bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2023–04–30
forty-two papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Sphingolipids accumulate in aged muscle, and their reduction counteracts sarcopenia.
  2. NAD+ and human muscle health.
  3. Mitochondrial dynamics define muscle fiber type by modulating cellular metabolic pathways.
  4. Aging disrupts MANF-mediated immune modulation during skeletal muscle regeneration.
  5. Unravelling the Effects of Syndecan-4 Knockdown on Skeletal Muscle Functions.
  6. A human skeletal muscle stem/myotube model reveals multiple signaling targets of cancer secretome in skeletal muscle.
  7. Immune modulation by MANF improves regeneration in aged skeletal muscle.
  8. Neuromuscular electrical stimulation enhances the ability of serum extracellular vesicles to regenerate aged skeletal muscle after injury.
  9. Editorial: Muscle plasticity: Regulation of adaptive changes in muscles and mitochondrial dynamics.
  10. PARP1 mediated PARylation contributes to myogenic progression and glucocorticoid transcriptional response.
  11. New tools for the investigation of muscle fiber-type spatial distributions across histological sections.
  12. Electrical pulse stimulation-induced muscle contraction alters the microRNA and mRNA profiles of circulating extracellular vesicles in mice.
  13. Skeletal and cardiac muscle have different protein turnover responses in a model of right heart failure.
  14. CircTmeff1 Promotes Muscle Atrophy by Interacting with TDP-43 and Encoding A Novel TMEFF1-339aa Protein.
  15. Old muscle stem cells are rejuvenated by a young environment.
  16. PAC1 deficiency protects obese male mice from immobilization-induced muscle atrophy by suppressing FoxO-atrogene axis.
  17. Bile Acids Alter the Autophagy and Mitogenesis in Skeletal Muscle Cells.
  18. Sex-specific alteration in human muscle transcriptome with age.
  19. Metabolically fitter with fibronectin.
  20. Exercise Improves the Coordination of the Mitochondrial Unfolded Protein Response and Mitophagy in Aging Skeletal Muscle.
  21. Healthy aging and muscle function are positively associated with NAD+ abundance in humans.
  22. Passive heat stress induces mitochondrial adaptations in skeletal muscle.
  23. FiNuTyper: design and validation of an automated deep learning-based platform for simultaneous fiber and nucleus type analysis in human skeletal muscle.
  24. Generation of two induced pluripotent stem cell lines from spinal muscular atrophy type 1 patients carrying no functional copies of SMN1 gene.
  25. Stable isotope-labeled carnitine reveals its rapid transport into muscle cells and acetylation during contraction.
  26. Neutral Effect of Skeletal Muscle Mineralocorticoid Receptor on Glucose Metabolism in Mice.
  27. Combined effects of heavy ion exposure and simulated Lunar gravity on skeletal muscle.
  28. Branched-chain amino acid catabolism in muscle affects systemic BCAA levels but not insulin resistance.
  29. 3D bioprinted functional skeletal muscle models have potential applications for studies of muscle wasting in cancer cachexia.
  30. Regulation of Pax3 by Proteasomal Degradation of Monoubiquitinated Protein in Skeletal Muscle Progenitors.
  31. Structure-Function relationships in the skeletal muscle extracellular matrix.
  32. Age-related increase in CD47 reduces muscle repair.
  33. Polycomb Ezh1 maintains murine muscle stem cell quiescence through non-canonical regulation of Notch signaling.
  34. Dysregulated cellular redox status during hyperammonemia causes mitochondrial dysfunction and senescence by inhibiting sirtuin-mediated deacetylation.
  35. Biological age is increased by stress and restored upon recovery.
  36. Skeletal muscle mitochondrial interactome remodeling is linked to functional decline in aged female mice.
  37. Pleiotropic effects of mitochondria in aging.
  38. Natural antisense transcript of MYOG regulates development and regeneration in skeletal muscle by shielding the binding sites of MicroRNAs of MYOG mRNA 3'UTR.
  39. m6A epitranscriptomic regulation of tissue homeostasis during primate aging.
  40. Young extracellular vesicles rejuvenate aged muscle.
  41. Senescence diversity in muscle aging.
  42. Muscle Atrophy: From Bench to Bedside.
  1. Nat Aging. 2022 Dec;2(12): 1159-1175
    Sphingolipids accumulate in aged muscle, and their reduction counteracts sarcopenia.
    Pirkka-Pekka Laurila, Martin Wohlwend, Tanes Imamura de Lima, Peiling Luan, Sébastien Herzig, Nadège Zanou, Barbara Crisol, Maroun Bou-Sleiman, Eleonora Porcu, Hector Gallart-Ayala, Michal K Handzlik, Qi Wang, Suresh Jain, Davide D'Amico, Minna Salonen, Christian M Metallo, Zoltan Kutalik, Thomas O Eichmann, Nicolas Place, Julijana Ivanisevic, Jari Lahti, Johan G Eriksson, Johan Auwerx.
      Age-related muscle dysfunction and sarcopenia are major causes of physical incapacitation in older adults and currently lack viable treatment strategies. Here we find that sphingolipids accumulate in mouse skeletal muscle upon aging and that both genetic and pharmacological inhibition of sphingolipid synthesis prevent age-related decline in muscle mass while enhancing strength and exercise capacity. Inhibition of sphingolipid synthesis confers increased myogenic potential and promotes protein synthesis. Within the sphingolipid pathway, we show that accumulation of dihydroceramides is the culprit disturbing myofibrillar homeostasis. The relevance of sphingolipid pathways in human aging is demonstrated in two cohorts, the UK Biobank and Helsinki Birth Cohort Study in which gene expression-reducing variants of SPTLC1 and DEGS1 are associated with improved and reduced fitness of older individuals, respectively. These findings identify sphingolipid synthesis inhibition as an attractive therapeutic strategy for age-related sarcopenia and co-occurring pathologies.
    DOI:  https://doi.org/10.1038/s43587-022-00309-6
  2. Nat Aging. 2022 Mar;2(3): 195-196
    NAD+ and human muscle health.
    Stephen J Gardell, Paul M Coen.
      
    DOI:  https://doi.org/10.1038/s43587-022-00192-1
  3. Cell Rep. 2023 Apr 24. pii: S2211-1247(23)00445-X. [Epub ahead of print]42(5): 112434
    Mitochondrial dynamics define muscle fiber type by modulating cellular metabolic pathways.
    Tatsuki Yasuda, Takaya Ishihara, Ayaka Ichimura, Naotada Ishihara.
      Skeletal muscle is highly developed after birth, consisting of glycolytic fast-twitch and oxidative slow-twitch fibers; however, the mechanisms of fiber-type-specific differentiation are poorly understood. Here, we found an unexpected role of mitochondrial fission in the differentiation of fast-twitch oxidative fibers. Depletion of the mitochondrial fission factor dynamin-related protein 1 (Drp1) in mouse skeletal muscle and cultured myotubes results in specific reduction of fast-twitch muscle fibers independent of respiratory function. Altered mitochondrial fission causes activation of the Akt/mammalian target of rapamycin (mTOR) pathway via mitochondrial accumulation of mTOR complex 2 (mTORC2), and rapamycin administration rescues the reduction of fast-twitch fibers in vivo and in vitro. Under Akt/mTOR activation, the mitochondria-related cytokine growth differentiation factor 15 is upregulated, which represses fast-twitch fiber differentiation. Our findings reveal a crucial role of mitochondrial dynamics in the activation of mTORC2 on mitochondria, resulting in the differentiation of muscle fibers.
    Keywords:  Akt; CP: Metabolism; Drp1; GDF-15; mTOR; mitochondria; mitochondrial dynamics; muscle atrophy; muscle differentiation
    DOI:  https://doi.org/10.1016/j.celrep.2023.112434
  4. Nat Aging. 2023 Mar 23.
    Aging disrupts MANF-mediated immune modulation during skeletal muscle regeneration.
    Neuza S Sousa, Margarida F Brás, Inês B Antunes, Päivi Lindholm, Joana Neves, Pedro Sousa-Victor.
      Age-related decline in skeletal muscle regenerative capacity is multifactorial, yet the contribution of immune dysfunction to regenerative failure is unknown. Macrophages are essential for effective debris clearance and muscle stem cell activity during muscle regeneration, but the regulatory mechanisms governing macrophage function during muscle repair are largely unexplored. Here, we uncover a new mechanism of immune modulation operating during skeletal muscle regeneration that is disrupted in aged animals and relies on the regulation of macrophage function. The immune modulator mesencephalic astrocyte-derived neurotrophic factor (MANF) is induced following muscle injury in young mice but not in aged animals, and its expression is essential for regenerative success. Regenerative impairments in aged muscle are associated with defects in the repair-associated myeloid response similar to those found in MANF-deficient models and could be improved through MANF delivery. We propose that restoring MANF levels is a viable strategy to improve myeloid response and regenerative capacity in aged muscle.
    DOI:  https://doi.org/10.1038/s43587-023-00382-5
  5. Int J Mol Sci. 2023 Apr 08. pii: 6933. [Epub ahead of print]24(8):
    Unravelling the Effects of Syndecan-4 Knockdown on Skeletal Muscle Functions.
    Mónika Sztretye, Zoltán Singlár, Nyamkhuu Ganbat, Dána Al-Gaadi, Kitti Szabó, Zoltán Márton Köhler, László Dux, Anikó Keller-Pintér, László Csernoch, Péter Szentesi.
      The remodelling of the extracellular matrix plays an important role in skeletal muscle development and regeneration. Syndecan-4 is a cell surface proteoglycan crucial for muscle differentiation. Syndecan-4-/- mice have been reported to be unable to regenerate following muscle damage. To investigate the consequences of the decreased expression of Syndecan-4, we have studied the in vivo and in vitro muscle performance and the excitation-contraction coupling machinery in young and aged Syndecan-4+/- (SDC4) mice. In vivo grip force was decreased significantly as well as the average and maximal speed of voluntary running in SDC4 mice, regardless of their age. The maximal in vitro twitch force was reduced in both EDL and soleus muscles from young and aged SDC4 mice. Ca2+ release from the sarcoplasmic reticulum decreased significantly in the FDB fibres of young SDC4 mice, while its voltage dependence was unchanged regardless of age. These findings were present in muscles from young and aged mice as well. On C2C12 murine skeletal muscle cells, we have also found altered calcium homeostasis upon Syndecan-4 silencing. The decreased expression of Syndecan-4 leads to reduced skeletal muscle performance in mice and altered motility in C2C12 myoblasts via altered calcium homeostasis. The altered muscle force performance develops at an early age and is maintained throughout the life course of the animal until old age.
    Keywords:  Syndecan-4; aging; calcium homeostasis; force; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms24086933
  6. iScience. 2023 Apr 21. 26(4): 106541
    A human skeletal muscle stem/myotube model reveals multiple signaling targets of cancer secretome in skeletal muscle.
    Ruizhong Wang, Brijesh Kumar, Poornima Bhat-Nakshatri, Aditi S Khatpe, Michael P Murphy, Kristen E Wanczyk, Edward Simpson, Duojiao Chen, Hongyu Gao, Yunlong Liu, Emma H Doud, Amber L Mosley, Harikrishna Nakshatri.
      Skeletal muscle dysfunction or reprogramming due to the effects of the cancer secretome is observed in multiple malignancies. Although mouse models are routinely used to study skeletal muscle defects in cancer, because of species specificity of certain cytokines/chemokines in the secretome, a human model system is required. Here, we establish simplified multiple skeletal muscle stem cell lines (hMuSCs), which can be differentiated into myotubes. Using single nuclei ATAC-seq (snATAC-seq) and RNA-seq (snRNA-seq), we document chromatin accessibility and transcriptomic changes associated with the transition of hMuSCs to myotubes. Cancer secretome accelerated stem to myotube differentiation, altered the alternative splicing machinery and increased inflammatory, glucocorticoid receptor, and wound healing pathways in hMuSCs. Additionally, cancer secretome reduced metabolic and survival pathway associated miR-486, AKT, and p53 signaling in hMuSCs. hMuSCs underwent myotube differentiation when engrafted into NSG mice and thus providing a humanized in vivo skeletal muscle model system to study cancer cachexia.
    Keywords:  Cancer systems biology; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2023.106541
  7. Nat Aging. 2023 Apr 07.
    Immune modulation by MANF improves regeneration in aged skeletal muscle.
      
    DOI:  https://doi.org/10.1038/s43587-023-00411-3
  8. Exp Gerontol. 2023 Apr 20. pii: S0531-5565(23)00100-6. [Epub ahead of print] 112179
    Neuromuscular electrical stimulation enhances the ability of serum extracellular vesicles to regenerate aged skeletal muscle after injury.
    Allison C Bean, Amrita Sahu, Camilla Piechocki, Alice Gualerzi, Silvia Picciolini, Marzia Bedoni, Fabrisia Ambrosio.
      Exercise promotes healthy aging of skeletal muscle. This benefit may be mediated by youthful factors in the circulation released in response to an exercise protocol. While the bulk of the studies to date have explored soluble proteins as systemic mediators of rejuvenating effect of exercise on tissue function, here we showed that the beneficial effect of skeletal muscle contractile activity on aged muscle function is mediated, at least in part, by enhanced regenerative properties of circulating extracellular vesicles (EVs). Muscle contractile activity elicited by neuromuscular electrical stimulation (NMES) decreased intensity of expression of the tetraspanin surface marker, CD63, on circulating EVs. Moreover, NMES shifted the biochemical Raman fingerprint of circulating EVs in aged animals with significant changes in lipid and sugar content in response to NMES when compared to controls. As a demonstration of the physiological relevance of these EV changes, we showed that intramuscular administration of EVs derived from aged animals subjected to NMES enhanced aged skeletal muscle healing after injury. These studies suggest that repetitive muscle contractile activity enhances the regenerative properties of circulating EVs in aged animals.
    Keywords:  Aging; Exercise; Exosomes; Myokines; Regeneration; Regenerative rehabilitation
    DOI:  https://doi.org/10.1016/j.exger.2023.112179
  9. Front Physiol. 2023 ;14 1192759
    Editorial: Muscle plasticity: Regulation of adaptive changes in muscles and mitochondrial dynamics.
    Prasanna Katti, Yuho Kim, N Ravi Sundaresan, Gilles Gouspillou, Antentor Hinton.
      
    Keywords:  HIIT; TCAP-1; mitochondria; muscles; resistant exercise; sarcopenia
    DOI:  https://doi.org/10.3389/fphys.2023.1192759
  10. Cell Death Discov. 2023 Apr 22. 9(1): 133
    PARP1 mediated PARylation contributes to myogenic progression and glucocorticoid transcriptional response.
    Arnold Tan, Awais Z Younis, Alexander Evans, Jade V Creighton, Clare Coveny, David J Boocock, Craig Sale, Gareth G Lavery, Amanda S Coutts, Craig L Doig.
      The ADP-ribosyltransferase, PARP1 enzymatically generates and applies the post-translational modification, ADP-Ribose (ADPR). PARP1 roles in genome maintenance are well described, but recent work highlights roles in many fundamental processes including cellular identity and energy homeostasis. Herein, we show in both mouse and human skeletal muscle cells that PARP1-mediated PARylation is a regulator of the myogenic program and the muscle transcriptional response to steroid hormones. Chemical PARP1 modulation impacts the expression of major myocellular proteins, including troponins, key in dictating muscle contractile force. Whilst PARP1 in absence of DNA damage is often assumed to be basally inactive, we show PARylation to be acutely sensitive to extracellular glucose concentrations and the steroid hormone class, glucocorticoids which exert considerable authority over muscle tissue mass. Specifically, we find during myogenesis, a transient and significant rise in PAR. This early-stage differentiation event, if blocked with PARP1 inhibition, reduced the abundance of important muscle proteins in the fully differentiated myotubes. This suggests that PAR targets during early-stage differentiation are central to the proper development of the muscle contractile unit. We also show that reduced PARP1 in myoblasts impacts a variety of metabolic pathways in line with the recorded actions of glucocorticoids. Currently, as both regulators of myogenesis and muscle mass loss, glucocorticoids represent a clinical conundrum. Our work goes on to identify that PARP1 influences transcriptional activation by glucocorticoids of a subset of genes critical to human skeletal muscle pathology. These genes may therefore signify a regulatory battery of targets through which selective glucocorticoid modulation could be achieved. Collectively, our data provide clear links between PARP1-mediated PARylation and skeletal muscle homeostatic mechanisms crucial to tissue mass maintenance and endocrine response.
    DOI:  https://doi.org/10.1038/s41420-023-01420-2
  11. Skelet Muscle. 2023 04 22. 13(1): 7
    New tools for the investigation of muscle fiber-type spatial distributions across histological sections.
    Anna K Redmond, Tilman M Davies, Matthew R Schofield, Philip W Sheard.
       BACKGROUND: The functional and metabolic properties of skeletal muscles are partly a function of the spatial arrangement of fibers across the muscle belly. Many muscles feature a non-uniform spatial pattern of fiber types, and alterations to the arrangement can reflect age or disease and correlate with changes in muscle mass and strength. Despite the significance of this event, descriptions of spatial fiber-type distributions across a muscle section are mainly provided qualitatively, by eye. Whilst several quantitative methods have been proposed, difficulties in implementation have meant that robust statistical analysis of fiber type distributions has not yielded new insight into the biological processes that drive the age- or disease-related changes in fiber type distributions.
    METHODS: We review currently available approaches for analysis of data reporting fast/slow fiber type distributions on muscle sections before proposing a new method based on a generalized additive model. We compare current approaches with our new method by analysis of sections of three mouse soleus muscles that exhibit visibly different spatial fiber patterns, and we also apply our model to a dataset representing the fiber type proportions and distributions of the mouse tibialis anterior.
    RESULTS: We highlight how current methods can lead to differing interpretations when applied to the same dataset and demonstrate how our new method is the first to permit location-based estimation of fiber-type probabilities, in turn enabling useful graphical representation.
    CONCLUSIONS: We present an open-access online application that implements current methods as well as our new method and which aids the interpretation of a variety of statistical tools for the spatial analysis of muscle fiber distributions.
    Keywords:  Aging; Clumping; Fiber type; Neuromuscular disease; Pattern; Skeletal muscle; Spatial distribution; Statistical methods
    DOI:  https://doi.org/10.1186/s13395-023-00316-0
  12. Am J Physiol Regul Integr Comp Physiol. 2023 Apr 24.
    Electrical pulse stimulation-induced muscle contraction alters the microRNA and mRNA profiles of circulating extracellular vesicles in mice.
    Noriaki Kawanishi, Takaki Tominaga, Katsuhiko Suzuki.
      Extracellular vesicles, such as exosomes, are secreted by skeletal muscle tissues and may play a role in physiological adaptations induced by exercise. Endurance exercise changes the microRNA (miRNA) profile of circulating extracellular vesicles; however, the effects of resistance exercise are unknown. In this study, we examined the effect of resistance exercise as electrical pulse stimulation (EPS)-induced muscle contraction on the miRNA and mRNA profiles of circulating extracellular vesicles in mice using a comprehensive RNA sequencing-based approach. EPS-induced muscle contraction resulted in changes in the miRNA profile of circulating extracellular vesicles. In particular, 90 min after EPS-induced muscle contraction, a considerable increase in expression of muscle-specific microRNAs, such as miR-1, miR-133, and miR-206, was observed. Furthermore, we found that the expression of 208 mRNAs was considerably altered immediately after EPS-induced muscle contraction and that of 267 mRNAs changed considerably after 90 min. Gene ontology enrichment analysis showed that mRNA expression changes in circulating extracellular vesicles after EPS-induced muscle contraction promoted angiogenesis and regulated the immune response. Changes in the properties of circulating extracellular vesicles owing to muscle contraction may play an important role in resistance exercise-induced physiological adaptations.
    Keywords:  exosomes; extracellular vesicles; miRNA; muscle contraction
    DOI:  https://doi.org/10.1152/ajpregu.00121.2022
  13. Geroscience. 2023 Apr 29.
    Skeletal and cardiac muscle have different protein turnover responses in a model of right heart failure.
    Danielle R Bruns, Benjamin D McNair, Frederick F Peelor, Agnieszka K Borowik, Atul Pranay, Aykhan Yusifov, Benjamin F Miller.
      Right heart failure (RHF) is a common and deadly disease in aged populations. Extra-cardiac outcomes of RHF such as skeletal muscle atrophy contribute to morbidity and mortality. Despite the significance of maintaining right ventricular (RV) and muscle function, the mechanisms of RHF and muscle atrophy are unclear. Metformin (MET) improves cardiac and muscle function through the regulation of metabolism and the cellular stress response. However, whether MET is a viable therapeutic for RHF and muscle atrophy is not yet known. We used deuterium oxide labeling to measure individual protein turnover in the RV as well as subcellular skeletal muscle proteostasis in aged male mice subjected to 4 weeks of hypobaric hypoxia (HH)-induced RHF. Mice exposed to HH had elevated RV mass and impaired RV systolic function, neither of which was prevented by MET. HH resulted in a higher content of glycolytic, cardiac, and antioxidant proteins in the RV, most of which were inhibited by MET. The synthesis of these key RV proteins was generally unchanged by MET, suggesting MET accelerated protein breakdown. HH resulted in a loss of skeletal muscle mass due to inhibited protein synthesis alongside myofibrillar protein breakdown. MET did not impact HH-induced muscle protein turnover and did not prevent muscle wasting. Together, we show tissue-dependent responses to HH-induced RHF where the RV undergoes hypertrophic remodeling with higher expression of metabolic and stress response proteins. Skeletal muscle undergoes loss of protein mass and atrophy, primarily due to myofibrillar protein breakdown. MET did not prevent HH-induced RV dysfunction or muscle wasting, suggesting that the identification of other therapies to attenuate RHF and concomitant muscle atrophy is warranted.
    Keywords:  Hypoxia; Metformin aging; Muscle atrophy; Right ventricle
    DOI:  https://doi.org/10.1007/s11357-023-00777-7
  14. Adv Sci (Weinh). 2023 Apr 23. e2206732
    CircTmeff1 Promotes Muscle Atrophy by Interacting with TDP-43 and Encoding A Novel TMEFF1-339aa Protein.
    Rui Chen, Tingting Yang, Bing Jin, Wanru Xu, Yuwei Yan, Nathanael Wood, H Immo Lehmann, Siqi Wang, Xiaolan Zhu, Weilin Yuan, Hongjian Chen, Zhengyu Liu, Guoping Li, T Scott Bowen, Jin Li, Junjie Xiao.
      Skeletal muscle atrophy is a common clinical feature of many acute and chronic conditions. Circular RNAs (circRNAs) are covalently closed RNA transcripts that are involved in various physiological and pathological processes, but their role in muscle atrophy remains unknown. Global circRNA expression profiling indicated that circRNAs are involved in the pathophysiological processes of muscle atrophy. circTmeff1 is identified as a potential circRNA candidate that influences muscle atrophy. It is further identified that circTmeff1 is highly expressed in multiple types of muscle atrophy in vivo and in vitro. Moreover, the overexpression of circTmeff1 triggers muscle atrophy in vitro and in vivo, while the knockdown of circTmeff1 expression rescues muscle atrophy in vitro and in vivo. In particular, the knockdown of circTmeff1 expression partially rescues muscle mass in mice during established atrophic settings. Mechanistically, circTmeff1 directly interacts with TAR DNA-binding protein 43 (TDP-43) and promotes aggregation of TDP-43 in mitochondria, which triggers the release of mitochondrial DNA (mtDNA) into cytosol and activation of the cyclic GMP-AMP synthase (cGAS)/ stimulator of interferon genes (STING) pathway. Unexpectedly, TMEFF1-339aa is identified as a novel protein encoded by circTmeff1 that mediates its pro-atrophic effects. Collectively, the inhibition of circTmeff1 represents a novel therapeutic approach for multiple types of skeletal muscle atrophy.
    Keywords:  TDP-43; circular RNA; muscle atrophy; translation
    DOI:  https://doi.org/10.1002/advs.202206732
  15. Nat Aging. 2023 Mar;3(3): 241
    Old muscle stem cells are rejuvenated by a young environment.
    Hannah Walters.
      
    DOI:  https://doi.org/10.1038/s43587-023-00386-1
  16. Endocrinology. 2023 Apr 27. pii: bqad065. [Epub ahead of print]
    PAC1 deficiency protects obese male mice from immobilization-induced muscle atrophy by suppressing FoxO-atrogene axis.
    Qifang Li, Kiyo-Aki Ishii, Kyoko Kamoshita, Kenta Takahashi, Halimulati Abuduwaili, Hiroaki Takayama, Cynthia M Galicia-Medina, Ryota Tanida, Hein Ko Oo, Guzel Gafiyatullina, Xingyu Yao, Tuerdiguli Abuduyimiti, Jun Hamazaki, Hisanori Goto, Yujiro Nakano, Yumie Takeshita, Kenichi Harada, Shigeo Murata, Toshinari Takamura.
      Muscle atrophy is the cause and consequence of obesity. Proteasome dysfunction mediates obesity-induced endoplasmic reticulum (ER) stress and insulin resistance in the liver and adipose tissues. However, obesity-associated regulation of proteasome function and its role in the skeletal muscles remains under-investigated. Here, we established skeletal muscle-specific 20S proteasome assembly chaperone-1 (PAC1) knockout (mPAC1KO) mice. A high-fat diet (HFD) activated proteasome function by ∼8 fold in the skeletal muscles, which was reduced by 50% in mPAC1KO mice. mPAC1KO induced unfolded protein responses in the skeletal muscles, which were reduced by HFD. Although the skeletal muscle mass and functions were not different between the genotypes, genes involved in the ubiquitin proteasome complex, immune response, endoplasmic stress, and myogenesis were coordinately upregulated in the skeletal muscles of mPAC1KO mice. Therefore, we introduced an immobilization-induced muscle atrophy model in obesity by combining HFD and immobilization. mPAC1KO downregulated atrogin-1 and MuRF1, together with their upstream Foxo1 and Klf15, and protected against disused skeletal muscle mass reduction. In conclusion, obesity elevates proteasome functions in the skeletal muscles. PAC1 deficiency protects mice from immobilization-induced muscle atrophy in obesity. These findings suggest obesity-induced proteasome activation as a possible therapeutic target for immobilization-induced muscle atrophy.
    Keywords:  Atrogin-1; FoxO1; MuRF1; Muscle atrophy; Obesity; Proteasome
    DOI:  https://doi.org/10.1210/endocr/bqad065
  17. Adv Exp Med Biol. 2023 ;1408 183-199
    Bile Acids Alter the Autophagy and Mitogenesis in Skeletal Muscle Cells.
    Franco Tacchi, Josué Orozco-Aguilar, Mayalen Valero-Breton, Claudio Cabello-Verrugio.
      Muscle atrophy decreases muscle mass with the subsequent loss of muscle function. Among the mechanisms that trigger sarcopenia is mitochondrial dysfunction. Mitochondria, whose primary function is to produce ATP, are dynamic organelles that present the process of formation (mitogenesis) and elimination (mitophagy). Failure of any of these processes contributes to mitochondrial malfunction. Mitogenesis is mainly controlled by Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α), a transcriptional coactivator that regulates the expression of TFAM, which participates in mitogenesis. Mitophagy is a process of selective autophagy. Autophagy corresponds to a degradative pathway of protein complexes and organelles. Liver disease caused sarcopenia and increased bile acids in the blood. We demonstrated that the treatment with cholic (CA) or deoxycholic (DCA) bile acids generates mitochondrial dysfunction and loss of biomass. This work assessed whether CA and DCA alter autophagy and mitogenesis. For this, western blot evaluated the autophagy process by determining the protein levels of the LC3II/LC3I ratio. In addition, we assessed mitogenesis using a luciferase-coupled plasmid reporter for the PGC-1α promoter and the protein levels of TFAM by western blot. Our results indicate that treatment with CA or DCA induces autophagy, represented by an increase in the LC3II/LC3I ratio. In addition, a decreased autophagic flux was observed. On the other hand, when treated with CA or DCA, a decrease in the activity of the PGC-1α promoter was observed. However, the levels of TFAM increased in myotubes incubated with CA and DCA. Our results demonstrate that CA and DCA modulate autophagy ad mitogenesis in C2C12 myotubes.
    Keywords:  Autophagy; Bile acids; Mitochondrial biogenesis; Mitophagy; Sarcopenia
    DOI:  https://doi.org/10.1007/978-3-031-26163-3_10
  18. Geroscience. 2023 Apr 27.
    Sex-specific alteration in human muscle transcriptome with age.
    Mohini Gharpure, Jie Chen, Resheek Nerella, Sagar Vyavahare, Sandeep Kumar, Carlos M Isales, Mark Hamrick, Satish Adusumilli, Sadanand Fulzele.
      Sarcopenia is a medical condition that progressively develops with age and results in reduced skeletal muscle mass, alteration in muscle composition, and decreased muscle strength. Several clinical studies suggested that sarcopenia disproportionally affects males and females with age. Despite this knowledge, the molecular mechanism governing the pathophysiology is not well understood in a sex-specific manner. In this study, we utilized human gastrocnemius muscles from males and females to identify differentially regulated genes with age. We found 269 genes with at least a twofold expression difference in the aged muscle transcriptome. Among the female muscle samples, there were 239 differentially regulated genes, and the novel protein-coding genes include KIF20A, PIMREG, MTRNR2L6, TRPV6, EFNA2, RNF24, and SFN. In aged male skeletal muscle, there were 166 differentially regulated genes, and the novel-protein coding genes are CENPK, CDKN2A, BHLHA15, and EPHA. Gene Ontology (GO) enrichment revealed glucose catabolism, NAD metabolic processes, and muscle fiber transition pathways that are involved in aged female skeletal muscle, whereas replicative senescence, cytochrome C release, and muscle composition pathways are disrupted in aged male skeletal muscle. Targeting these novels, differentially regulated genes, and signaling pathways could serve as sex-specific therapeutic targets to combat the age-related onset of sarcopenia and promote healthy aging.
    Keywords:  Aging; Muscle; Sarcopenia; Sex
    DOI:  https://doi.org/10.1007/s11357-023-00795-5
  19. Sci Signal. 2023 04 25. 16(782): eadi3398
    Metabolically fitter with fibronectin.
    Wei Wong.
      Activation of hepatic autophagy by skeletal muscle-secreted fibronectin underlies the metabolic benefits of exercise.
    DOI:  https://doi.org/10.1126/scisignal.adi3398
  20. Life (Basel). 2023 Apr 13. pii: 1006. [Epub ahead of print]13(4):
    Exercise Improves the Coordination of the Mitochondrial Unfolded Protein Response and Mitophagy in Aging Skeletal Muscle.
    Yan Wang, Jialin Li, Ziyi Zhang, Runzi Wang, Hai Bo, Yong Zhang.
      The mitochondrial unfolded protein response (UPRmt) and mitophagy are two mitochondrial quality control (MQC) systems that work at the molecular and organelle levels, respectively, to maintain mitochondrial homeostasis. Under stress conditions, these two processes are simultaneously activated and compensate for each other when one process is insufficient, indicating mechanistic coordination between the UPRmt and mitophagy that is likely controlled by common upstream signals. This review focuses on the molecular signals regulating this coordination and presents evidence showing that this coordination mechanism is impaired during aging and promoted by exercise. Furthermore, the bidirectional regulation of reactive oxygen species (ROS) and AMPK in modulating this mechanism is discussed. The hierarchical surveillance network of MQC can be targeted by exercise-derived ROS to attenuate aging, which offers a molecular basis for potential therapeutic interventions for sarcopenia.
    Keywords:  UPRmt; aging; endurance exercise; mitochondrial homeostasis; mitochondrial network; mitophagy; reactive oxygen species; skeletal muscle
    DOI:  https://doi.org/10.3390/life13041006
  21. Nat Aging. 2022 Mar;2(3): 254-263
    Healthy aging and muscle function are positively associated with NAD+ abundance in humans.
    Georges E Janssens, Lotte Grevendonk, Ruben Zapata Perez, Bauke V Schomakers, Johan de Vogel-van den Bosch, Jan M W Geurts, Michel van Weeghel, Patrick Schrauwen, Riekelt H Houtkooper, Joris Hoeks.
      Skeletal muscle is greatly affected by aging, resulting in a loss of metabolic and physical function. However, the underlying molecular processes and how (lack of) physical activity is involved in age-related metabolic decline in muscle function in humans is largely unknown. Here, we compared, in a cross-sectional study, the muscle metabolome from young to older adults, whereby the older adults were exercise trained, had normal physical activity levels or were physically impaired. Nicotinamide adenine dinucleotide (NAD+) was one of the most prominent metabolites that was lower in older adults, in line with preclinical models. This lower level was even more pronounced in impaired older individuals, and conversely, exercise-trained older individuals had NAD+ levels that were more similar to those found in younger individuals. NAD+ abundance positively correlated with average number of steps per day and mitochondrial and muscle functioning. Our work suggests that a clear association exists between NAD+ and health status in human aging.
    DOI:  https://doi.org/10.1038/s43587-022-00174-3
  22. Int J Hyperthermia. 2023 ;40(1): 2205066
    Passive heat stress induces mitochondrial adaptations in skeletal muscle.
    Erik D Marchant, W Bradley Nelson, Robert D Hyldahl, Jayson R Gifford, Chad R Hancock.
      The mitochondria are central to skeletal muscle metabolic health. Impaired mitochondrial function is associated with various muscle pathologies, including insulin resistance and muscle atrophy. As a result, continuous efforts are made to find ways to improve mitochondrial health in the context of disuse and disease. While exercise is known to cause robust improvements in mitochondrial health, not all individuals are able to exercise. This creates a need for alternate interventions which elicit some of the same benefits as exercise. Passive heating (i.e., application of heat in the absence of muscle contractions) is one potential intervention which has been shown to increase mitochondrial enzyme content and activity, and to improve mitochondrial respiration. Associated with increases in mitochondrial content and/or function, passive heating can also improve insulin sensitivity in the context of type II diabetes and preserve muscle mass in the face of limb disuse. This area of research remains in its infancy, with many questions yet to be answered about how to maximize the benefits of passive heating and elucidate the mechanisms by which heat stress affects muscle mitochondria.
    Keywords:  HSP; Heat; atrophy; chaperones; heat shock response (i.e.; hypoxia; metabolism; microenvironment; mitochondria; pH; perfusion effects; physiological effects of hyperthermia (i.e.,; redox); skeletal muscle; thermal; thermotolerance)
    DOI:  https://doi.org/10.1080/02656736.2023.2205066
  23. Acta Physiol (Oxf). 2023 Apr 25. e13982
    FiNuTyper: design and validation of an automated deep learning-based platform for simultaneous fiber and nucleus type analysis in human skeletal muscle.
    August Lundquist, Enikő Lázár, Nan Sophia Han, Eric B Emanuelsson, Stefan M Reitzner, Mark A Chapman, Vera Shirokova, Kanar Alkass, Henrik Druid, Susanne Petri, Carl Johan Sundberg, Olaf Bergmann.
       AIM: While manual quantification is still considered the gold standard for skeletal muscle histological analysis, it is time-consuming and prone to investigator bias. To address this challenge, we assembled an automated image analysis pipeline, FiNuTyper (Fiber and Nucleus Typer).
    METHODS: We integrated recently developed deep learning-based image segmentation methods, optimized for unbiased evaluation of fresh and postmortem human skeletal muscle, and utilized SERCA1 and SERCA2 as type-specific myonucleus and myofiber markers after validating them against the traditional use of MyHC isoforms.
    RESULTS: Parameters including cross-sectional area, myonuclei per fiber, myonuclear domain, central myonuclei per fiber, and grouped myofiber ratio were determined in a fiber type-specific manner, revealing that a large degree of sex- and muscle-related heterogeneity could be detected using the pipeline. Our platform was also tested on pathological muscle tissue (ALS and IBM) and adapted for the detection of other resident cell types (leukocytes, satellite cells, capillary endothelium).
    CONCLUSION: In summary, we present an automated image analysis tool for the simultaneous quantification of myofiber and myonuclear types, to characterize the composition and structure of healthy and diseased human skeletal muscle.
    Keywords:  SERCA; Skeletal muscle; automated image analysis; myofibers; myonuclei
    DOI:  https://doi.org/10.1111/apha.13982
  24. Stem Cell Res. 2023 Apr 17. pii: S1873-5061(23)00081-8. [Epub ahead of print]69 103095
    Generation of two induced pluripotent stem cell lines from spinal muscular atrophy type 1 patients carrying no functional copies of SMN1 gene.
    Wenshu Zeng, Xiaohui Kong, Christina Alamana, Yu Liu, Jessica Guzman, Paul D Pang, John W Day, Joseph C Wu.
      Spinal muscular atrophy (SMA) is a severe neurodegenerative muscular disease caused by the homozygous loss of survival of motor neuron 1 (SMN1) genes. SMA patients exhibit marked skeletal muscle (SKM) loss, eventually leading to death. Here we generated two iPSC lines from two SMA type I patients with homozygous SMN1 mutations and validated the pluripotency and the ability to differentiate into three germ layers. The iPSC lines can be applied to generate skeletal muscles to model muscle atrophy of SMA that persists after treatment of motor neurons and will serve as a complementary platform for drug screening in vitro.
    Keywords:  Disease modeling; Human induced pluripotent stem cells; Skeletal muscle (SKM); Spinal muscular atrophy (SMA); Survival of motor neuron (SMN1)
    DOI:  https://doi.org/10.1016/j.scr.2023.103095
  25. Heliyon. 2023 Apr;9(4): e15281
    Stable isotope-labeled carnitine reveals its rapid transport into muscle cells and acetylation during contraction.
    Yasuro Furuichi, Naoko Goto-Inoue, Saki Uchida, Shun Masuda, Yasuko Manabe, Nobuharu L Fujii.
      Carnitine plays multiple roles in skeletal muscle metabolism, including fatty acid transport and buffering of excess acetyl-CoA in the mitochondria. The skeletal muscle cannot synthesize carnitine; therefore, carnitine must be taken up from the blood into the cytoplasm. Carnitine metabolism, its uptake into cells, and the subsequent reactions of carnitine are accelerated by muscle contraction. Isotope tracing enables the marking of target molecules and monitoring of tissue distribution. In this study, stable isotope-labeled carnitine tracing was combined with matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) imaging to determine carnitine distribution in mouse skeletal muscle tissues. Deuterium-labeled carnitine (d3-carnitine) was intravenously injected into the mice and diffused to the skeletal muscles for 30 and 60 min. To examine whether muscle contraction changes the distribution of carnitine and its derivatives, unilateral in situ muscle contraction was performed; 60 min muscle contraction showed increased d3-carnitine and its derivative d3-acetylcarnitine in the muscle, indicating that carnitine uptake in cells is promptly converted to acetylcarnitine, consequently, buffering accumulated acetyl-CoA. While the endogenous carnitine was localized in the slow type fibers rather than fast type, the contraction-induced distributions of d3-carnitine and acetylcarnitine were not necessarily associated with muscle fiber type. In conclusion, the combination of isotope tracing and MALDI-MS imaging can reveal carnitine flux during muscle contraction and show the significance of carnitine in skeletal muscles.
    Keywords:  Acetylation; Mass spectrometry imaging; Metabolite tracing
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e15281
  26. Int J Mol Sci. 2023 Apr 18. pii: 7412. [Epub ahead of print]24(8):
    Neutral Effect of Skeletal Muscle Mineralocorticoid Receptor on Glucose Metabolism in Mice.
    Alessandra Feraco, Stefania Gorini, Caterina Mammi, Mauro Lombardo, Andrea Armani, Massimiliano Caprio.
      The mineralocorticoid receptor (MR) is able to regulate the transcription of a number of genes in the myotube, although its roles in skeletal muscle (SM) metabolism still await demonstration. SM represents a major site for glucose uptake, and its metabolic derangements play a pivotal role in the development of insulin resistance (IR). The aim of this study was to investigate the contribution of SM MR in mediating derangements of glucose metabolism in a mouse model of diet-induced obesity. We observed that mice fed a high-fat diet (HFD mice) showed impaired glucose tolerance compared to mice fed a normal diet (ND mice). Mice fed a 60% HFD treated with the MR antagonist Spironolactone (HFD + Spiro) for 12 weeks revealed an improvement in glucose tolerance, as measured with an intraperitoneal glucose tolerance test, compared with HFD mice. To investigate if blockade of SM MR could contribute to the favorable metabolic effects observed with pharmacological MR antagonism, we analyzed MR expression in the gastrocnemius, showing that SM MR protein abundance is downregulated by HFD compared to ND mice and that pharmacological treatment with Spiro was able to partially revert this effect in HFD + Spiro mice. Differently from what we have observed in adipose tissue, where HDF increased adipocyte MR expression, SM MR protein was down-regulated in our experimental model, suggesting a completely different role of SM MR in the regulation of glucose metabolism. To confirm this hypothesis, we investigated the effects of MR blockade on insulin signaling in a cellular model of IRin C2C12 myocytes, which were treated with or without Spiro. We confirmed MR protein downregulation in insulin-resistant myotubes. We also analyzed Akt phosphorylation upon insulin stimulation, and we did not observe any difference between palmitate- and palmitate + Spiro-treated cells. These results were confirmed by in vitro glucose uptake analysis. Taken together, our data indicate that reduced activity of SM MR does not improve insulin signaling in mouse skeletal myocytes and does not contribute to the favorable metabolic effects on glucose tolerance and IR induced by systemic pharmacological MR blockade.
    Keywords:  inflammation; insulin resistance; insulin signaling; lipid infiltration; myokines; obesity
    DOI:  https://doi.org/10.3390/ijms24087412
  27. Life Sci Space Res (Amst). 2023 May;pii: S2214-5524(23)00017-2. [Epub ahead of print]37 39-49
    Combined effects of heavy ion exposure and simulated Lunar gravity on skeletal muscle.
    Michael P Wiggs, Yang Lee, Kevin L Shimkus, Colleen I O'Reilly, Florence Lima, Brandon R Macias, Yasaman Shirazi-Fard, Elizabeth S Greene, Jeffrey M Hord, Leslie A Braby, Chad C Carroll, John M Lawler, Susan A Bloomfield, James D Fluckey.
       BACKGROUND: The limitations to prolonged spaceflight include unloading-induced atrophy of the musculoskeletal system which may be enhanced by exposure to the space radiation environment. Previous results have concluded that partial gravity, comparable to the Lunar surface, may have detrimental effects on skeletal muscle. However, little is known if these outcomes are exacerbated by exposure to low-dose rate, high-energy radiation common to the space environment. Therefore, the present study sought to determine the impact of highly charge, high-energy (HZE) radiation on skeletal muscle when combined with partial weightbearing to simulate Lunar gravity. We hypothesized that partial unloading would compromise skeletal muscle and these effects would be exacerbated by radiation exposure.
    METHODS: For month old female BALB/cByJ mice were -assigned to one of 2 groups; either full weight bearing (Cage Controls, CC) or partial weight bearing equal to 1/6th bodyweight (G/6). Both groups were then divided to receive either a single whole body absorbed dose of 0.5 Gy of 300 MeV 28Si ions (RAD) or a sham treatment (SHAM). Radiation exposure experiments were performed at the NASA Space Radiation Laboratory (NSRL) located at Brookhaven National Laboratory on Day 0, followed by 21 d of CC or G/6 loading. Muscles of the hind limb were used to measure protein synthesis and other histological measures.
    RESULTS: Twenty-one days of Lunar gravity (G/6) resulted in lower soleus, plantaris, and gastrocnemius muscle mass. Radiation exposure did not further impact muscle mass. 28Si exposure in normal ambulatory animals (RAD+CC) did not impact gastrocnemius muscle mass when compared to SHAM+CC (p>0.05), but did affect the soleus, where mass was higher following radiation compared to SHAM (p<0.05). Mixed gastrocnemius muscle protein synthesis was lower in both unloading groups. Fiber type composition transitioned towards a faster isoform with partial unloading and was not further impacted by radiation. The combined effects of partial loading and radiation partially mitigated fiber cross-sectional area when compared to partial loading alone. Radiation and G/6 reduced the total number of myonuclei per fiber while leading to elevated BrdU content of skeletal muscle. Similarly, unloading and radiation resulted in higher collagen content of muscle when compared to controls, but the effects of combined exposure were not additive.
    CONCLUSIONS: The results of this study confirm that partial weightbearing causes muscle atrophy, in part due to reductions of muscle protein synthesis in the soleus and gastrocnemius as well as reduced peripheral nuclei per fiber. Additionally, we present novel data illustrating 28Si exposure reduced nuclei in muscle fibers despite higher satellite cell fusion, but did not exacerbate muscle atrophy, CSA changes, or collagen content. In conclusion, both partial loading and HZE radiation can negatively impact muscle morphology.
    Keywords:  Disuse; HZE; Partial weight bearing; Protein synthesis; Radiation; Unloading
    DOI:  https://doi.org/10.1016/j.lssr.2023.02.003
  28. Nat Metab. 2023 Apr;5(4): 589-606
    Branched-chain amino acid catabolism in muscle affects systemic BCAA levels but not insulin resistance.
    Megan C Blair, Michael D Neinast, Cholsoon Jang, Qingwei Chu, Jae Woo Jung, Jessie Axsom, Marc R Bornstein, Chelsea Thorsheim, Kristina Li, Atsushi Hoshino, Steven Yang, Rachel J Roth Flach, Bei B Zhang, Joshua D Rabinowitz, Zoltan Arany.
      Elevated levels of plasma branched-chain amino acids (BCAAs) have been associated with insulin resistance and type 2 diabetes since the 1960s. Pharmacological activation of branched-chain α-ketoacid dehydrogenase (BCKDH), the rate-limiting enzyme of BCAA oxidation, lowers plasma BCAAs and improves insulin sensitivity. Here we show that modulation of BCKDH in skeletal muscle, but not liver, affects fasting plasma BCAAs in male mice. However, despite lowering BCAAs, increased BCAA oxidation in skeletal muscle does not improve insulin sensitivity. Our data indicate that skeletal muscle controls plasma BCAAs, that lowering fasting plasma BCAAs is insufficient to improve insulin sensitivity and that neither skeletal muscle nor liver account for the improved insulin sensitivity seen with pharmacological activation of BCKDH. These findings suggest potential concerted contributions of multiple tissues in the modulation of BCAA metabolism to alter insulin sensitivity.
    DOI:  https://doi.org/10.1038/s42255-023-00794-y
  29. Biomater Adv. 2023 Apr 19. pii: S2772-9508(23)00149-8. [Epub ahead of print]150 213426
    3D bioprinted functional skeletal muscle models have potential applications for studies of muscle wasting in cancer cachexia.
    Andrea García-Lizarribar, Aranzazu Villasante, Jose Antonio Lopez-Martin, Marta Flandez, M Carmen Soler-Vázquez, Dolors Serra, Laura Herrero, Ana Sagrera, Alejo Efeyan, Josep Samitier.
      Acquired muscle diseases such as cancer cachexia are responsible for the poor prognosis of many patients suffering from cancer. In vitro models are needed to study the underlying mechanisms of those pathologies. Extrusion bioprinting is an emerging tool to emulate the aligned architecture of fibers while implementing additive manufacturing techniques in tissue engineering. However, designing bioinks that reconcile the rheological needs of bioprinting and the biological requirements of muscle tissue is a challenging matter. Here we formulate a biomaterial with dual crosslinking to modulate the physical properties of bioprinted models. We design 3D bioprinted muscle models that resemble the mechanical properties of native tissue and show improved proliferation and high maturation of differentiated myotubes suggesting that the GelMA-AlgMA-Fibrin biomaterial possesses myogenic properties. The electrical stimulation of the 3D model confirmed the contractile capability of the tissue and enhanced the formation of sarcomeres. Regarding the functionality of the models, they served as platforms to recapitulate skeletal muscle diseases such as muscle wasting produced by cancer cachexia. The genetic expression of 3D models demonstrated a better resemblance to the muscular biopsies of cachectic mouse models. Altogether, this biomaterial is aimed to fabricate manipulable skeletal muscle in vitro models in a non-costly, fast and feasible manner.
    Keywords:  Bioprinting; Cachexia; Skeletal muscle; Tissue-engineering
    DOI:  https://doi.org/10.1016/j.bioadv.2023.213426
  30. Cell. 2023 Apr 27. pii: S0092-8674(23)00279-9. [Epub ahead of print]186(9): 2035
    Regulation of Pax3 by Proteasomal Degradation of Monoubiquitinated Protein in Skeletal Muscle Progenitors.
    Stéphane C Boutet, Marie-Hélène Disatnik, Lauren S Chan, Kevin Iori, Thomas A Rando.
      
    DOI:  https://doi.org/10.1016/j.cell.2023.03.018
  31. J Biomech. 2023 Apr 17. pii: S0021-9290(23)00162-8. [Epub ahead of print]152 111593
    Structure-Function relationships in the skeletal muscle extracellular matrix.
    Richard L Lieber, Gretchen Meyer.
      The vast majority of skeletal muscle biomechanical studies have rightly focused on its active contractile properties. However, skeletal muscle passive biomechanical properties have significant clinical impact in aging and disease and are yet incompletely understood. This review focuses on the passive biomechanical properties of the skeletal muscle extracellular matrix (ECM) and suggests aspects of its structural basis. Structural features of the muscle ECM such as perimysial cables, collagen cross-links and endomysial structures have been described, but the way in which these structures combine to create passive biomechanical properties is not completely known. We highlight the presence and organization of perimysial cables. We also demonstrate that the analytical approaches that define passive biomechanical properties are not necessarily straight forward. For example, multiple equations, such as linear, exponential, and polynomial are commonly used to fit raw stress-strain data. Similarly, multiple definitions of zero strain exist that affect muscle biomechanical property calculations. Finally, the appropriate length range over which to measure the mechanical properties is not clear. Overall, this review summarizes our current state of knowledge in these areas and suggests experimental approaches to measuring the structural and functional properties of skeletal muscle.
    Keywords:  Comparative biomechanics; Muscle mechanics; Passive stiffness; Titin
    DOI:  https://doi.org/10.1016/j.jbiomech.2023.111593
  32. Nat Aging. 2023 Jan;3(1): 6
    Age-related increase in CD47 reduces muscle repair.
    Yahyah Aman.
      
    DOI:  https://doi.org/10.1038/s43587-022-00359-w
  33. Dev Cell. 2023 Apr 24. pii: S1534-5807(23)00158-2. [Epub ahead of print]
    Polycomb Ezh1 maintains murine muscle stem cell quiescence through non-canonical regulation of Notch signaling.
    Xuesong Feng, A Hongjun Wang, Aster H Juan, Kyung Dae Ko, Kan Jiang, Giulia Riparini, Veronica Ciuffoli, Aissah Kaba, Christopher Lopez, Faiza Naz, Michal Jarnik, Elizabeth Aliberti, Shenyuan Hu, Jessica Segalés, Mamduh Khateb, Natalia Acevedo-Luna, Davide Randazzo, Tom H Cheung, Pura Muñoz-Cánoves, Stefania Dell'Orso, Vittorio Sartorelli.
      Organismal homeostasis and regeneration are predicated on committed stem cells that can reside for long periods in a mitotically dormant but reversible cell-cycle arrest state defined as quiescence. Premature escape from quiescence is detrimental, as it results in stem cell depletion, with consequent defective tissue homeostasis and regeneration. Here, we report that Polycomb Ezh1 confers quiescence to murine muscle stem cells (MuSCs) through a non-canonical function. In the absence of Ezh1, MuSCs spontaneously exit quiescence. Following repeated injuries, the MuSC pool is progressively depleted, resulting in failure to sustain proper muscle regeneration. Rather than regulating repressive histone H3K27 methylation, Ezh1 maintains gene expression of the Notch signaling pathway in MuSCs. Selective genetic reconstitution of the Notch signaling corrects stem cell number and re-establishes quiescence of Ezh1-/- MuSCs.
    Keywords:  Ezh1; Notch signaling; Polycomb; cilia; epigenetics; muscle regeneration; muscle stem cells
    DOI:  https://doi.org/10.1016/j.devcel.2023.04.005
  34. Aging Cell. 2023 Apr 26. e13852
    Dysregulated cellular redox status during hyperammonemia causes mitochondrial dysfunction and senescence by inhibiting sirtuin-mediated deacetylation.
    Saurabh Mishra, Nicole Welch, Manikandan Karthikeyan, Annette Bellar, Ryan Musich, Shashi Shekhar Singh, Dongmei Zhang, Jinendiran Sekar, Amy H Attaway, Aruna Chelluboyina, Shuhui Wang Lorkowski, Sanjoy Roychowdhary, Ling Li, Belinda Willard, Jonathan D Smith, Charles L Hoppel, Vidula Vachharajani, Avinash Kumar, Srinivasan Dasarathy.
      Perturbed metabolism of ammonia, an endogenous cytotoxin, causes mitochondrial dysfunction, reduced NAD+ /NADH (redox) ratio, and postmitotic senescence. Sirtuins are NAD+ -dependent deacetylases that delay senescence. In multiomics analyses, NAD metabolism and sirtuin pathways are enriched during hyperammonemia. Consistently, NAD+ -dependent Sirtuin3 (Sirt3) expression and deacetylase activity were decreased, and protein acetylation was increased in human and murine skeletal muscle/myotubes. Global acetylomics and subcellular fractions from myotubes showed hyperammonemia-induced hyperacetylation of cellular signaling and mitochondrial proteins. We dissected the mechanisms and consequences of hyperammonemia-induced NAD metabolism by complementary genetic and chemical approaches. Hyperammonemia inhibited electron transport chain components, specifically complex I that oxidizes NADH to NAD+ , that resulted in lower redox ratio. Ammonia also caused mitochondrial oxidative dysfunction, lower mitochondrial NAD+ -sensor Sirt3, protein hyperacetylation, and postmitotic senescence. Mitochondrial-targeted Lactobacillus brevis NADH oxidase (MitoLbNOX), but not NAD+ precursor nicotinamide riboside, reversed ammonia-induced oxidative dysfunction, electron transport chain supercomplex disassembly, lower ATP and NAD+ content, protein hyperacetylation, Sirt3 dysfunction and postmitotic senescence in myotubes. Even though Sirt3 overexpression reversed ammonia-induced hyperacetylation, lower redox status or mitochondrial oxidative dysfunction were not reversed. These data show that acetylation is a consequence of, but is not the mechanism of, lower redox status or oxidative dysfunction during hyperammonemia. Targeting NADH oxidation is a potential approach to reverse and potentially prevent ammonia-induced postmitotic senescence in skeletal muscle. Since dysregulated ammonia metabolism occurs with aging, and NAD+ biosynthesis is reduced in sarcopenia, our studies provide a biochemical basis for cellular senescence and have relevance in multiple tissues.
    Keywords:  acetylation; human inducible pluripotent stem cells; mitochondria; multiomics; redox; sirtuin; skeletal muscle; systems biology
    DOI:  https://doi.org/10.1111/acel.13852
  35. Cell Metab. 2023 Apr 04. pii: S1550-4131(23)00093-1. [Epub ahead of print]
    Biological age is increased by stress and restored upon recovery.
    Jesse R Poganik, Bohan Zhang, Gurpreet S Baht, Alexander Tyshkovskiy, Amy Deik, Csaba Kerepesi, Sun Hee Yim, Ake T Lu, Amin Haghani, Tong Gong, Anna M Hedman, Ellika Andolf, Göran Pershagen, Catarina Almqvist, Clary B Clish, Steve Horvath, James P White, Vadim N Gladyshev.
      Aging is classically conceptualized as an ever-increasing trajectory of damage accumulation and loss of function, leading to increases in morbidity and mortality. However, recent in vitro studies have raised the possibility of age reversal. Here, we report that biological age is fluid and exhibits rapid changes in both directions. At epigenetic, transcriptomic, and metabolomic levels, we find that the biological age of young mice is increased by heterochronic parabiosis and restored following surgical detachment. We also identify transient changes in biological age during major surgery, pregnancy, and severe COVID-19 in humans and/or mice. Together, these data show that biological age undergoes a rapid increase in response to diverse forms of stress, which is reversed following recovery from stress. Our study uncovers a new layer of aging dynamics that should be considered in future studies. The elevation of biological age by stress may be a quantifiable and actionable target for future interventions.
    Keywords:  aging; biological age; dynamics; epigenetic aging clocks; recovery; stress
    DOI:  https://doi.org/10.1016/j.cmet.2023.03.015
  36. Nat Aging. 2023 Mar;3(3): 313-326
    Skeletal muscle mitochondrial interactome remodeling is linked to functional decline in aged female mice.
    Anna A Bakhtina, Gavin A Pharaoh, Matthew D Campbell, Andrew Keller, Rudolph S Stuppard, David J Marcinek, James E Bruce.
      Genomic, transcriptomic and proteomic approaches have been used to gain insight into molecular underpinnings of aging in laboratory animals and in humans. However, protein function in biological systems is under complex regulation and includes factors besides abundance levels, such as modifications, localization, conformation and protein-protein interactions. By making use of quantitative chemical cross-linking technologies, we show that changes in the muscle mitochondrial interactome contribute to mitochondrial functional decline in aging in female mice. Specifically, we identify age-related changes in protein cross-links relating to assembly of electron transport system complexes I and IV, activity of glutamate dehydrogenase, and coenzyme-A binding in fatty acid β-oxidation and tricarboxylic acid cycle enzymes. These changes show a remarkable correlation with complex I respiration differences within the same young-old animal pairs. Each observed cross-link can serve as a protein conformational or protein-protein interaction probe in future studies, which will provide further molecular insights into commonly observed age-related phenotypic differences. Therefore, this data set could become a valuable resource for additional in-depth molecular studies that are needed to better understand complex age-related molecular changes.
    DOI:  https://doi.org/10.1038/s43587-023-00366-5
  37. Nat Aging. 2022 Mar;2(3): 199-213
    Pleiotropic effects of mitochondria in aging.
    Tanes Lima, Terytty Yang Li, Adrienne Mottis, Johan Auwerx.
      Aging is typified by a progressive decline in mitochondrial activity and stress resilience. Here, we review how mitochondrial stress pathways have pleiotropic effects on cellular and systemic homeostasis, which can comprise protective or detrimental responses during aging. We describe recent evidence arguing that defects in these conserved adaptive pathways contribute to aging and age-related diseases. Signaling pathways regulating the mitochondrial unfolded protein response, mitochondrial membrane dynamics, and mitophagy are discussed, emphasizing how their failure contributes to heteroplasmy and de-regulation of key metabolites. Our current understanding of how these processes are controlled and interconnected explains how mitochondria can widely impact fundamental aspects of aging.
    DOI:  https://doi.org/10.1038/s43587-022-00191-2
  38. Biochem Biophys Res Commun. 2023 Apr 18. pii: S0006-291X(23)00465-5. [Epub ahead of print]662 93-103
    Natural antisense transcript of MYOG regulates development and regeneration in skeletal muscle by shielding the binding sites of MicroRNAs of MYOG mRNA 3'UTR.
    Yunqian Yin, Genghua Chen, Zetong Lin, Danlu Zhang, Wujian Lin, Wen Luo.
      Natural antisense transcripts (NATs) are endogenous RNAs opposite to sense transcripts, and they can significantly contribute to regulating various biological processes through multiple epigenetic mechanisms. NATs can affect their sense transcripts to regulate the growth and development of skeletal muscle. Our analysis of third-generation full-length transcriptome sequencing data revealed that NATs represented a significant portion of the lncRNA, accounting for up to 30.19%-33.35%. The expression of NATs correlated with myoblast differentiation, and genes expressing NATs were mainly involved in RNA synthesis, protein transport, and cell cycle. We found a NAT of MYOG (MYOG-NAT) in the data. We found that the MYOG-NAT could promote the differentiation of myoblasts in vitro. Additionally, knockdown of MYOG-NAT in vivo led to muscle fiber atrophy and muscle regeneration retardation. Molecular biology experiments demonstrated that MYOG-NAT enhances the stability of MYOG mRNA by competing with miR-128-2-5p, miR-19a-5p, and miR-19b-5p for binding to MYOG mRNA 3'UTR. These findings suggest that MYOG-NAT plays a critical role in skeletal muscle development and provides insights into the post-transcriptional regulation of NATs.
    Keywords:  MYOG; Muscle differentiation; Muscle regeneration; Myoblast; Natural antisense transcript; Third-generation full-length transcriptome sequencing
    DOI:  https://doi.org/10.1016/j.bbrc.2023.04.050
  39. Nat Aging. 2023 Apr 06.
    m6A epitranscriptomic regulation of tissue homeostasis during primate aging.
    Zeming Wu, Mingming Lu, Di Liu, Yue Shi, Jie Ren, Si Wang, Ying Jing, Sheng Zhang, Qian Zhao, Hongyu Li, Zihui Yu, Zunpeng Liu, Shijia Bi, Tuo Wei, Yun-Gui Yang, Jingfa Xiao, Juan Carlos Izpisua Belmonte, Jing Qu, Weiqi Zhang, Weimin Ci, Guang-Hui Liu.
      How N6-methyladenosine (m6A), the most abundant mRNA modification, contributes to primate tissue homeostasis and physiological aging remains elusive. Here, we characterize the m6A epitranscriptome across the liver, heart and skeletal muscle in young and old nonhuman primates. Our data reveal a positive correlation between m6A modifications and gene expression homeostasis across tissues as well as tissue-type-specific aging-associated m6A dynamics. Among these tissues, skeletal muscle is the most susceptible to m6A loss in aging and shows a reduction in the m6A methyltransferase METTL3. We further show that METTL3 deficiency in human pluripotent stem cell-derived myotubes leads to senescence and apoptosis, and identify NPNT as a key element downstream of METTL3 involved in myotube homeostasis, whose expression and m6A levels are both decreased in senescent myotubes. Our study provides a resource for elucidating m6A-mediated mechanisms of tissue aging and reveals a METTL3-m6A-NPNT axis counteracting aging-associated skeletal muscle degeneration.
    DOI:  https://doi.org/10.1038/s43587-023-00393-2
  40. Nat Aging. 2021 Dec;1(12): 1078-1080
    Young extracellular vesicles rejuvenate aged muscle.
    Sara Ancel, Jerome N Feige.
      
    DOI:  https://doi.org/10.1038/s43587-021-00153-0
  41. Nat Aging. 2022 Jul;2(7): 570-572
    Senescence diversity in muscle aging.
    Matej Durik, William M Keyes.
      
    DOI:  https://doi.org/10.1038/s43587-022-00255-3
  42. Int J Mol Sci. 2023 Apr 20. pii: 7551. [Epub ahead of print]24(8):
    Muscle Atrophy: From Bench to Bedside.
    Daniel Taillandier.
      The loss of muscle mass is a common adaptation to some physiological situations (e [...].
    DOI:  https://doi.org/10.3390/ijms24087551
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