bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2023‒01‒01
eighteen papers selected by
Anna Vainshtein
Craft Science Inc.
  1. Editorial: The fiber profile of skeletal muscles as a fingerprint of muscle quality.
  2. The circadian E3 ligase FBXL21 regulates myoblast differentiation and sarcomere architecture via MYOZ1 ubiquitination and NFAT signaling.
  3. Innately expressed estrogen-related receptors in the skeletal muscle are indispensable for exercise fitness.
  4. Overexpression of miR-29ab1 Cluster Results in Excessive Muscle Growth in 1-Month-old Mice by Inhibiting Mstn.
  5. Ergogenic effects of caffeine are mediated by myokines.
  6. C-C motif chemokine ligand 2 promotes myogenesis of myoblasts via the AKT-mTOR pathway.
  7. MBNL-dependent impaired development within the neuromuscular system in Myotonic Dystrophy type 1.
  8. Isolation of Quiescent Stem Cell Populations from Individual Skeletal Muscles.
  9. Update on anti-fibrotic pharmacotherapies in skeletal muscle disease.
  10. Skeletal Muscle Nuclei in Mice are not Post-mitotic.
  11. The Cellular and Molecular Signature of ALS in Muscle.
  12. Transcriptomic analysis of human ALS skeletal muscle reveals a disease-specific pattern of dysregulated circRNAs.
  13. Improving Physiological Relevance of Cell Culture: The Possibilities, Considerations and Future Directions of the Ex Vivo Co-Culture Model.
  14. Heterogeneous levels of delta-like 4 within a multinucleated niche cell maintains muscle stem cell diversity.
  15. Myokine, a key cytokine for physical exercise to alleviate sarcopenic obesity.
  16. The impact of high fat feeding and Parkin overexpression on skeletal muscle mass, mitochondrial respiration and H2O2 emission.
  17. Creatine modulates cellular energy metabolism and protects against cancer cachexia-associated muscle wasting.
  18. Transplanting rejuvenated blood stem cells extends lifespan of aged immunocompromised mice.
  1. Front Physiol. 2022 ;13 1105252
    Editorial: The fiber profile of skeletal muscles as a fingerprint of muscle quality.
    Emiliana Giacomello, Luana Toniolo.
      
    Keywords:  fiber profile; fiber size; metabolic activity; myosin heavy chain; oxidative capacity; skeletal muscle
    DOI:  https://doi.org/10.3389/fphys.2022.1105252
  2. PLoS Genet. 2022 Dec 27. 18(12): e1010574
    The circadian E3 ligase FBXL21 regulates myoblast differentiation and sarcomere architecture via MYOZ1 ubiquitination and NFAT signaling.
    Ji Ye Lim, Eunju Kim, Collin M Douglas, Marvin Wirianto, Chorong Han, Kaori Ono, Sun Young Kim, Justin H Ji, Celia Tran, Zheng Chen, Karyn A Esser, Seung-Hee Yoo.
      Numerous molecular and physiological processes in the skeletal muscle undergo circadian time-dependent oscillations in accordance with daily activity/rest cycles. The circadian regulatory mechanisms underlying these cyclic processes, especially at the post-transcriptional level, are not well defined. Previously, we reported that the circadian E3 ligase FBXL21 mediates rhythmic degradation of the sarcomere protein TCAP in conjunction with GSK-3β, and Psttm mice harboring an Fbxl21 hypomorph allele show reduced muscle fiber diameter and impaired muscle function. To further elucidate the regulatory function of FBXL21 in skeletal muscle, we investigated another sarcomere protein, Myozenin1 (MYOZ1), that we identified as an FBXL21-binding protein from yeast 2-hybrid screening. We show that FBXL21 binding to MYOZ1 led to ubiquitination-mediated proteasomal degradation. GSK-3β co-expression and inhibition were found to accelerate and decelerate FBXL21-mediated MYOZ1 degradation, respectively. Previously, MYOZ1 has been shown to inhibit calcineurin/NFAT signaling important for muscle differentiation. In accordance, Fbxl21 KO and MyoZ1 KO in C2C12 cells impaired and enhanced myogenic differentiation respectively compared with control C2C12 cells, concomitant with distinct effects on NFAT nuclear localization and NFAT target gene expression. Importantly, in Psttm mice, both the levels and diurnal rhythm of NFAT2 nuclear localization were significantly diminished relative to wild-type mice, and circadian expression of NFAT target genes associated with muscle differentiation was also markedly dampened. Furthermore, Psttm mice exhibited significant disruption of sarcomere structure with a considerable excess of MYOZ1 accumulation in the Z-line. Taken together, our study illustrates a pivotal role of FBXL21 in sarcomere structure and muscle differentiation by regulating MYOZ1 degradation and NFAT2 signaling.
    DOI:  https://doi.org/10.1371/journal.pgen.1010574
  3. FASEB J. 2023 Feb;37(2): e22727
    Innately expressed estrogen-related receptors in the skeletal muscle are indispensable for exercise fitness.
    Danesh H Sopariwala, Andrea S Rios, Guangsheng Pei, Anirban Roy, Meiricris Tomaz da Silva, Hao Thi Thu Nguyen, Addison Saley, Rachel Van Drunen, Anastasia Kralli, Kristin Mahan, Zhongming Zhao, Ashok Kumar, Vihang A Narkar.
      Transcriptional determinants in the skeletal muscle that govern exercise capacity, while poorly defined, could provide molecular insights into how exercise improves fitness. Here, we have elucidated the role of nuclear receptors, estrogen-related receptor alpha and gamma (ERRα/γ) in regulating myofibrillar composition, contractility, and exercise capacity in skeletal muscle. We used muscle-specific single or double (DKO) ERRα/γ knockout mice to investigate the effect of ERRα/γ deletion on muscle and exercise parameters. Individual knockout of ERRα/γ did not have a significant impact on the skeletal muscle. On the other hand, DKO mice exhibit pale muscles compared to wild-type (WT) littermates. RNA-seq analysis revealed a predominant decrease in expression of genes linked to mitochondrial and oxidative metabolism in DKO versus WT muscles. DKO muscles exhibit marked repression of oxidative enzymatic capacity, as well as mitochondrial number and size compared to WT muscles. Mitochondrial function is also impaired in single myofibers isolated from DKO versus WT muscles. In addition, mutant muscles exhibit reduced angiogenic gene expression and decreased capillarity. Consequently, DKO mice have a significantly reduced exercise capacity, further reflected in poor fatigue resistance of DKO mice in in vivo contraction assays. These results show that ERRα and ERRγ together are a critical link between muscle aerobic capacity and exercise tolerance. The ERRα/γ mutant mice could be valuable for understanding the long-term impact of impaired mitochondria and vascular supply on the pathogenesis of muscle-linked disorders.
    Keywords:  angiogenesis; estrogen-related receptors; exercise; mitochondria; skeletal muscle
    DOI:  https://doi.org/10.1096/fj.202201518R
  4. DNA Cell Biol. 2022 Dec 19.
    Overexpression of miR-29ab1 Cluster Results in Excessive Muscle Growth in 1-Month-old Mice by Inhibiting Mstn.
    Chuncheng Liu, Yuxin Cao, Lei Li, Yiting Wang, Qingyong Meng.
      Skeletal muscle mass is closely related to strength and health. Multiple genes and signaling pathways are involved in the regulation of skeletal muscle hypertrophy. miR-29 can participate in various processes of skeletal muscle development through different target genes. However, studies are needed on the function of miR-29 in skeletal muscle during mouse puberty. We used mice in which overexpression of miR-29ab1 cluster could be induced specifically within skeletal muscle, and investigated the effects of miR-29 overexpression on skeletal muscle at 1 month of age. We found that the overexpression of miR-29ab1 cluster in juvenile mice caused skeletal muscle mass and myofiber cross-sectional area to increase. The study on the mechanism of miR-29 inducing skeletal muscle hypertrophy had found that miR-29 achieved its function by inhibiting the expression of Mstn. At the same time, injured myofibers were present within miR-29ab1 cluster overexpressing skeletal muscle. The damage of skeletal muscle may be due to the inhibition of the type IV collagen by miR-29. These results indicate that although the overexpression of miR-29ab1 cluster can induce skeletal muscle hypertrophy in mouse juvenile, it simultaneously causes skeletal muscle damage.
    Keywords:  Mstn; hypertrophy; miR-29ab1 cluster; muscle
    DOI:  https://doi.org/10.1089/dna.2022.0247
  5. Front Sports Act Living. 2022 ;4 969623
    Ergogenic effects of caffeine are mediated by myokines.
    Shingo Takada, Yoshizuki Fumoto, Shintaro Kinugawa.
      Exercise has long been known to effectively improve and enhance skeletal muscle function and performance. The favorable effects of exercise on remote organs other than skeletal muscle are well known, but the underlying mechanism has remained elusive. Recent studies have indicated that skeletal muscle not only enables body movement, but also contributes to body homeostasis and the systemic stress response via the expression and/or secretion of cytokines (so-called myokines). Not only the induction of muscle contraction itself, but also changes in intracellular calcium concentration ([Ca2+]i) have been suggested to be involved in myokine production and secretion. Caffeine is widely known as a Ca2+ ionophore, which improves skeletal muscle function and exercise performance (i.e., an "ergogenic aid"). Interestingly, some studies reported that caffeine or an increase in [Ca2+]i enhances the expression and/or secretion of myokines. In this review, we discuss the association between caffeine as an ergogenic aid and myokine regulation.
    Keywords:  BDNF; Ca2+-induced Ca2+ release; calcium ion (Ca)2+; ergogenic aid; exercise mimetic; mitochondria; myokine; skeletal muscle
    DOI:  https://doi.org/10.3389/fspor.2022.969623
  6. Aging (Albany NY). 2022 Dec 27. 14
    C-C motif chemokine ligand 2 promotes myogenesis of myoblasts via the AKT-mTOR pathway.
    Mi Kyung Kwak, Eun Suk Ha, Jiwoo Lee, Yun Mi Choi, Beom-Jun Kim, Eun-Gyoung Hong.
      Muscle mass decreases with aging, while the C-C motif chemokine ligand 2 (CCL2) increases with aging; in this context, CCL2 can be considered a potential aging-promoting factor. Thus, CCL2 knockout mice are expected to exhibit anti-aging effects including protection against loss of muscle mass. However, instead, muscle amount and recovery of damaged muscles are decreased in CCL2 knockout mice. Therefore, we hypothesized that increasing CCL2 in the elderly might be related to compensation for loss of muscle mass. To confirm the relationship between muscle and CCL2, we sought to establish the role of CCL2 in C2C12 cells and Human Skeletal Muscle Myoblast (HSMM) cells. The myotube (MT) fusion index increased with CCL2 compared to 5day CCL2 vehicle only (27.0 % increase, P<0.05) in immunocytochemistry staining (ICC) data. CCL2 also restored MTs atrophy caused by dexamethasone (21.8 % increase, P<0.0001). p-mTOR/mTOR and p-AKT/total AKT increased with CCL2 compared to CCL2 vehicle only (18.3 and 30.5% increase respectively, P<0.05) and decreased with CCR2-siRNA compared to CCL2 (38.9 % (P<0.05) and 56.7% (P<0.005) reduction respectively). In conclusion, CCL2 positively affects myogenesis by CCR2 via AKT-mTOR signaling pathways. CCL2 might have potential as a therapeutic target for low muscle mass and muscle recovery.
    Keywords:  CCL2; CCR2; aging; low muscle mass; myogenesis
    DOI:  https://doi.org/10.18632/aging.204451
  7. Neuropathol Appl Neurobiol. 2022 Dec 28. e12876
    MBNL-dependent impaired development within the neuromuscular system in Myotonic Dystrophy type 1.
    Julie Tahraoui-Bories, Antoine Mérien, Anchel Gonzàlez-Barriga, Jeanne Lainé, Céline Leteur, Hélène Polvèche, Alexandre Carteron, Juliette Duchesne De Lamotte, Camille Nicoleau, Jérome Polentes, Margot Jarrige, Màrio Gomes-Pereira, Erwann Ventre, Pauline Poydenot, Denis Furling, Laurent Schaeffer, Claire Legay, Cécile Martinat.
      AIMS: Myotonic dystrophy type I (DM1) is one the most frequent muscular dystrophies in adults. Although DM1 has long been considered mainly a muscle disorder, growing evidence suggests the involvement of peripheral nerves in the pathogenicity of DM1 raising the question of whether motoneurons (MNs) actively contribute to neuromuscular defects in DM1.METHODS: By using micropatterned 96-well plates as a co-culture platform, we generated a functional neuromuscular model combining DM1 and MBNL-knock-out human induced pluripotent stem cells-derived MNs and human healthy skeletal muscle cells.
    RESULTS: This approach led to the identification of pre-synaptic defects which affect the formation or stability of the neuromuscular junction at an early developmental stage. These neuropathological defects could be reproduced by the loss of RNA-binding MBNL proteins, whose loss of function in vivo is associated with muscular defects associated with DM1. These experiments indicate that the functional defects associated with MNs can be directly attributed to MBNL family proteins. Comparative transcriptomic analyses also revealed specific neuronal-related processes regulated by these proteins that are commonly misregulated in DM1.
    CONCLUSIONS: Beyond the application to DM1, our approach to generating a robust and reliable human neuromuscular system should facilitate disease modelling studies and drug screening assays.
    Keywords:  Induced pluripotent stem cells; MBNL proteins; Motoneurons; Myotonic Dystrophy type 1; Neuromuscular junction
    DOI:  https://doi.org/10.1111/nan.12876
  8. J Vis Exp. 2022 Dec 09.
    Isolation of Quiescent Stem Cell Populations from Individual Skeletal Muscles.
    Zofija Frimand, Shubhangi Das Barman, Troels Rønn Kjær, Ermelinda Porpiglia, Antoine de Morrée.
      Skeletal muscle harbors distinct populations of adult stem cells that contribute to the homeostasis and repair of the tissue. Skeletal muscle stem cells (MuSCs) have the ability to make new muscle, whereas fibro-adipogenic progenitors (FAPs) contribute to stromal supporting tissues and have the ability to make fibroblasts and adipocytes. Both MuSCs and FAPs reside in a state of prolonged reversible cell cycle exit, called quiescence. The quiescent state is key to their function. Quiescent stem cells are commonly purified from multiple muscle tissues pooled together in a single sample. However, recent studies have revealed distinct differences in the molecular profiles and quiescence depth of MuSCs isolated from different muscles. The present protocol describes the isolation and study of MuSCs and FAPs from individual skeletal muscles and presents strategies to perform molecular analysis of stem cell activation. It details how to isolate and digest muscles of different developmental origin, thicknesses, and functions, such as the diaphragm, triceps, gracilis, tibialis anterior (TA), gastrocnemius (GA), soleus, extensor digitorum longus (EDL), and the masseter muscles. MuSCs and FAPs are purified by fluorescence-activated cell sorting (FACS) and analyzed by immunofluorescence staining and 5-ethynyl-2´-deoxyuridine (EdU) incorporation assay.
    DOI:  https://doi.org/10.3791/64557
  9. Curr Opin Pharmacol. 2022 Dec 23. pii: S1471-4892(22)00159-X. [Epub ahead of print]68 102332
    Update on anti-fibrotic pharmacotherapies in skeletal muscle disease.
    Laura Muraine, Mona Bensalah, Gillian Butler-Browne, Anne Bigot, Capucine Trollet, Vincent Mouly, Elisa Negroni.
      Fibrosis, defined as an excessive accumulation of extracellular matrix, is the end point of a defective regenerative process, unresolved inflammation and/or chronic damage. Numerous muscle disorders (MD) are characterized by high levels of fibrosis associated with muscle wasting and weakness. Fibrosis alters muscle homeostasis/regeneration and fiber environment and may interfere with gene and cell therapies. Slowing down or reversing fibrosis is a crucial therapeutic goal to maintain muscle identity in the context of therapies. Several pathways are implicated in the modulation of the fibrotic progression and multiple therapeutic compounds targeting fibrogenic signals have been tested in MDs, mostly in the context of Duchenne Muscular Dystrophy. In this review, we present an up-to-date overview of pharmacotherapies that have been tested to reduce fibrosis in the skeletal muscle.
    DOI:  https://doi.org/10.1016/j.coph.2022.102332
  10. Function (Oxf). 2023 ;4(1): zqac059
    Skeletal Muscle Nuclei in Mice are not Post-mitotic.
    Agnieszka K Borowik, Arik Davidyan, Frederick F Peelor, Evelina Voloviceva, Stephen M Doidge, Matthew P Bubak, Christopher B Mobley, John J McCarthy, Esther E Dupont-Versteegden, Benjamin F Miller.
      The skeletal muscle research field generally accepts that nuclei in skeletal muscle fibers (ie, myonuclei) are post-mitotic and unable to proliferate. Because our deuterium oxide (D2O) labeling studies showed DNA synthesis in skeletal muscle tissue, we hypothesized that resident myonuclei can replicate in vivo. To test this hypothesis, we used a mouse model that temporally labeled myonuclei with GFP followed by D2O labeling during normal cage activity, functional overload, and with satellite cell ablation. During normal cage activity, we observed deuterium enrichment into myonuclear DNA in 7 out of 7 plantaris (PLA), 6 out of 6 tibialis anterior (TA), 5 out of 7 gastrocnemius (GAST), and 7 out of 7 quadriceps (QUAD). The average fractional synthesis rates (FSR) of DNA in myonuclei were: 0.0202 ± 0.0093 in PLA, 0.0239 ± 0.0040 in TA, 0.0076 ± 0. 0058 in GAST, and 0.0138 ± 0.0039 in QUAD, while there was no replication in myonuclei from EDL. These FSR values were largely reproduced in the overload and satellite cell ablation conditions, although there were higher synthesis rates in the overloaded PLA muscle. We further provided evidence that myonuclear replication is through endoreplication, which results in polyploidy. These novel findings contradict the dogma that skeletal muscle nuclei are post-mitotic and open potential avenues to harness the intrinsic replicative ability of myonuclei for muscle maintenance and growth.
    Keywords:  DNA synthesis; Growth; Muscle; Stable isotope; myonuclei
    DOI:  https://doi.org/10.1093/function/zqac059
  11. J Pers Med. 2022 Nov 08. pii: 1868. [Epub ahead of print]12(11):
    The Cellular and Molecular Signature of ALS in Muscle.
    Ekene Anakor, William John Duddy, Stephanie Duguez.
      Amyotrophic lateral sclerosis is a disease affecting upper and lower motor neurons. Although motor neuron death is the core event of ALS pathology, it is increasingly recognized that other tissues and cell types are affected in the disease, making potentially major contributions to the occurrence and progression of pathology. We review here the known cellular and molecular characteristics of muscle tissue affected by ALS. Evidence of toxicity in skeletal muscle tissue is considered, including metabolic dysfunctions, impaired proteostasis, and deficits in muscle regeneration and RNA metabolism. The role of muscle as a secretory organ, and effects on the skeletal muscle secretome are also covered, including the increase in secretion of toxic factors or decrease in essential factors that have consequences for neuronal function and survival.
    Keywords:  motor neurone disease; muscle metabolism; muscle regeneration; muscle secretome; muscle-nerve communication; neuromuscular junction
    DOI:  https://doi.org/10.3390/jpm12111868
  12. Aging (Albany NY). 2022 Dec 30. 14
    Transcriptomic analysis of human ALS skeletal muscle reveals a disease-specific pattern of dysregulated circRNAs.
    Dimitrios Tsitsipatis, Krystyna Mazan-Mamczarz, Ying Si, Allison B Herman, Jen-Hao Yang, Abhishek Guha, Yulan Piao, Jinshui Fan, Jennifer L Martindale, Rachel Munk, Xiaoling Yang, Supriyo De, Brijesh K Singh, Ritchie Ho, Myriam Gorospe, Peter H King.
      Circular RNAs are abundant, covalently closed transcripts that arise in cells through back-splicing and display distinct expression patterns across cells and developmental stages. While their functions are largely unknown, their intrinsic stability has made them valuable biomarkers in many diseases. Here, we set out to examine circRNA patterns in amyotrophic lateral sclerosis (ALS). By RNA-sequencing analysis, we first identified circRNAs and linear RNAs that were differentially abundant in skeletal muscle biopsies from ALS compared to normal individuals. By RT-qPCR analysis, we confirmed that 8 circRNAs were significantly elevated and 10 were significantly reduced in ALS, while the linear mRNA counterparts, arising from shared precursor RNAs, generally did not change. Several of these circRNAs were also differentially abundant in motor neurons derived from human induced pluripotent stem cells (iPSCs) bearing ALS mutations, and across different disease stages in skeletal muscle from a mouse model of ALS (SOD1G93A). Interestingly, a subset of the circRNAs significantly elevated in ALS muscle biopsies were significantly reduced in the spinal cord samples from ALS patients and ALS (SOD1G93A) mice. In sum, we have identified differentially abundant circRNAs in ALS-relevant tissues (muscle and spinal cord) that could inform about neuromuscular molecular programs in ALS and guide the development of therapies.
    Keywords:  amyotrophic lateral sclerosis; circular RNAs; human skeletal muscle; human spinal cord tissue; neurodegenerative disease
    DOI:  https://doi.org/10.18632/aging.204450
  13. Am J Physiol Cell Physiol. 2022 Dec 26.
    Improving Physiological Relevance of Cell Culture: The Possibilities, Considerations and Future Directions of the Ex Vivo Co-Culture Model.
    Sophie L Allen, Bradley T Elliott, Brian P Carson, Leigh Breen.
      In vitro models provide an important platform for the investigation of cellular growth and atrophy to inform, or extend mechanistic insights from, logistically challenging in vivo trials. While these models allow for the identification of candidate mechanistic pathways, many models involve supraphysiological dosages, non-physiological conditions, or experimental changes relating to individual proteins or receptors, all of which limit translation to human trials. To overcome these drawbacks, the use of ex vivo human plasma and serum has been used in cellular models to investigate changes in myotube hypertrophy, cellular protein synthesis, anabolic and catabolic markers in response to differing age, disease states, and nutrient status. However, there are currently no concurrent guidelines outlining the optimal methodology for this model. This review discusses the key methodological considerations surrounding the use of ex vivoplasma and serum, with a focus in application to skeletal muscle cell lines (i.e., C2C12, L6 and LHCN-M2) and human primary skeletal muscle cells (HSMC) as a means to investigate molecular signaling in models of atrophy and hypertrophy, alongside future directions.
    Keywords:  cell culture; ex vivo; in vitro; plasma; serum
    DOI:  https://doi.org/10.1152/ajpcell.00473.2022
  14. Elife. 2022 Dec 30. pii: e68180. [Epub ahead of print]11
    Heterogeneous levels of delta-like 4 within a multinucleated niche cell maintains muscle stem cell diversity.
    Susan Eliazer, Xuefeng Sun, Emilie Barruet, Andrew S Brack.
      The quiescent muscle stem cell (QSC) pool is heterogeneous and generally characterized by the presence and levels of intrinsic myogenic transcription factors. Whether extrinsic factors maintain the diversity of states across the QSC pool remains unknown. The muscle fiber is a multinucleated syncytium that serves as a niche to QSCs, raising the possibility that the muscle fiber regulates the diversity of states across the QSC pool. Here, we show that the muscle fiber maintains a continuum of quiescent states, through a gradient of Notch ligand, Dll4, produced by the fiber and captured by QSCs. The abundance of Dll4 captured by the QSC correlates with the protein levels of the stem cell (SC) identity marker, Pax7. Niche-specific loss of Dll4 decreases QSC diversity and shifts the continuum to cell states that are biased toward more proliferative and committed fates. We reveal that fiber-derived Mindbomb1 (Mib1), an E3 ubiquitin ligase activates Dll4 and controls the heterogeneous levels of Dll4. In response to injury, with a Dll4-replenished niche, the normal continuum and diversity of the SC pool is restored, demonstrating bidirectionality within the SC continuum. Our data show that a post-translational mechanism controls heterogeneity of Notch ligands in a multinucleated niche cell to maintain a continuum of metastable states within the SC pool during tissue homeostasis.
    Keywords:  cell biology; cell states; heterogeneity; metastable; mouse; muscle; niche; stem cells
    DOI:  https://doi.org/10.7554/eLife.68180
  15. Mol Biol Rep. 2022 Dec 26.
    Myokine, a key cytokine for physical exercise to alleviate sarcopenic obesity.
    Lei Zhang, Junjie Lv, Cenyi Wang, Yuanyuan Ren, Ming Yong.
      Skeletal muscle has a robust endocrine function as a powerful organ and can secrete and release cytokines or polypeptides known as myokines. These myokines have significant regulatory effects on signal transduction in skeletal muscle and the metabolism of peripheral tissues and organs and exert biological effects via autocrine, paracrine, or endocrine forms. Obesity and aging cause myokine secretion dysregulation, and hastening sarcopenic obesity (SO) development. Exercise is currently an excellent intervention and prevention method for SO. Meanwhile, exercise impacts many organs and tissues. These organs and tissues will produce various myokines in response to movement and metabolism throughout the body to govern muscle differentiation, growth, and remodeling. According to accumulating data, exercise can increase the release of myokines from diverse tissues into the blood and postpone the SO onset and progression by influencing protein metabolism, inflammation, mitochondrial quality control, and other mechanisms.
    Keywords:  Cytokine; Myokines; Physical exercise; Sarcopenic obesity
    DOI:  https://doi.org/10.1007/s11033-022-07821-3
  16. Am J Physiol Cell Physiol. 2022 Dec 26.
    The impact of high fat feeding and Parkin overexpression on skeletal muscle mass, mitochondrial respiration and H2O2 emission.
    Olivier Reynaud, Jennifer Wang, Marie-Belle Ayoub, Jean-Philippe Leduc-Gaudet, Dominique Mayaki, Maude Dulac, Sabah N A Hussain, Raynald Bergeron, Gilles Gouspillou.
      Obesity is a major risk factor for developing various health problems, including insulin resistance and type 2 diabetes. Although controversial, accumulation of mitochondrial dysfunction, and notably an increase in mitochondrial reactive oxygen species (ROS) production, was proposed as a key contributor leading to obesity-induced insulin resistance. Here, our goal was to investigate whether Parkin overexpression, a key regulator of the removal of dysfunctional mitochondria through mitophagy, could confer protection against obesity-induced mitochondrial dysfunction. To this end, intramuscular injections of adeno-associated viruses (AAV) were performed to overexpress Parkin in limb muscle of 6-month-old mice fed a control diet (CD) or a high fat diet (HFD) for 12 weeks. An AAV expressing GFP was used as control. HFD increased fat mass, altered glycemia and resulted in insulin resistance. Parkin overexpression resulted in an increase in muscle mass in both CD and HFD mice. In CD mice, Parkin overexpression increased maximal mitochondrial respiration and lowered H2O2 emission. HFD increased mitochondrial respiration and, surprisingly, also lowered H2O2 emission. Parkin overexpression did not significantly impact mitochondrial function in HFD mice. Taken altogether, our results indicate that Parkin overexpression positively impacts muscle and mitochondrial health under basal conditions and challenge the notion that intrinsic mitochondrial dysfunction is involved in the development of insulin resistance caused by high fat feeding.
    Keywords:  High fat diet; insulin resistance; mitochondrial function; obesity; skeletal muscle
    DOI:  https://doi.org/10.1152/ajpcell.00388.2022
  17. Front Pharmacol. 2022 ;13 1086662
    Creatine modulates cellular energy metabolism and protects against cancer cachexia-associated muscle wasting.
    Lulu Wei, Ranran Wang, Kai Lin, Xiaolu Jin, Li Li, Junaid Wazir, Wenyuan Pu, Panpan Lian, Renwei Lu, Shiyu Song, Quan Zhao, Jiabin Li, Hongwei Wang.
      Cancer cachexia is a multifactorial syndrome defined by progressive loss of body weight with specific depletion of skeletal muscle and adipose tissue. Since there are no FDA-approved drugs that are available, nutritional intervention is recommended as a supporting therapy. Creatine supplementation has an ergogenic effect in various types of sports training, but the regulatory effects of creatine supplementation in cancer cachexia remain unknown. In this study, we investigated the impact of creatine supplementation on cachectic weight loss and muscle loss protection in a tumor-bearing cachectic mouse model, and the underlying molecular mechanism of body weight protection was further assessed. We observed decreased serum creatine levels in patients with cancer cachexia, and the creatine content in skeletal muscle was also significantly decreased in cachectic skeletal muscle in the C26 tumor-bearing mouse model. Creatine supplementation protected against cancer cachexia-associated body weight loss and muscle wasting and induced greater improvements in grip strength. Mechanistically, creatine treatment altered the dysfunction and morphological abnormalities of mitochondria, thus protecting against cachectic muscle wasting by inhibiting the abnormal overactivation of the ubiquitin proteasome system (UPS) and autophagic lysosomal system (ALS). In addition, electron microscopy revealed that creatine supplementation alleviated the observed increase in the percentage of damaged mitochondria in C26 mice, indicating that nutritional intervention with creatine supplementation effectively counteracts mitochondrial dysfunction to mitigate muscle loss in cancer cachexia. These results uncover a previously uncharacterized role for creatine in cachectic muscle wasting by modulating cellular energy metabolism to reduce the level of muscle cell atrophy.
    Keywords:  autophagy; cancer cachexia; metabolism; mitochondria; ubiquitination
    DOI:  https://doi.org/10.3389/fphar.2022.1086662
  18. NPJ Regen Med. 2022 Dec 29. 7(1): 78
    Transplanting rejuvenated blood stem cells extends lifespan of aged immunocompromised mice.
    Sara Montserrat-Vazquez, Noelle J Ali, Francesca Matteini, Javier Lozano, Tu Zhaowei, Eva Mejia-Ramirez, Gina Marka, Angelika Vollmer, Karin Soller, Mehmet Sacma, Vadim Sakk, Loris Mularoni, Jan Philipp Mallm, Mireya Plass, Yi Zheng, Hartmut Geiger, M Carolina Florian.
      One goal of regenerative medicine is to rejuvenate tissues and extend lifespan by restoring the function of endogenous aged stem cells. However, evidence that somatic stem cells can be targeted in vivo to extend lifespan is still lacking. Here, we demonstrate that after a short systemic treatment with a specific inhibitor of the small RhoGTPase Cdc42 (CASIN), transplanting aged hematopoietic stem cells (HSCs) from treated mice is sufficient to extend the healthspan and lifespan of aged immunocompromised mice without additional treatment. In detail, we show that systemic CASIN treatment improves strength and endurance of aged mice by increasing the myogenic regenerative potential of aged skeletal muscle stem cells. Further, we show that CASIN modifies niche localization and H4K16ac polarity of HSCs in vivo. Single-cell profiling reveals changes in HSC transcriptome, which underlie enhanced lymphoid and regenerative capacity in serial transplantation assays. Overall, we provide proof-of-concept evidence that a short systemic treatment to decrease Cdc42 activity improves the regenerative capacity of different endogenous aged stem cells in vivo, and that rejuvenated HSCs exert a broad systemic effect sufficient to extend murine health- and lifespan.
    DOI:  https://doi.org/10.1038/s41536-022-00275-y
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