealed a novel mediator for DMPK mRNA and foci regulation in DM1 cells with the potential to identify targets for future therapeutic intervention.
    Keywords:  HSP90; Myotonic dystrophy; RNA foci; small molecule screening
    DOI:  https://doi.org/10.1080/10985549.2024.2408025
  24. J Physiol. 2024 Oct 14.
      
    Keywords:  disordered relaxed state; myosin heavy chain; nemaline myopathy; super relaxed state
    DOI:  https://doi.org/10.1113/JP287483
  25. Acta Physiol (Oxf). 2024 Oct 18. e14243
       AIM: Duchenne muscular dystrophy is a progressive muscle-wasting disease caused by mutations in the dystrophin gene. Despite progress in dystrophin-targeted gene therapies, it is still a fatal disease requiring novel therapeutics that can be used synergistically or alternatively to emerging gene therapy. Defective autophagy and disorganized microtubule networks contribute to dystrophic pathogenesis, yet the mechanisms by which microtubule alterations regulate autophagy remain elusive. The present study was designed to uncover possible mechanisms underpinning the role of microtubules in regulating autophagy in dystrophic mice.
    METHODS: Mdx mice were also supplemented with Tubastatin A, a pharmacological inhibitor of histone deacetylase 6, and pathophysiology was assessed. Mdx mice with a genetic deletion of the Nox-2 scaffolding subunit p47phox were used to assess redox dependence on tubulin acetylation.
    RESULTS: Our data show decreased acetylation of α-tubulin with enhanced histone deacetylase 6 expression. Tubastatin A increases tubulin acetylation and Q-SNARE complex formation but does not alter microtubule organization or density, indicating improved autophagosome-lysosome fusion. Tubastatin A increases the acetylation of peroxiredoxin and protects it from hyper-oxidation, hence modulating intracellular redox status in mdx mice. Tubastatin A reduces muscle damage and enhances force production. Genetic down regulation of Nox2 activity in the mdx mice promotes autophagosome maturation but not autolysosome formation.
    CONCLUSION: Our data highlight that autophagy is differentially regulated by redox and acetylation in mdx mice. By improving autophagy through promoting tubulin acetylation, Tubastatin A decreases the dystrophic phenotype and improves muscle function, suggesting a great potential for clinical translation and treating dystrophic patients.
    Keywords:  Duchenne muscular dystrophy; acetylation; autolysosome; autophagy; microtubule; redox
    DOI:  https://doi.org/10.1111/apha.14243
  26. bioRxiv. 2024 Oct 09. pii: 2024.08.11.606848. [Epub ahead of print]
      A majority of human genes produce non-protein-coding RNA (ncRNA), and some have roles in development and disease. Neither ncRNA nor human skeletal muscle is ideally studied using short-read sequencing, so we used a customised RNA pipeline and network modelling to study cell-type specific ncRNA responses during muscle growth at scale. We completed five human resistance-training studies (n=144 subjects), identifying 61% who successfully accrued muscle-mass. We produced 288 transcriptome-wide profiles and found 110 ncRNAs linked to muscle growth in vivo, while a transcriptome-driven network model demonstrated interactions via a number of discrete functional pathways and single-cell types. This analysis included established hypertrophy-related ncRNAs, including CYTOR - which was leukocyte-associated (FDR = 4.9 x10 -7 ). Novel hypertrophy-linked ncRNAs included PPP1CB-DT (myofibril assembly genes, FDR = 8.15 x 10 -8 ), and EEF1A1P24 and TMSB4XP8 (vascular remodelling and angiogenesis genes, FDR = 2.77 x 10 -5 ). We also discovered that hypertrophy lncRNA MYREM shows a specific myonuclear expression pattern in vivo . Our multi-layered analyses established that single-cell-associated ncRNA are identifiable from bulk muscle transcriptomic data and that hypertrophy-linked ncRNA genes mediate their association with muscle growth via multiple cell types and a set of interacting pathways.
    One Sentence Summary: We used an optimised transcriptomic strategy to identify a set of ncRNA genes regulated during skeletal muscle hypertrophy in one hundred and forty-four people, with network modelling and spatial imaging providing biological context.
    DOI:  https://doi.org/10.1101/2024.08.11.606848
  27. Sci Rep. 2024 10 16. 14(1): 24279
      Amyotrophic lateral sclerosis (ALS) progressively impairs motor neurons, leading to muscle weakness and loss of voluntary muscle control. This study compared the effects of SOD1 mutation on masticatory and limb muscles from disease onset to death in ALS model mice. Notably, limb muscles begin to atrophy soon after ALS-like phenotype appear, whereas masticatory muscles maintain their volume and function in later stages. Our analysis showed that, unlike limb muscles, masticatory muscles retain their normal structure and cell makeup throughout most of the disease course. We found an increase in the number of muscle satellite cells (SCs), which are essential for muscle repair, in masticatory muscles. In addition, we observed no reduction in the number of muscle nuclei and no muscle fibre-type switching in masticatory muscles. This indicates that masticatory muscles have a higher resistance to ALS-related damage than limb muscles, likely because of differences in cell composition and repair mechanisms. Understanding why masticatory muscles are less affected by ALS could lead to the development of new treatments. This study highlights the importance of studying different muscle groups in ALS to clarify disease aetiology and mechanisms.
    Keywords:  Amyotrophic lateral sclerosis; Gastrocnemius muscle; Masseter muscles; Satellite cells; Voluntary muscle control
    DOI:  https://doi.org/10.1038/s41598-024-74669-x
  28. J Mol Endocrinol. 2024 Oct 01. pii: JME-24-0033. [Epub ahead of print]
      Contrary to the popular perception that the bone is merely a structural organ, decades of research have established its functional importance in whole-body metabolism. Osteocytes, which comprise >80% of all bone cells, were also initially thought to be terminally differentiated dormant cells lacking metabolic functions. However, new research is increasingly providing evidence that osteocytes not only play a role in the structural integrity of the bone, but also have secretory functions which regulate other bone cells as well as other organs including skeletal muscle - the structural-mechanical neighbor of the bone - via paracrine, and endocrine pathways. However, the publicly available preclinical and clinical data pertaining to the factors secreted by osteocytes and their functions in the musculoskeletal system largely fail to reach a consensus. This review is thus aimed to objectively collate all information available in the public domain for efficient access by researchers in the field. We strongly believe that this review will help researchers in an unbiased design of therapeutic strategies for musculoskeletal disorders.
    DOI:  https://doi.org/10.1530/JME-24-0033
  29. Mol Biol Rep. 2024 Oct 17. 51(1): 1062
       BACKGROUND: One of the probable causes of statin myotoxicity is an imbalance between protein synthesis and degradation. These processes are regulated by the PI3K/Akt/mTOR pathway and the ubiquitin‒proteasome system (UPS). The aim of this study was to assess whether the effects of atorvastatin on PI3K/Akt/mTOR pathway downstream proteins, the FoxO3a transcription factor and the UPS genes, i.e., MuRF-1 and MAFbx, depend on muscle fibre type.
    METHODS AND RESULTS: Atorvastatin (50 mg/kg) was administered to Wistar rats. The levels of selected PI3K/Akt/mTOR pathway proteins were assayed via Western blotting, whereas MuRF-1, MAFbx and FoxO3a mRNA levels were measured using reverse transcription quantitative polymerase chain reaction (RT‒qPCR). Gomöri trichrome staining was performed to assess skeletal muscle pathology. A decrease in the P-Akt/Akt ratio was observed in the gastrocnemius muscle (MG), whereas an increase in the P-Akt/Akt ratio was observed in the soleus muscle (SOL). FoxO3a gene expression increased in the SOL and extensor digitorum longus (EDL) muscles. MuRF-1 gene expression increased in the MG, and MAFbx expression increased in the EDL. No histopathological changes were observed in any of the tested muscles.
    CONCLUSIONS: In the absence of overt muscle damage, atorvastatin decreased the P-Akt/Akt ratio in the MG, indicating an increase in inactive Akt. Consistent with the decrease in Akt activation, rpS6 phosphorylation decreased. In SOL, atorvastatin increased the P-Akt/Akt ratio, indicating Akt activation. P-FoxO3a and the P-FoxO3a/FoxO3a ratio increased, suggesting that FoxO3a inactivation occurred. Moreover, in the SOL, atorvastatin did not affect the expression of atrophy-related genes. These findings indicate that atorvastatin has no adverse effect on the Akt pathway in the SOL. Our results showed that the effects of atorvastatin on the Akt signalling pathway and atrophy-related gene expression depend on muscle type.
    Keywords:  Akt pathway; Atorvastatin; Atrophy-related genes; Skeletal muscle fibres
    DOI:  https://doi.org/10.1007/s11033-024-10005-w
  30. Ageing Res Rev. 2024 Oct 10. pii: S1568-1637(24)00348-9. [Epub ahead of print]101 102530
      Human aging is characterized by a gradual decline in physiological functions and an increased susceptibility to various diseases. The complex mechanisms underlying human aging are still not fully elucidated. Single-cell sequencing (SCS) technologies have revolutionized aging research by providing unprecedented resolution and detailed insights into cellular diversity and dynamics. In this review, we discuss the application of various SCS technologies in human aging research, encompassing single-cell, genomics, transcriptomics, epigenomics, and proteomics. We also discuss the combination of multiple omics layers within single cells and the integration of SCS technologies with advanced methodologies like spatial transcriptomics and mass spectrometry. These approaches have been essential in identifying aging biomarkers, elucidating signaling pathways associated with aging, discovering novel aging cell subpopulations, uncovering tissue-specific aging characteristics, and investigating aging-related diseases. Furthermore, we provide an overview of aging-related databases that offer valuable resources for enhancing our understanding of the human aging process.
    Keywords:  Aging-related diseases; Biomarkers; Human aging; Single-cell multi-omics; Single-cell sequencing
    DOI:  https://doi.org/10.1016/j.arr.2024.102530
  31. Autophagy. 2024 Oct 14. 1-3
      Mitophagy, the selective autophagic clearance of damaged mitochondria, is considered vital for maintaining mitochondrial quality and cellular homeostasis; however, its molecular mechanisms, particularly under basal conditions, and its role in cellular physiology remain poorly characterized. We recently demonstrated that basal mitophagy is a key feature of primary human cells and is downregulated by immortalization, suggesting its dependence on the primary cell state. Mechanistically, we demonstrated that the PINK1-PRKN-SQSTM1 pathway regulates basal mitophagy, with SQSTM1 sensing superoxide-enriched mitochondria through its redox-sensitive cysteine residues, which mediate SQSTM1 oligomerization and mitophagy activation. We developed STOCK1N-57534, a small molecule that targets and promotes this SQSTM1 activation mechanism. Treatment with STOCK1N-57534 reactivates mitophagy downregulated in senescent and naturally aged donor-derived primary cells, improving cellular senescence(-like) phenotypes. Our findings highlight that basal mitophagy is protective against cellular senescence and aging, positioning its pharmacological reactivation as a promising anti-aging strategy.Abbreviation: IR: ionizing radiation; ROS: reactive oxygen species; SARs: selective autophagy receptors.
    Keywords:  Aging; SQSTM1/p62; autophagy; mitochondria; mitophagy; senescence
    DOI:  https://doi.org/10.1080/15548627.2024.2414461
  32. Bio Protoc. 2024 Oct 05. 14(19): e5076
      The neuromuscular junction (NMJ) is an interface between motor neurons and skeletal muscle fibers, facilitating the transmission of signals that initiate muscle contraction. Its pivotal role lies in ensuring efficient communication between the nervous system and muscles, allowing for precise and coordinated movements essential for everyday activities and overall motor function. To provide insights into neuromuscular disease and development, understanding the physiology of NMJ is essential. We target acetylcholine receptors (AChR) by immunofluorescence assay (IFA) with α-bungarotoxin (BTX; snake venom neurotoxins binding to AChR) to visualize and quantify the NMJ. Changes in AChR distribution or structure can indicate alterations in receptor density, which may be associated with neuromuscular disorders or conditions that affect synaptic transmission. This protocol provides the methodology for isolating and longitudinally sectioning gastrocnemius muscle for AChR-targeted IFA for confocal microscopy and performing quantitative analysis of NMJs. Key features • Visualizes and quantifies NMJs using α-bungarotoxin. • Utilizes high-resolution confocal microscopy for detailed imaging.
    Keywords:  Acetylcholine receptor; Immunofluorescence assay; Neuromuscular junction; α-bungarotoxin
    DOI:  https://doi.org/10.21769/BioProtoc.5076
  33. Mol Ther Nucleic Acids. 2024 Dec 10. 35(4): 102320
      Gene replacement therapies primarily rely on adeno-associated virus (AAV) vectors for transgene expression. However, episomal expression can decline over time due to vector loss or epigenetic silencing. CRISPR-based integration methods offer promise for long-term transgene insertion. While the development of transgene integration methods has made substantial progress, identifying optimal insertion loci remains challenging. Skeletal muscle is a promising tissue for gene replacement owing to low invasiveness of intramuscular injections, relative proportion of body mass, the multinucleated nature of muscle, and the potential for reduced adverse effects. Leveraging endogenous promoters in skeletal muscle, we evaluated two highly expressing loci using homology-independent targeted integration (HITI) to integrate reporter or therapeutic genes in mouse myoblasts and skeletal muscle tissue. We hijacked the muscle creatine kinase (Ckm) and myoglobin (Mb) promoters by co-delivering CRISPR-Cas9 and a donor plasmid with promoterless constructs encoding green fluorescent protein (GFP) or human Factor IX (hFIX). Additionally, we deeply profiled our genome and transcriptome outcomes from targeted integration and evaluated the safety of the proposed sites. This study introduces a proof-of-concept technology for achieving high-level therapeutic gene expression in skeletal muscle, with potential applications in targeted integration-based medicine and synthetic biology.
    Keywords:  CRISPR; MT: RNA/DNA Editing; endogenous-promoter; gene editing; homology-independent targeted integration (HITI); integration; muscle; muscle-specific promoters; overexpression; sequencing
    DOI:  https://doi.org/10.1016/j.omtn.2024.102320
  34. Aging (Albany NY). 2024 Oct 16. 16
    Yu-Xuan Lyu, Qiang Fu, Dominika Wilczok, Kejun Ying, Aaron King, Adam Antebi, Aleksandar Vojta, Alexandra Stolzing, Alexey Moskalev, Anastasia Georgievskaya, Andrea B Maier, Andrea Olsen, Anja Groth, Anna Katharina Simon, Anne Brunet, Aisyah Jamil, Anton Kulaga, Asif Bhatti, Benjamin Yaden, Bente Klarlund Pedersen, Björn Schumacher, Boris Djordjevic, Brian Kennedy, Chieh Chen, Christine Yuan Huang, Christoph U Correll, Coleen T Murphy, Collin Y Ewald, Danica Chen, Dario Riccardo Valenzano, Dariusz Sołdacki, David Erritzoe, David Meyer, David A Sinclair, Eduardo Nunes Chini, Emma C Teeling, Eric Morgen, Eric Verdin, Erik Vernet, Estefano Pinilla, Evandro F Fang, Evelyne Bischof, Evi M Mercken, Fabian Finger, Folkert Kuipers, Frank W Pun, Gabor Gyülveszi, Gabriele Civiletto, Garri Zmudze, Gil Blander, Harold A Pincus, Joshua McClure, James L Kirkland, James Peyer, Jamie N Justice, Jan Vijg, Jennifer R Gruhn, Jerry McLaughlin, Joan Mannick, João Passos, Joseph A Baur, Joe Betts-LaCroix, John M Sedivy, John R Speakman, Jordan Shlain, Julia von Maltzahn, Katrin I Andreasson, Kelsey Moody, Konstantinos Palikaras, Kristen Fortney, Laura J Niedernhofer, Lene Juel Rasmussen, Liesbeth M Veenhoff, Lisa Melton, Luigi Ferrucci, Marco Quarta, Maria Koval, Maria Marinova, Mark Hamalainen, Maximilian Unfried, Michael S Ringel, Milos Filipovic, Mourad Topors, Natalia Mitin, Nawal Roy, Nika Pintar, Nir Barzilai, Paolo Binetti, Parminder Singh, Paul Kohlhaas, Paul D Robbins, Paul Rubin, Peter O Fedichev, Petrina Kamya, Pura Muñoz-Canoves, Rafael de Cabo, Richard G A Faragher, Rob Konrad, Roberto Ripa, Robin Mansukhani, Sabrina Büttner, Sara A Wickström, Sebastian Brunemeier, Sergey Jakimov, Shan Luo, Sharon Rosenzweig-Lipson, Shih-Yin Tsai, Stefanie Dimmeler, Thomas A Rando, Tim R Peterson, Tina Woods, Tony Wyss-Coray, Toren Finkel, Tzipora Strauss, Vadim N Gladyshev, Valter D Longo, Varun B Dwaraka, Vera Gorbunova, Victoria A Acosta-Rodríguez, Vincenzo Sorrentino, Vittorio Sebastiano, Wenbin Li, Yousin Suh, Alex Zhavoronkov, Morten Scheibye-Knudsen, Daniela Bakula.
      The recent unprecedented progress in ageing research and drug discovery brings together fundamental research and clinical applications to advance the goal of promoting healthy longevity in the human population. We, from the gathering at the Aging Research and Drug Discovery Meeting in 2023, summarised the latest developments in healthspan biotechnology, with a particular emphasis on artificial intelligence (AI), biomarkers and clocks, geroscience, and clinical trials and interventions for healthy longevity. Moreover, we provide an overview of academic research and the biotech industry focused on targeting ageing as the root of age-related diseases to combat multimorbidity and extend healthspan. We propose that the integration of generative AI, cutting-edge biological technology, and longevity medicine is essential for extending the productive and healthy human lifespan.
    Keywords:  artificial intelligence; biotechnology; healthy longevity
    DOI:  https://doi.org/10.18632/aging.206135
  35. Brain. 2024 Oct 14. pii: awae323. [Epub ahead of print]
      Muscle diseases cover a diverse group of disorders that in most cases are hereditary. The rarity of the individual muscle diseases provides a challenge for researchers when wanting to establish natural history of the conditions and when trying to develop diagnostic tools, therapies, and outcome measures to evaluate disease progression. With emerging molecular therapies in many genetic muscle diseases, as well as biological therapies for the immune-mediated ones, biological biomarkers play an important role in both drug development and evaluation. In this review, we focus on the role of biological biomarkers in muscle diseases and discuss their utility as surrogate endpoints in therapeutic trials. We categorise these as either 1) disease unspecific markers, 2) markers of specific pathways that may be used for more than one disease or 3) disease-specific markers. We also propose that evaluation of specific therapeutic interventions benefits from biological markers that match the intervention.
    Keywords:  FSHD; biomarkers; muscle diseases; trial endpoints
    DOI:  https://doi.org/10.1093/brain/awae323
  36. Dokl Biochem Biophys. 2024 Oct 11.
      Activation of the transcription factors FoxO3a and NF-κB is necessary for muscle atrophy, which occurs during cancer cachexia and detraining. It is not known how high-intensity interval training (HIIT) and detraining affect activation of these pathways. Two-month-old male Sprague-Dawley rats were assigned to sedentary control (SC) (n = 6) and HIIT (HIIT) (n = 18) groups. The HIIT group was divided into three subgroups: HIIT (n = 6), HIIT + 7-day detraining (n = 6), and HIIT + 14-day detraining (n = 6). The expression of FoxO3a, NF-κB, MuRF1, and PGC-1α in the soleus muscle was examined by RT-PCR using CYBR Green. The 2-Ct, Livak method was used to calculate the changes in data expression. The soleus muscle mass increased after HIIT (35.10%) and decreased after 7- and 14-day of detraining (15 and 21%, respectively). The mRNA expression levels of NF-κB, MuRF1, and PGC1α in the soleus muscle were upregulated, and FoxO3a levels were significantly lower in the HIIT group compare to the SC group (p = 0.001). Taken together, the activity of the FoxO3a/MuRF1 pathway, but not NF-κB /MuRF1, can promote atrophy due to detraining, and MuRF1 is not always a good marker of atrophy.
    Keywords:  FoxO3a; MuRF1; NF-κB; PGC1α; detraining; high intensity interval training
    DOI:  https://doi.org/10.1134/S1607672924600817