bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2023–05–28
thirty papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Exercise metabolism and adaptation in skeletal muscle.
  2. The EDA2R-NIK Axis Promotes Muscle Atrophy and Cancer Cachexia.
  3. Duchenne muscular dystrophy disease severity impacts skeletal muscle progenitor cells systemic delivery.
  4. Slo1 deficiency impaired skeletal muscle regeneration and slow-twitch fibre formation.
  5. Physical exercise attenuates age-related muscle atrophy and exhibits anti-ageing effects via the adiponectin receptor 1 signalling.
  6. The gut-muscle axis shapes exercise performance.
  7. Platelet-derived chemokines promote skeletal muscle regeneration by guiding neutrophil recruitment to injured muscles.
  8. Decreased insulin-like growth factor-1 expression in response to mechanical loading is associated with skeletal muscle anabolic resistance in cancer cachexia.
  9. Physical activity impacts resting skeletal muscle myosin conformation and lowers its ATP consumption.
  10. Up- and Downregulated Genes after Long-Term Muscle Atrophy Induced by Denervation in Mice Detected Using RNA-Seq.
  11. Cancer cachexia: molecular mechanisms and treatment strategies.
  12. Mitochondrial transplantation as a possible therapeutic option for sarcopenia.
  13. Loss of the matrix metalloproteinase-10 causes premature features of aging in satellite cells.
  14. LPGAT1/LPLAT7 regulates acyl chain profiles at the sn-1 position of phospholipids in murine skeletal muscles.
  15. miR-136-5p/FZD4 axis is critical for Wnt signaling-mediated myogenesis and skeletal muscle regeneration.
  16. Inhibitory SMAD6 interferes with BMP dependent generation of muscle progenitor cells and perturbs proximodistal pattern of murine limb muscles.
  17. Non-canonical telomere protection role of FOXO3a of human skeletal muscle cells regulated by the TRF2-redox axis.
  18. Activation of skeletal muscle is controlled by a dual-filament mechano-sensing mechanism.
  19. Skeletal muscle overexpression of sAnk1.5 in transgenic mice does not predispose to type 2 diabetes.
  20. Decoding the transcriptome of muscular dystrophy due to Ptrf deficiency using single-nucleus RNA sequencing.
  21. A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy.
  22. Small molecule drugs to improve sarcomere function in those with acquired and inherited myopathies.
  23. Myogenesis in C2C12 Cells Requires Phosphorylation of ATF6α by p38 MAPK.
  24. Simple and efficient differentiation of human iPSCs into contractible skeletal muscles for muscular disease modeling.
  25. Muscular Sestrins: Roles in Exercise Physiology and Stress Resistance.
  26. Accounting Gut Microbiota as the Mediator of Beneficial Effects of Dietary (Poly)phenols on Skeletal Muscle in Aging.
  27. AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin-dependent cell migration.
  28. Effects of energy drinks on myogenic differentiation of murine C2C12 myoblasts.
  29. Brown adipose tissue and aging: A potential role for exercise.
  30. Single-cell analysis reveals the lncRNA-MEG3/miRNA-133a-3p/PRRT2 axis regulates skeletal muscle regeneration and myogenesis.
  1. Nat Rev Mol Cell Biol. 2023 May 24.
    Exercise metabolism and adaptation in skeletal muscle.
    Jonathon A B Smith, Kevin A Murach, Kenneth A Dyar, Juleen R Zierath.
      Viewing metabolism through the lens of exercise biology has proven an accessible and practical strategy to gain new insights into local and systemic metabolic regulation. Recent methodological developments have advanced understanding of the central role of skeletal muscle in many exercise-associated health benefits and have uncovered the molecular underpinnings driving adaptive responses to training regimens. In this Review, we provide a contemporary view of the metabolic flexibility and functional plasticity of skeletal muscle in response to exercise. First, we provide background on the macrostructure and ultrastructure of skeletal muscle fibres, highlighting the current understanding of sarcomeric networks and mitochondrial subpopulations. Next, we discuss acute exercise skeletal muscle metabolism and the signalling, transcriptional and epigenetic regulation of adaptations to exercise training. We address knowledge gaps throughout and propose future directions for the field. This Review contextualizes recent research of skeletal muscle exercise metabolism, framing further advances and translation into practice.
    DOI:  https://doi.org/10.1038/s41580-023-00606-x
  2. Cancer Discov. 2023 May 26. OF1
    The EDA2R-NIK Axis Promotes Muscle Atrophy and Cancer Cachexia.
      Activation of EDA2R signaling promotes the atrophy of skeletal muscle in cancer through NIK activity.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-079
  3. Front Physiol. 2023 ;14 1190524
    Duchenne muscular dystrophy disease severity impacts skeletal muscle progenitor cells systemic delivery.
    Kholoud K Saleh, Corey Switzler, Michael R Hicks, Lily Gane, Devin E Gibbs, April D Pyle.
      Duchenne muscular dystrophy (DMD) is caused by an out-of-frame mutation in the DMD gene that results in the absence of a functional dystrophin protein, leading to a devastating progressive lethal muscle-wasting disease. Muscle stem cell-based therapy is a promising avenue for improving muscle regeneration. However, despite the efforts to deliver the optimal cell population to multiple muscles most efforts have failed. Here we describe a detailed optimized method of for the delivery of human skeletal muscle progenitor cells (SMPCs) to multiple hindlimb muscles in healthy, dystrophic and severely dystrophic mouse models. We show that systemic delivery is inefficient and is affected by the microenvironment. We found that significantly less human SMPCs were detected in healthy gastrocnemius muscle cross-sections, compared to both dystrophic and severely dystrophic gastrocnemius muscle. Human SMPCs were found to be detected inside blood vessels distinctly in healthy, dystrophic and severely dystrophic muscles, with prominent clotting identified in severely dystrophic muscles after intra arterial (IA) systemic cell delivery. We propose that muscle microenvironment and the severity of muscular dystrophy to an extent impacts the systemic delivery of SMPCs and that overall systemic stem cell delivery is not currently efficient or safe to be used in cell based therapies for DMD. This work extends our understanding of the severe nature of DMD, which should be taken into account when considering stem cell-based systemic delivery platforms.
    Keywords:  duchenne muscular dystrophy; intra-arterial cell delivery; skeletal muscle; skeletal muscle progenitor cells; systemic delivery
    DOI:  https://doi.org/10.3389/fphys.2023.1190524
  4. J Cachexia Sarcopenia Muscle. 2023 May 22.
    Slo1 deficiency impaired skeletal muscle regeneration and slow-twitch fibre formation.
    Chao Xia, Yonghui Wang, Tianyuan Jiang, Yan Hu, Yang Chen, Xinrun Ma, Xuemei Zhang, Yanhong Gao.
       BACKGROUND: It has been observed that Slo1 knockout mice have reduced motor function, and people with certain Slo1 mutations have movement problems, but there is no answer whether the movement disorder is caused by the loss of Slo1 in the nervous system, or skeletal muscle, or both. Here, to ascertain in which tissues Slo1 functions to regulate motor function and offer deeper insight in treating related movement disorder, we generated skeletal muscle-specific Slo1 knockout mice, studied the functional changes in Slo1-deficient skeletal muscle and explored the underlying mechanism.
    METHODS: We used skeletal muscle-specific Slo1 knockout mice (Myf5-Cre; Slo1flox/flox mice, called CKO) as in vivo models to examine the role of Slo1 in muscle growth and muscle regeneration. The forelimb grip strength test was used to assess skeletal muscle function and treadmill exhaustion test was used to test whole-body endurance. Mouse primary myoblasts derived from CKO (myoblast/CKO) mice were used to extend the findings to in vitro effects on myoblast differentiation and fusion. Quantitative real-time PCR, western blot and immunofluorescence approaches were used to analyse Slo1 expression during myoblast differentiation and muscle regeneration. To investigate the involvement of genes in the regulation of muscle dysfunction induced by Slo1 deletion, RNA-seq analysis was performed in primary myoblasts. Immunoprecipitation and mass spectrometry were used to identify the protein interacting with Slo1. A dual-luciferase reporter assay was used to identify whether Slo1 deletion affects NFAT activity.
    RESULTS: We found that the body weight and size of CKO mice were not significantly different from those of Slo1flox/flox mice (called WT). Deficiency of Slo1 in muscles leads to reduced endurance (~30% reduction, P < 0.05) and strength (~30% reduction, P < 0.001). Although there was no difference in the general morphology of the muscles, electron microscopy revealed a considerable reduction in the content of mitochondria in the soleus muscle (~40% reduction, P < 0.01). We found that Slo1 was expressed mainly on the cell membrane and showed higher expression in slow-twitch fibres. Slo1 protein expression is progressively reduced during muscle postnatal development and regeneration after injury, and the expression is strongly reduced during myoblast differentiation. Slo1 deletion impaired myoblast differentiation and slow-twitch fibre formation. Mechanistically, RNA-seq analysis showed that Slo1 influences the expression of genes related to myogenic differentiation and slow-twitch fibre formation. Slo1 interacts with FAK to influence myogenic differentiation, and Slo1 deletion diminishes NFAT activity.
    CONCLUSIONS: Our data reveal that Slo1 deficiency impaired skeletal muscle regeneration and slow-twitch fibre formation.
    Keywords:  Muscle regeneration; Myoblast; Myogenesis; Skeletal muscle; Slo1; Slow-twitch fibre formation
    DOI:  https://doi.org/10.1002/jcsm.13253
  5. J Cachexia Sarcopenia Muscle. 2023 May 24.
    Physical exercise attenuates age-related muscle atrophy and exhibits anti-ageing effects via the adiponectin receptor 1 signalling.
    Yuan-Li Chen, Yi-Cheng Ma, Jie Tang, Dan Zhang, Qiu Zhao, Jian-Jun Liu, Hong-Shu Tang, Jin-Yu Zhang, Guang-Hui He, Chi-Hui Zhong, Yu-Tong Wu, Heng-Ruo Wen, Lan-Qing Ma, Cheng-Gang Zou.
       BACKGROUND: Although the adiponectin signalling exerts exercise-mimicking effects, whether this pathway contributes to the anti-ageing benefits of physical exercise has not been established yet.
    METHODS: Swim exercise training and wheel running were used to measure lifespan in the nematode Caenorhabditis elegans and skeletal muscle quality in mice, respectively. Muscle weight, muscle fibre cross-sectional area (CSA) and myonuclei number were used to evaluate muscle mass. RNA sequencing (RNA-Seq) analysis of skeletal muscle in exercised mice was used to study the underlying mechanisms. Western blot and immunofluorescence were performed to explore autophagy- and senescence-related markers.
    RESULTS: The C. elegans adiponectin receptor PAQR-1/AdipoR1, but not PAQR-2/AdipoR2, was activated (3.55-fold and 3.48-fold increases in p-AMPK on Days 1 and 6, respectively, P < 0.001), which was involved in lifespan extension in exercised worms. Exercise training increased skeletal muscle mass index (1.29-fold, P < 0.01), muscle weight (1.75-fold, P < 0.001), myonuclei number (1.33-fold, P < 0.05), muscle fibre CSA (1.39-fold, P < 0.05) and capillary abundance (2.19-fold, P < 0.001 for capillary density; 1.58-fold, P < 0.01 for capillary number) in aged mice. Physical exercise reduced protein (2.94-fold, P < 0.001) and mRNA levels (1.70-fold, P < 0.001) of p16INK4a , a marker for cellular senescence, in skeletal muscle of aged mice. These beneficial effects of exercise on skeletal muscle of mice were dependent on AdipoR1. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis for differentially expressed genes in skeletal muscle between exercised mice with and without AdipoR1 knockdown by RNA-Seq analysis revealed that several KEGG pathways, such as 'AMPK signalling pathway' (P < 0.001), 'FOXO signalling pathway' (P < 0.001) and 'autophagy' (P < 0.001) were overrepresented. Knockdown of FoxO3a inhibited exercise-mediated beneficial effects on skeletal muscle quality of mice by inhibiting autophagy/mitophagy (3.81-fold reduction in LC3-II protein, P < 0.001; 1.53-fold reduction in BNIP3 protein, P < 0.05). Knockdown of daf-16, the FoxO homologue in C. elegans, reduced autophagy (2.77-fold and 2.06-fold reduction in GFP::LGG-1 puncta in seam cells and the intestine, respectively, P < 0.05) and blocked lifespan extension by exercise in worms.
    CONCLUSIONS: Our findings provide insights into how the AdipoR1 pathway has an impact on the anti-ageing benefits of exercise and implicate that activation of the AdipoR1 signalling may represent a potential therapeutic strategy for reducing age-related loss of skeletal muscle.
    Keywords:  AdipoR1; C. elegans; FOXO; autophagy; exercise; rodent; skeletal muscle loss
    DOI:  https://doi.org/10.1002/jcsm.13257
  6. J Physiol. 2023 May 26.
    The gut-muscle axis shapes exercise performance.
    Tomer Jordi Chaffer, Fahimeh Jafarnezhad-Ansariha.
      
    Keywords:  Endurance performance; Exercise training; Gut microbiome; Gut-muscle axis; Skeletal muscle
    DOI:  https://doi.org/10.1113/JP284905
  7. Nat Commun. 2023 May 22. 14(1): 2900
    Platelet-derived chemokines promote skeletal muscle regeneration by guiding neutrophil recruitment to injured muscles.
    Flavia A Graca, Anna Stephan, Benjamin A Minden-Birkenmaier, Abbas Shirinifard, Yong-Dong Wang, Fabio Demontis, Myriam Labelle.
      Skeletal muscle regeneration involves coordinated interactions between different cell types. Injection of platelet-rich plasma is circumstantially considered an aid to muscle repair but whether platelets promote regeneration beyond their role in hemostasis remains unexplored. Here, we find that signaling via platelet-released chemokines is an early event necessary for muscle repair in mice. Platelet depletion reduces the levels of the platelet-secreted neutrophil chemoattractants CXCL5 and CXCL7/PPBP. Consequently, early-phase neutrophil infiltration to injured muscles is impaired whereas later inflammation is exacerbated. Consistent with this model, neutrophil infiltration to injured muscles is compromised in male mice with Cxcl7-knockout platelets. Moreover, neo-angiogenesis and the re-establishment of myofiber size and muscle strength occurs optimally in control mice post-injury but not in Cxcl7ko mice and in neutrophil-depleted mice. Altogether, these findings indicate that platelet-secreted CXCL7 promotes regeneration by recruiting neutrophils to injured muscles, and that this signaling axis could be utilized therapeutically to boost muscle regeneration.
    DOI:  https://doi.org/10.1038/s41467-023-38624-0
  8. Growth Horm IGF Res. 2023 May 18. pii: S1096-6374(23)00014-X. [Epub ahead of print]69-70 101536
    Decreased insulin-like growth factor-1 expression in response to mechanical loading is associated with skeletal muscle anabolic resistance in cancer cachexia.
    Mitsunori Miyazaki, Atsushi Sawada, Daisuke Sawamura, Susumu Yoshida.
       OBJECTIVE: Cachexia is a systemic metabolic syndrome characterized by loss of body weight and skeletal muscle mass during chronic wasting diseases, such as cancer. Skeletal muscle in cancer cachexia is less responsive to anabolic factors including mechanical loading; however, the precise molecular mechanism is largely unknown. In this study, we examined the underlying mechanism of anabolic resistance in skeletal muscle in a cancer cachexia model.
    METHODS: CD2F1 mice (male, 8 weeks old) were subcutaneously transplanted (1 × 106 cells per mouse) with a mouse colon cancer-derived cell line (C26) as a model of cancer cachexia. Mechanical overload of the plantaris muscle by synergist tenotomy was performed during the 2nd week and the plantaris muscle was sampled at the 4th week following C26 transplantation.
    RESULTS: The hypertrophic response of skeletal muscle (increased skeletal muscle weight/protein synthesis efficiency and activation of mechanistic target of rapamycin complex 1 signaling) associated with mechanical overload was significantly suppressed during cancer cachexia. Screening of gene expression profile and pathway analysis using microarray revealed that blunted muscle protein synthesis was associated with cancer cachexia and was likely induced by downregulation of insulin-like growth factor-1 (IGF-1) and impaired activation of IGF-1-dependent signaling.
    CONCLUSIONS: These observations indicate that cancer cachexia induces resistance to muscle protein synthesis, which may be a factor for inhibiting the anabolic adaptation of skeletal muscle to physical exercise in cancer patients.
    Keywords:  Insulin-like growth factor 1; Mechanistic target of rapamycin; Protein synthesis; cancer cachexia
    DOI:  https://doi.org/10.1016/j.ghir.2023.101536
  9. J Gen Physiol. 2023 Jul 03. pii: e202213268. [Epub ahead of print]155(7):
    Physical activity impacts resting skeletal muscle myosin conformation and lowers its ATP consumption.
    Christopher T A Lewis, Lee Tabrizian, Joachim Nielsen, Jenni Laitila, Thomas N Beck, Mathilde S Olsen, Marija M Ognjanovic, Per Aagaard, Rune Hokken, Simon Laugesen, Arthur Ingersen, Jesper L Andersen, Casper Soendenbroe, Jørn W Helge, Flemming Dela, Steen Larsen, Ronni E Sahl, Tue Rømer, Mikkel T Hansen, Jacob Frandsen, Charlotte Suetta, Julien Ochala.
      It has recently been established that myosin, the molecular motor protein, is able to exist in two conformations in relaxed skeletal muscle. These conformations are known as the super-relaxed (SRX) and disordered-relaxed (DRX) states and are finely balanced to optimize ATP consumption and skeletal muscle metabolism. Indeed, SRX myosins are thought to have a 5- to 10-fold reduction in ATP turnover compared with DRX myosins. Here, we investigated whether chronic physical activity in humans would be associated with changes in the proportions of SRX and DRX skeletal myosins. For that, we isolated muscle fibers from young men of various physical activity levels (sedentary, moderately physically active, endurance-trained, and strength-trained athletes) and ran a loaded Mant-ATP chase protocol. We observed that in moderately physically active individuals, the amount of myosin molecules in the SRX state in type II muscle fibers was significantly greater than in age-matched sedentary individuals. In parallel, we did not find any difference in the proportions of SRX and DRX myosins in myofibers between highly endurance- and strength-trained athletes. We did however observe changes in their ATP turnover time. Altogether, these results indicate that physical activity level and training type can influence the resting skeletal muscle myosin dynamics. Our findings also emphasize that environmental stimuli such as exercise have the potential to rewire the molecular metabolism of human skeletal muscle through myosin.
    DOI:  https://doi.org/10.1085/jgp.202213268
  10. Life (Basel). 2023 Apr 29. pii: 1111. [Epub ahead of print]13(5):
    Up- and Downregulated Genes after Long-Term Muscle Atrophy Induced by Denervation in Mice Detected Using RNA-Seq.
    Shoko Sawano, Misaki Fukushima, Taiki Akasaka, Mako Nakamura, Ryuichi Tatsumi, Yoshihide Ikeuchi, Wataru Mizunoya.
      Skeletal muscle atrophy occurs rapidly as a result of inactivity. Although there are many reports on changes in gene expression during the early phase of muscle atrophy, the patterns of up-and downregulated gene expression after long-term and equilibrated muscle atrophy are poorly understood. In this study, we comprehensively examined the changes in gene expression in long-term denervated mouse muscles using RNA-Seq. The murine right sciatic nerve was denervated, and the mice were housed for five weeks. The cross-sectional areas of the hind limb muscles were measured using an X-ray CT system 35 days after denervation. After 28 d of denervation, the cross-sectional area of the muscle decreased to approximately 65% of that of the intact left muscle and reached a plateau. Gene expression in the soleus and extensor digitorum longus (EDL) muscles on the 36th day was analyzed using RNA-Seq and validated using RT-qPCR. RNA-Seq analysis revealed that three genes-Adora1, E230016M11Rik, and Gm10718-were upregulated and one gene-Gm20515-was downregulated in the soleus muscle; additionally, four genes-Adora1, E230016M11Rik, Pigh, and Gm15557-were upregulated and one gene-Fzd7-was downregulated in the EDL muscle (FDR < 0.05). Among these genes, E230016M11Rik, one of the long non-coding RNAs, was significantly upregulated in both the muscles. These findings indicate that E230016M11Rik could be a candidate gene for the maintenance of atrophied skeletal muscle size and an atrophic state.
    Keywords:  RNA-Seq; atrophy; denervation; fiber type; gene expression; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.3390/life13051111
  11. J Hematol Oncol. 2023 May 22. 16(1): 54
    Cancer cachexia: molecular mechanisms and treatment strategies.
    Tania Setiawan, Ita Novita Sari, Yoseph Toni Wijaya, Nadya Marcelina Julianto, Jabir Aliyu Muhammad, Hyeok Lee, Ji Heon Chae, Hyog Young Kwon.
      Muscle wasting is a consequence of physiological changes or a pathology characterized by increased catabolic activity that leads to progressive loss of skeletal muscle mass and strength. Numerous diseases, including cancer, organ failure, infection, and aging-associated diseases, are associated with muscle wasting. Cancer cachexia is a multifactorial syndrome characterized by loss of skeletal muscle mass, with or without the loss of fat mass, resulting in functional impairment and reduced quality of life. It is caused by the upregulation of systemic inflammation and catabolic stimuli, leading to inhibition of protein synthesis and enhancement of muscle catabolism. Here, we summarize the complex molecular networks that regulate muscle mass and function. Moreover, we describe complex multi-organ roles in cancer cachexia. Although cachexia is one of the main causes of cancer-related deaths, there are still no approved drugs for cancer cachexia. Thus, we compiled recent ongoing pre-clinical and clinical trials and further discussed potential therapeutic approaches for cancer cachexia.
    Keywords:  Cachexia; Cancer; Multi-organ; Muscle wasting; Sarcopenia; Treatment
    DOI:  https://doi.org/10.1186/s13045-023-01454-0
  12. J Mol Med (Berl). 2023 May 20.
    Mitochondrial transplantation as a possible therapeutic option for sarcopenia.
    Ibrahim Turkel, Berkay Ozerklig, Merve Yılmaz, Oner Ulger, Gokhan Burcin Kubat, Meltem Tuncer.
      With advancing age, the skeletal muscle phenotype is characterized by a progressive loss of mass, strength, and quality. This phenomenon, known as sarcopenia, has a negative impact on quality of life and increases the risk of morbidity and mortality in older adults. Accumulating evidence suggests that damaged and dysfunctional mitochondria play a critical role in the pathogenesis of sarcopenia. Lifestyle modifications, such as physical activity, exercise, and nutrition, as well as medical interventions with therapeutic agents, are effective in the management of sarcopenia and offer solutions to maintain and improve skeletal muscle health. Although a great deal of effort has been devoted to the identification of the best treatment option, these strategies are not sufficient to overcome sarcopenia. Recently, it has been reported that mitochondrial transplantation may be a possible therapeutic approach for the treatment of mitochondria-related pathological conditions such as ischemia, liver toxicity, kidney injury, cancer, and non-alcoholic fatty liver disease. Given the role of mitochondria in the function and metabolism of skeletal muscle, mitochondrial transplantation may be a possible option for the treatment of sarcopenia. In this review, we summarize the definition and characteristics of sarcopenia and molecular mechanisms associated with mitochondria that are known to contribute to sarcopenia. We also discuss mitochondrial transplantation as a possible option. Despite the progress made in the field of mitochondrial transplantation, further studies are needed to elucidate the role of mitochondrial transplantation in sarcopenia. KEY MESSAGES: Sarcopenia is the progressive loss of skeletal muscle mass, strength, and quality. Although the specific mechanisms that lead to sarcopenia are not fully understood, mitochondria have been identified as a key factor in the development of sarcopenia. Damaged and dysfunctional mitochondria initiate various cellular mediators and signaling pathways, which largely contribute to the age-related loss of skeletal muscle mass and strength. Mitochondrial transplantation has been reported to be a possible option for the treatment/prevention of several diseases. Mitochondrial transplantation may be a possible therapeutic option for improving skeletal muscle health and treating sarcopenia. Mitochondrial transplantation as a possible treatment option for sarcopenia.
    Keywords:  Mitochondrial dysfunction; Mitochondrial transplantation; Sarcopenia; Skeletal muscle
    DOI:  https://doi.org/10.1007/s00109-023-02326-3
  13. Front Cell Dev Biol. 2023 ;11 1128534
    Loss of the matrix metalloproteinase-10 causes premature features of aging in satellite cells.
    Miriam Bobadilla Muñoz, Josune Orbe, Gloria Abizanda, Florencio J D Machado, Amaia Vilas, Asier Ullate-Agote, Leire Extramiana, Arantxa Baraibar Churio, Xabier L Aranguren, Gloria Cantero, Neira Sáinz Amillo, José Antonio Rodríguez, Luis Ramos García, Juan Pablo Romero Riojas, Ainara Vallejo-Illarramendi, Carmen Paradas, Adolfo López de Munain, José Antonio Páramo, Felipe Prósper, Ana Pérez-Ruiz.
      Aged muscles accumulate satellite cells with a striking decline response to damage. Although intrinsic defects in satellite cells themselves are the major contributors to aging-associated stem cell dysfunction, increasing evidence suggests that changes in the muscle-stem cell local microenvironment also contribute to aging. Here, we demonstrate that loss of the matrix metalloproteinase-10 (MMP-10) in young mice alters the composition of the muscle extracellular matrix (ECM), and specifically disrupts the extracellular matrix of the satellite cell niche. This situation causes premature features of aging in the satellite cells, contributing to their functional decline and a predisposition to enter senescence under proliferative pressure. Similarly, reduction of MMP-10 levels in young satellite cells from wild type animals induces a senescence response, while addition of the protease delays this program. Significantly, the effect of MMP-10 on satellite cell aging can be extended to another context of muscle wasting, muscular dystrophy. Systemic treatment of mdx dystrophic mice with MMP-10 prevents the muscle deterioration phenotype and reduces cellular damage in the satellite cells, which are normally under replicative pressure. Most importantly, MMP-10 conserves its protective effect in the satellite cell-derived myoblasts isolated from a Duchenne muscular dystrophy patient by decreasing the accumulation of damaged DNA. Hence, MMP-10 provides a previously unrecognized therapeutic opportunity to delay satellite cell aging and overcome satellite cell dysfunction in dystrophic muscles.
    Keywords:  DNA damage; ECM; MMP-10; aging; muscle repair; satellite cell; senescence
    DOI:  https://doi.org/10.3389/fcell.2023.1128534
  14. J Biol Chem. 2023 May 20. pii: S0021-9258(23)01876-8. [Epub ahead of print] 104848
    LPGAT1/LPLAT7 regulates acyl chain profiles at the sn-1 position of phospholipids in murine skeletal muscles.
    Tomoki Sato, Shuhei Umebayashi, Nanami Senoo, Takumi Akahori, Hiyori Ichida, Noriyuki Miyoshi, Takuya Yoshida, Yuki Sugiura, Naoko Goto-Inoue, Hiroki Kawana, Hideo Shindou, Takashi Baba, Yuki Maemoto, Yasutomi Kamei, Takao Shimizu, Junken Aoki, Shinji Miura.
      Skeletal muscle consists of both fast- and slow-twitch fibers. Phospholipids are important structural components of cellular membranes, and the diversity of their fatty acid composition affects membrane fluidity and permeability. Although some studies have shown that acyl chain species in phospholipids differ among various muscle fiber types, the mechanisms underlying these differences are unclear. To investigate this, we analyzed phosphatidylcholine (PC) and phosphatidylethanolamine (PE) molecules in the murine extensor digitorum longus (EDL; fast-twitch) and soleus (slow-twitch) muscles. In the EDL muscle, the vast majority (93.6%) of PC molecules was palmitate-containing PC (16:0-PC), whereas in the soleus muscle, in addition to 16:0-PC, 27.9% of PC molecules was stearate-containing PC (18:0-PC). Most palmitate and stearate were bound at the sn-1 position of 16:0- and 18:0-PC, respectively, and 18:0-PC was found in type I and IIa fibers. The amount of 18:0-PE was higher in the soleus than in the EDL muscle. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) increased the amount of 18:0-PC in the EDL. Lysophosphatidylglycerol acyltransferase 1 (LPGAT1) was highly expressed in the soleus compared with that in the EDL muscle and was upregulated by PGC-1α. LPGAT1 knockout decreased the incorporation of stearate into PC and PE in vitro and ex vivo and the amount of 18:0-PC and 18:0-PE in murine skeletal muscle with an increase in the level of 16:0-PC and 16:0-PE. Moreover, knocking out LPGAT1 decreased the amount of stearate-containing-phosphatidylserine (18:0-PS), suggesting that LPGAT1 regulated the acyl chain profiles of phospholipids, namely PC, PE, and PS, in the skeletal muscle.
    Keywords:  acyltransferase; fast-twitch; glycerophospholipid; peroxisome proliferator-activated receptor γ coactivator-1α; phospholipid; phospholipid metabolism; phospholipid turnover; skeletal muscle; slow-twitch; transcription factor
    DOI:  https://doi.org/10.1016/j.jbc.2023.104848
  15. J Cell Physiol. 2023 May 23.
    miR-136-5p/FZD4 axis is critical for Wnt signaling-mediated myogenesis and skeletal muscle regeneration.
    Donghao Zhang, Lingqian Yin, Zhongzhen Lin, Chunlin Yu, Jingjing Li, Peng Ren, Chaowu Yang, Mohan Qiu, Yiping Liu.
      Skeletal muscle can undergo a regenerative process in response to injury or disease to maintain muscle quality and function. Myogenesis depends on the proliferation and differentiation of myoblasts, and miRNAs can maintain the balance between them by precisely regulating many key factors in the myogenic network. Here, we found that miR-136-5p was significantly upregulated during the proliferation and differentiation of C2C12 cells. We demonstrate that miR-136-5p acts as a myogenic negative regulator during the development of mouse C2C12 myoblasts. In terms of mechanism, miR-136-5p inhibits the formation of β-catenin/LEF/TCF DNA-binding factor transcriptional regulatory complex by targeting FZD4, a gating protein in the Wnt signaling pathway, thereby enhancing downstream myogenic factors and finally promoting myoblast proliferation and differentiation. In addition, in BaCl2 -induced muscle injury mouse model, miR-136-5p knockdown accelerated the regeneration of skeletal muscle after injury, and further led to the improvement of gastrocnemius muscle mass and muscle fiber diameter, while being suppressed by shFZD4 lentivirus infection. In summary, these results demonstrate the essential role of miR-136-5p/FZD4 axis in skeletal muscle regeneration. Given the conservation of miR-136-5p among species, miR-136-5p may be a new target for treating human skeletal muscle injury and improving the production of animal meat products.
    Keywords:  C2C12; FZD4; Myogenesis; miR-136-5p; skeletal muscle regeneration
    DOI:  https://doi.org/10.1002/jcp.31046
  16. Development. 2023 May 23. pii: dev.201504. [Epub ahead of print]
    Inhibitory SMAD6 interferes with BMP dependent generation of muscle progenitor cells and perturbs proximodistal pattern of murine limb muscles.
    Hasan Asfour, Estelle Hirsinger, Raquel Rouco, Faouzi Zarrouki, Shinichiro Hayashi, Sandra Swist, Thomas Braun, Ketan Patel, Frédéric Relaix, Guillaume Andrey, Sigmar Stricker, Delphine Duprez, Amalia Stantzou, Helge Amthor.
      The mechanism of pattern formation during limb muscle development remains poorly understood. The canonical view holds that naïve limb muscle progenitor cells (MPCs) invade a pre-established pattern of muscle connective tissue, thereby forming individual muscles. Here we show that early murine embryonic limb MPCs highly accumulate pSMAD1/5/9, demonstrating active signaling of bone morphogenetic proteins (BMP) in these cells. Overexpression of inhibitory SMAD6 in limb MPCs abrogated BMP signaling, impaired their migration and proliferation, and accelerated myogenic lineage progression. Fewer primary myofibers developed, causing an aberrant proximodistal muscle pattern. Patterning was not disturbed when SMAD6 was overexpressed in differentiated muscle, implying that the proximodistal muscle pattern depends on BMP-mediated expansion of MPCs prior to their differentiation. We show that limb MPCs differentially express Hox genes, and Hox-expressing MPCs displayed active BMP signaling. SMAD6 overexpression caused loss of HOXA11 in early limb MPCs. In conclusion, our data show that BMP signaling controls expansion of embryonic limb MPC as a prerequisite for establishing the proximodistal muscle pattern, a process that involves expression of Hox genes.
    Keywords:  BMP signaling; Embryonic muscle; Fetal muscle; HOX; Limb muscle; Muscle fiber; Myogenesis; Myogenic progenitor cell; PAX3; Patterning; SMAD6
    DOI:  https://doi.org/10.1242/dev.201504
  17. Commun Biol. 2023 May 25. 6(1): 561
    Non-canonical telomere protection role of FOXO3a of human skeletal muscle cells regulated by the TRF2-redox axis.
    Maria Sol Jacome Burbano, Jérôme D Robin, Serge Bauwens, Marjorie Martin, Emma Donati, Lucia Martínez, Peipei Lin, Sabrina Sacconi, Frédérique Magdinier, Eric Gilson.
      Telomeric repeat binding factor 2 (TRF2) binds to telomeres and protects chromosome ends against the DNA damage response and senescence. Although the expression of TRF2 is downregulated upon cellular senescence and in various aging tissues, including skeletal muscle tissues, very little is known about the contribution of this decline to aging. We previously showed that TRF2 loss in myofibers does not trigger telomere deprotection but mitochondrial dysfunction leading to an increased level of reactive oxygen species. We show here that this oxidative stress triggers the binding of FOXO3a to telomeres where it protects against ATM activation, revealing a previously unrecognized telomere protective function of FOXO3a, to the best of our knowledge. We further showed in transformed fibroblasts and myotubes that the telomere properties of FOXO3a are dependent on the C-terminal segment of its CR2 domain (CR2C) but independent of its Forkhead DNA binding domain and of its CR3 transactivation domain. We propose that these non-canonical properties of FOXO3a at telomeres play a role downstream of the mitochondrial signaling induced by TRF2 downregulation to regulate skeletal muscle homeostasis and aging.
    DOI:  https://doi.org/10.1038/s42003-023-04903-1
  18. Proc Natl Acad Sci U S A. 2023 05 30. 120(22): e2302837120
    Activation of skeletal muscle is controlled by a dual-filament mechano-sensing mechanism.
    Elisabetta Brunello, Lorenzo Marcucci, Malcolm Irving, Luca Fusi.
      Contraction of skeletal muscle is triggered by a transient rise in intracellular calcium concentration leading to a structural change in the actin-containing thin filaments that allows binding of myosin motors from the thick filaments. Most myosin motors are unavailable for actin binding in resting muscle because they are folded back against the thick filament backbone. Release of the folded motors is triggered by thick filament stress, implying a positive feedback loop in the thick filaments. However, it was unclear how thin and thick filament activation mechanisms are coordinated, partly because most previous studies of the thin filament regulation were conducted at low temperatures where the thick filament mechanisms are inhibited. Here, we use probes on both troponin in the thin filaments and myosin in the thick filaments to monitor the activation states of both filaments in near-physiological conditions. We characterize those activation states both in the steady state, using conventional titrations with calcium buffers, and during activation on the physiological timescale, using calcium jumps produced by photolysis of caged calcium. The results reveal three activation states of the thin filament in the intact filament lattice of a muscle cell that are analogous to those proposed previously from studies on isolated proteins. We characterize the rates of the transitions between these states in relation to thick filament mechano-sensing and show how thin- and thick-filament-based mechanisms are coupled by two positive feedback loops that switch on both filaments to achieve rapid cooperative activation of skeletal muscle.
    Keywords:  muscle regulation; myosin; skeletal muscle; troponin
    DOI:  https://doi.org/10.1073/pnas.2302837120
  19. Sci Rep. 2023 May 20. 13(1): 8195
    Skeletal muscle overexpression of sAnk1.5 in transgenic mice does not predispose to type 2 diabetes.
    E Pierantozzi, L Raucci, S Buonocore, E M Rubino, Q Ding, A Laurino, F Fiore, M Soldaini, J Chen, D Rossi, P Vangheluwe, H Chen, V Sorrentino.
      Genome-wide association studies (GWAS) and cis-expression quantitative trait locus (cis-eQTL) analyses indicated an association of the rs508419 single nucleotide polymorphism (SNP) with type 2 diabetes (T2D). rs508419 is localized in the muscle-specific internal promoter (P2) of the ANK1 gene, which drives the expression of the sAnk1.5 isoform. Functional studies showed that the rs508419 C/C variant results in increased transcriptional activity of the P2 promoter, leading to higher levels of sAnk1.5 mRNA and protein in skeletal muscle biopsies of individuals carrying the C/C genotype. To investigate whether sAnk1.5 overexpression in skeletal muscle might predispose to T2D development, we generated transgenic mice (TgsAnk1.5/+) in which the sAnk1.5 coding sequence was selectively overexpressed in skeletal muscle tissue. TgsAnk1.5/+ mice expressed up to 50% as much sAnk1.5 protein as wild-type (WT) muscles, mirroring the difference reported between individuals with the C/C or T/T genotype at rs508419. However, fasting glucose levels, glucose tolerance, insulin levels and insulin response in TgsAnk1.5/+ mice did not differ from those of age-matched WT mice monitored over a 12-month period. Even when fed a high-fat diet, TgsAnk1.5/+ mice only presented increased caloric intake, but glucose disposal, insulin tolerance and weight gain were comparable to those of WT mice fed a similar diet. Altogether, these data indicate that sAnk1.5 overexpression in skeletal muscle does not predispose mice to T2D susceptibility.
    DOI:  https://doi.org/10.1038/s41598-023-35393-0
  20. FASEB J. 2023 Jun;37(6): e22993
    Decoding the transcriptome of muscular dystrophy due to Ptrf deficiency using single-nucleus RNA sequencing.
    Xiaokai Li, Zhining Zhong, Ruowei Zhang, Jiaman Zhang, Yu Zhang, Sha Zeng, Qinjiao Du, Haoming Wang, Songling Zhang, Lu Lu, Mingzhou Li, Keren Long.
      Lacking PTRF (polymerase I and transcript release factor), an essential caveolae component, causes a secondary deficiency of caveolins resulting in muscular dystrophy. The transcriptome responses of different types of muscle fibers and mononuclear cells in skeletal muscle to muscular dystrophy caused by Ptrf deletion have not been explored. Here, we created muscular dystrophy mice by Ptrf knockout and applied single-nucleus RNA sequencing (snRNA-seq) to unveil the transcriptional changes of the skeletal muscle at single-nucleus resolution. 11 613 muscle nuclei (WT, 5838; Ptrf KO, 5775) were classified into 12 clusters corresponding to 11 nuclear types. Trajectory analysis revealed the potential transition between type IIb_1 and IIb_2 myonuclei upon muscular dystrophy. Functional enrichment analysis indicated that apoptotic signaling and enzyme-linked receptor protein signaling pathway were significantly enriched in type IIb_1 and IIb_2 myonuclei of Ptrf KO, respectively. The muscle structure development and the PI3K-AKT signaling pathway were significantly enriched in type IIa and IIx myonuclei of Ptrf KO. Meanwhile, metabolic pathway analysis showed a decrease in overall metabolic pathway activity of myonuclei subtypes upon muscular dystrophy, with the most decrease in type IIb_1 myonuclei. Gene regulatory network analysis found that the activity of Mef2c, Mef2d, Myf5, and Pax3 regulons was enhanced in type II myonuclei of Ptrf KO, especially in type IIb_2 myonuclei. In addition, we investigated the transcriptome changes in adipocytes and found that muscular dystrophy enhanced the lipid metabolic capacity of adipocytes. Our findings provide a valuable resource for exploring the molecular mechanism of muscular dystrophy due to Ptrf deficiency.
    Keywords:   Ptrf ; muscular dystrophy; myonuclei; skeletal muscle; snRNA-seq
    DOI:  https://doi.org/10.1096/fj.202201949RR
  21. EMBO Mol Med. 2023 May 24. e16951
    A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy.
    Nneka Southwell, Guido Primiano, Viraj Nadkarni, Nabeel Attarwala, Emelie Beattie, Dawson Miller, Sumaitaah Alam, Irene Liparulo, Yevgeniya I Shurubor, Maria Lucia Valentino, Valerio Carelli, Serenella Servidei, Steven S Gross, Giovanni Manfredi, Qiuying Chen, Marilena D'Aurelio.
      Mitochondrial diseases are a heterogeneous group of monogenic disorders that result from impaired oxidative phosphorylation (OXPHOS). As neuromuscular tissues are highly energy-dependent, mitochondrial diseases often affect skeletal muscle. Although genetic and bioenergetic causes of OXPHOS impairment in human mitochondrial myopathies are well established, there is a limited understanding of metabolic drivers of muscle degeneration. This knowledge gap contributes to the lack of effective treatments for these disorders. Here, we discovered fundamental muscle metabolic remodeling mechanisms shared by mitochondrial disease patients and a mouse model of mitochondrial myopathy. This metabolic remodeling is triggered by a starvation-like response that evokes accelerated oxidation of amino acids through a truncated Krebs cycle. While initially adaptive, this response evolves in an integrated multiorgan catabolic signaling, lipid store mobilization, and intramuscular lipid accumulation. We show that this multiorgan feed-forward metabolic response involves leptin and glucocorticoid signaling. This study elucidates systemic metabolic dyshomeostasis mechanisms that underlie human mitochondrial myopathies and identifies potential new targets for metabolic intervention.
    Keywords:  amino acid metabolism; glucocorticoids; leptin; mitochondrial myopathy; muscle wasting
    DOI:  https://doi.org/10.15252/emmm.202216951
  22. Am J Physiol Cell Physiol. 2023 May 22.
    Small molecule drugs to improve sarcomere function in those with acquired and inherited myopathies.
    Wout J Claassen, Rianne J Baelde, Ricardo A Galli, Josine M de Winter, Coen A C Ottenheijm.
      Muscle weakness is a hallmark of inherited or acquired myopathies. It is a major cause of functional impairment and can advance to life threatening respiratory insufficiency. During the past decade, several small molecule drugs that improve the contractility of skeletal muscle fibers have been developed. In this review we provide an overview of the available literature and the mechanisms of action of small molecule drugs that modulate the contractility of sarcomeres, the smallest contractile units in striated muscle, by acting on myosin and troponin. We also discuss their use in the treatment of skeletal myopathies. The first of three classes of drugs discussed here increase contractility by decreasing the dissociation rate of calcium from troponin and thereby sensitizing the muscle to calcium. The second two classes of drugs directly act on myosin and stimulate or inhibit the kinetics of myosin-actin interactions, which may be useful in patients with muscle weakness or stiffness.
    Keywords:  Muscle Physiology; Muscle disease
    DOI:  https://doi.org/10.1152/ajpcell.00047.2023
  23. Biomedicines. 2023 May 16. pii: 1457. [Epub ahead of print]11(5):
    Myogenesis in C2C12 Cells Requires Phosphorylation of ATF6α by p38 MAPK.
    Valentina Pagliara, Giuseppina Amodio, Vincenzo Vestuto, Silvia Franceschelli, Nicola Antonino Russo, Vittorio Cirillo, Giovanna Mottola, Paolo Remondelli, Ornella Moltedo.
      Activating transcription factor 6α (ATF6α) is an endoplasmic reticulum protein known to participate in unfolded protein response (UPR) during ER stress in mammals. Herein, we show that in mouse C2C12 myoblasts induced to differentiate, ATF6α is the only pathway of the UPR activated. ATF6α stimulation is p38 MAPK-dependent, as revealed by the use of the inhibitor SB203580, which halts myotube formation and, at the same time, impairs trafficking of ATF6α, which accumulates at the cis-Golgi without being processed in the p50 transcriptional active form. To further evaluate the role of ATF6α, we knocked out the ATF6α gene, thus inhibiting the C2C12 myoblast from undergoing myogenesis, and this occurred independently from p38 MAPK activity. The expression of exogenous ATF6α in knocked-out ATF6α cells recover myogenesis, whereas the expression of an ATF6α mutant in the p38 MAPK phosphorylation site (T166) was not able to regain myogenesis. Genetic ablation of ATF6α also prevents the exit from the cell cycle, which is essential for muscle differentiation. Furthermore, when we inhibited differentiation by the use of dexamethasone in C2C12 cells, we found inactivation of p38 MAPK and, consequently, loss of ATF6α activity. All these findings suggest that the p-p38 MAPK/ATF6α axis, in pathophysiological conditions, regulates myogenesis by promoting the exit from the cell cycle, an essential step to start myoblasts differentiation.
    Keywords:  C2C12; activating transcription factor 6 α (ATF6α); myogenesis; p38 Mitogen-Activated Protein Kinase (MAPK); unfolded protein response
    DOI:  https://doi.org/10.3390/biomedicines11051457
  24. Sci Rep. 2023 May 25. 13(1): 8146
    Simple and efficient differentiation of human iPSCs into contractible skeletal muscles for muscular disease modeling.
    Muhammad Irfanur Rashid, Takuji Ito, Fuyuki Miya, Daisuke Shimojo, Kanae Arimoto, Kazunari Onodera, Rina Okada, Takunori Nagashima, Kazuki Yamamoto, Zohora Khatun, Rayhanul Islam Shimul, Jun-Ichi Niwa, Masahisa Katsuno, Gen Sobue, Hideyuki Okano, Hidetoshi Sakurai, Kazunori Shimizu, Manabu Doyu, Yohei Okada.
      Pathophysiological analysis and drug discovery targeting human diseases require disease models that suitably recapitulate patient pathology. Disease-specific human induced pluripotent stem cells (hiPSCs) differentiated into affected cell types can potentially recapitulate disease pathology more accurately than existing disease models. Such successful modeling of muscular diseases requires efficient differentiation of hiPSCs into skeletal muscles. hiPSCs transduced with doxycycline-inducible MYOD1 (MYOD1-hiPSCs) have been widely used; however, they require time- and labor-consuming clonal selection, and clonal variations must be overcome. Moreover, their functionality should be carefully examined. Here, we demonstrated that bulk MYOD1-hiPSCs established with puromycin selection rather than G418 selection showed rapid and highly efficient differentiation. Interestingly, bulk MYOD1-hiPSCs exhibited average differentiation properties of clonally established MYOD1-hiPSCs, suggesting that it is possible to minimize clonal variations. Moreover, disease-specific hiPSCs of spinal bulbar muscular atrophy (SBMA) could be efficiently differentiated via this method into skeletal muscle that showed disease phenotypes, suggesting the applicability of this method for disease analysis. Finally, three-dimensional muscle tissues were fabricated from bulk MYOD1-hiPSCs, which exhibited contractile force upon electrical stimulation, indicating their functionality. Thus, our bulk differentiation requires less time and labor than existing methods, efficiently generates contractible skeletal muscles, and may facilitate the generation of muscular disease models.
    DOI:  https://doi.org/10.1038/s41598-023-34445-9
  25. Biomolecules. 2023 Apr 23. pii: 722. [Epub ahead of print]13(5):
    Muscular Sestrins: Roles in Exercise Physiology and Stress Resistance.
    Irene Hwang, Myungjin Kim.
      Sestrins are a family of stress-inducible proteins that are critical for stress adaptation and the maintenance of metabolic homeostasis. High expression of Sestrins is observed in skeletal and cardiac muscle tissues, suggesting their significance in the physiological homeostasis of these organs. Furthermore, expression of Sestrins is dynamically controlled in the tissues, based on the level of physical activity and the presence or absence of stress insults. Genetic studies in model organisms have shown that muscular Sestrin expression is critical for metabolic homeostasis, exercise adaptation, stress resistance, and repair and may mediate the beneficial effects of some available therapeutics. The current minireview summarizes and discusses recent findings that shed light on the role of Sestrins in regulating muscle physiology and homeostasis.
    Keywords:  Sestrin; exercise; heart; muscle; physiology; stress
    DOI:  https://doi.org/10.3390/biom13050722
  26. Nutrients. 2023 May 18. pii: 2367. [Epub ahead of print]15(10):
    Accounting Gut Microbiota as the Mediator of Beneficial Effects of Dietary (Poly)phenols on Skeletal Muscle in Aging.
    Andrea Ticinesi, Antonio Nouvenne, Nicoletta Cerundolo, Alberto Parise, Tiziana Meschi.
      Sarcopenia, the age-related loss of muscle mass and function increasing the risk of disability and adverse outcomes in older people, is substantially influenced by dietary habits. Several studies from animal models of aging and muscle wasting indicate that the intake of specific polyphenol compounds can be associated with myoprotective effects, and improvements in muscle strength and performance. Such findings have also been confirmed in a smaller number of human studies. However, in the gut lumen, dietary polyphenols undergo extensive biotransformation by gut microbiota into a wide range of bioactive compounds, which substantially contribute to bioactivity on skeletal muscle. Thus, the beneficial effects of polyphenols may consistently vary across individuals, depending on the composition and metabolic functionality of gut bacterial communities. The understanding of such variability has recently been improved. For example, resveratrol and urolithin interaction with the microbiota can produce different biological effects according to the microbiota metabotype. In older individuals, the gut microbiota is frequently characterized by dysbiosis, overrepresentation of opportunistic pathogens, and increased inter-individual variability, which may contribute to increasing the variability of biological actions of phenolic compounds at the skeletal muscle level. These interactions should be taken into great consideration for designing effective nutritional strategies to counteract sarcopenia.
    Keywords:  anthocyanins; curcumin; flavonoids; isoflavones; physical frailty; sarcopenia
    DOI:  https://doi.org/10.3390/nu15102367
  27. Nat Commun. 2023 May 22. 14(1): 2740
    AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin-dependent cell migration.
    Eva Crosas-Molist, Vittoria Graziani, Oscar Maiques, Pahini Pandya, Joanne Monger, Remi Samain, Samantha L George, Saba Malik, Jerrine Salise, Valle Morales, Adrien Le Guennec, R Andrew Atkinson, Rosa M Marti, Xavier Matias-Guiu, Guillaume Charras, Maria R Conte, Alberto Elosegui-Artola, Mark Holt, Victoria Sanz-Moreno.
      Cell migration is crucial for cancer dissemination. We find that AMP-activated protein kinase (AMPK) controls cell migration by acting as an adhesion sensing molecular hub. In 3-dimensional matrices, fast-migrating amoeboid cancer cells exert low adhesion/low traction linked to low ATP/AMP, leading to AMPK activation. In turn, AMPK plays a dual role controlling mitochondrial dynamics and cytoskeletal remodelling. High AMPK activity in low adhering migratory cells, induces mitochondrial fission, resulting in lower oxidative phosphorylation and lower mitochondrial ATP. Concurrently, AMPK inactivates Myosin Phosphatase, increasing Myosin II-dependent amoeboid migration. Reducing adhesion or mitochondrial fusion or activating AMPK induces efficient rounded-amoeboid migration. AMPK inhibition suppresses metastatic potential of amoeboid cancer cells in vivo, while a mitochondrial/AMPK-driven switch is observed in regions of human tumours where amoeboid cells are disseminating. We unveil how mitochondrial dynamics control cell migration and suggest that AMPK is a mechano-metabolic sensor linking energetics and the cytoskeleton.
    DOI:  https://doi.org/10.1038/s41467-023-38292-0
  28. Sci Rep. 2023 May 25. 13(1): 8481
    Effects of energy drinks on myogenic differentiation of murine C2C12 myoblasts.
    Sun Young Park, Georgia Karantenislis, Hannah T Rosen, Hong Sun.
      Energy drinks, often advertised as dietary supplements that enhance physical and mental performance, have gained increasing popularity among adolescents and athletes. Several studies on individual ingredients such as caffeine or taurine have reported either adverse or favorable influences on myogenic differentiation, a key process in muscle regeneration to repair microtears after an intense workout session. However, the impact of different energy drinks with various formulas on muscle differentiation has never been reported. This study aims to examine the in vitro effects of various energy drink brands on myogenic differentiation. Murine C2C12 myoblast cells were induced to differentiate into myotubes in the presence of one of eight energy drinks at varying dilutions. A dose-dependent inhibition of myotube formation was observed for all energy drinks, supported by reduced percentage of MHC-positive nuclei and fusion index. Moreover, expression of myogenic regulatory factor MyoG and differentiation marker MCK were also decreased. Furthermore, given the variation in formulas of different energy drinks, there were remarkable differences in the differentiation and fusion of myotubes between energy drinks. This is the first study to investigate the impact of various energy drinks on myogenic differentiation and our results suggest an inhibitory effect of energy drinks in muscle regeneration.
    DOI:  https://doi.org/10.1038/s41598-023-35338-7
  29. Exp Gerontol. 2023 May 23. pii: S0531-5565(23)00139-0. [Epub ahead of print] 112218
    Brown adipose tissue and aging: A potential role for exercise.
    Shinsuke Nirengi, Kristin Stanford.
      Aging is one of the primary risk factors for the development of type 2 diabetes and cardiovascular disease, and regular physical activity can help to delay, prevent, or manage the onset and development of many chronic diseases present in older adults. Brown adipose tissue (BAT) is thermogenic tissue that protects against age-related disease, but BAT activity decreases with age. In this review, we discuss how aging contributes to impaired BAT function by inducing a 'whitening' of the BAT and altering beta 3 adrenergic receptor (β3AR) signaling, uncoupling protein 1 (UCP1) gene expression, and mitochondria respiration, and potential mechanisms for exercise to counteract the effects of aging on BAT.
    Keywords:  Aging; Brown adipose tissue; Exercise; Mitochondria; UCP1
    DOI:  https://doi.org/10.1016/j.exger.2023.112218
  30. Genes Dis. 2023 Mar;10(2): 359-362
    Single-cell analysis reveals the lncRNA-MEG3/miRNA-133a-3p/PRRT2 axis regulates skeletal muscle regeneration and myogenesis.
    Yilong Yao, Zishuai Wang, Yun Chen, Lei Liu, Liyuan Wang, Guoqiang Yi, Yalan Yang, Dazhi Wang, Kui Li, Zhonglin Tang.
      
    DOI:  https://doi.org/10.1016/j.gendis.2022.04.012
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