bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2024‒05‒26
37 papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Characterization of the skeletal muscle arginine methylome in health and disease reveals remodeling in amyotrophic lateral sclerosis.
  2. CISD3/MiNT is required for complex I function, mitochondrial integrity, and skeletal muscle maintenance.
  3. LncRNA 4930581F22Rik promotes myogenic differentiation by regulating the ERK/MAPK signaling pathway.
  4. Metabolome in Tibialis and Soleus Muscles in Wild-Type and Pin1 Knockout Mice through High-Resolution Magic Angle Spinning 1H Nuclear Magnetic Resonance Spectroscopy.
  5. Imaging analysis for muscle stem cells and regeneration.
  6. The interactive effect of sustained sleep restriction and resistance exercise on skeletal muscle transcriptomics in young females.
  7. Differential impact of sex on regulation of skeletal muscle mitochondrial function and protein homeostasis by hypoxia-inducible factor-1α in normoxia.
  8. mTORC1 and BMP-Smad1/5 Regulation of Serum-Stimulated Myotube Hypertrophy: A Role for Autophagy.
  9. CaMKIIβ deregulation contributes to neuromuscular junction destabilization in Myotonic Dystrophy type I.
  10. Fibro-adipogenic progenitors in physiological adipogenesis and intermuscular adipose tissue remodeling.
  11. Aberrant myonuclear domains and impaired myofiber contractility despite marked hypertrophy in MYMK-related, Carey-Fineman-Ziter Syndrome.
  12. Sexual Dimorphisms in Skeletal Muscle: Current Concepts and Research Horizons.
  13. High nitrate levels in skeletal muscle contribute to nitric oxide generation via a nitrate/nitrite reductive pathway in mice that lack the nNOS enzyme.
  14. Piperine enhances contractile force in slow- and fast-twitch muscle.
  15. Eliminating elevated p53 signaling fails to rescue skeletal muscle defects or extend survival in lamin A/C-deficient mice.
  16. Proteomic reference map for sarcopenia research: mass spectrometric identification of key muscle proteins located in the sarcomere, cytoskeleton and the extracellular matrix.
  17. Time-course and muscle-specific gene expression of matrix metalloproteinases and inflammatory cytokines in response to acute treadmill exercise in rats.
  18. Leucyl-tRNA synthetase contributes to muscle weakness through mTORC1 activation and autophagy suppression in a mouse model of Duchenne Muscular Dystrophy.
  19. Skeletal Muscle Injury in Chronic Kidney Disease-From Histologic Changes to Molecular Mechanisms and to Novel Therapies.
  20. Dirk Pette, remembered for his pioneering muscle research.
  21. Targeting skeletal muscle health with exercise in people with type 1 diabetes: A protocol for HOMET1D, a prospective observational trial with matched controls.
  22. Deciphering the Therapeutic Role of Lactate in Combating Disuse-Induced Muscle Atrophy: An NMR-Based Metabolomic Study in Mice.
  23. Eicosapentaenoic acid increases proportion of type 1 muscle fibers through PPARδ and AMPK pathways in rats.
  24. Wheat seedlings extract ameliorates sarcopenia in aged mice by regulating protein synthesis and degradation with anti-inflammatory and mitochondrial biogenesis effects.
  25. GDE5/Gpcpd1 activity determines phosphatidylcholine composition in skeletal muscle and regulates contractile force in mice.
  26. The effect of muscle ultrastructure on the force, displacement and work capacity of skeletal muscle.
  27. Ablation of Sam50 is associated with fragmentation and alterations in metabolism in murine and human myotubes.
  28. Transcriptomics reveals transient and dynamic muscle fibrosis and atrophy differences following spinal cord injury in rats.
  29. Single-cell spatial transcriptomics reveals a dystrophic trajectory following a developmental bifurcation of myoblast cell fates in facioscapulohumeral muscular dystrophy.
  30. Failure of Autophagy in Pompe Disease.
  31. Global consensus for sarcopenia.
  32. The glucocorticoid receptor acts locally to protect dystrophic muscle and heart during disease.
  33. Unravelling the complexity of the mitochondrial Ca2+ uniporter: regulation, tissue specificity, and physiological implications.
  34. The effects of whey, pea, and collagen protein supplementation beyond the recommended dietary allowance on integrated myofibrillar protein synthetic rates in older males: a randomized controlled trial.
  35. Proteasome gene expression is controlled by coordinated functions of multiple transcription factors.
  36. Characterising 24-h skeletal muscle gene expression alongside metabolic & endocrine responses under diurnal conditions.
  37. Influence of Amino Acids and Exercise on Muscle Protein Turnover, Particularly in Cancer Cachexia.
  1. FASEB J. 2024 May 31. 38(10): e23647
    Characterization of the skeletal muscle arginine methylome in health and disease reveals remodeling in amyotrophic lateral sclerosis.
    Julian P H Wong, Ronnie Blazev, Yaan-Kit Ng, Craig A Goodman, Magdalene K Montgomery, Kevin I Watt, Christian S Carl, Matthew J Watt, Christian T Voldstedlund, Erik A Richter, Peter J Crouch, Frederik J Steyn, Shyuan T Ngo, Benjamin L Parker.
      Arginine methylation is a protein posttranslational modification important for the development of skeletal muscle mass and function. Despite this, our understanding of the regulation of arginine methylation under settings of health and disease remains largely undefined. Here, we investigated the regulation of arginine methylation in skeletal muscles in response to exercise and hypertrophic growth, and in diseases involving metabolic dysfunction and atrophy. We report a limited regulation of arginine methylation under physiological settings that promote muscle health, such as during growth and acute exercise, nor in disease models of insulin resistance. In contrast, we saw a significant remodeling of asymmetric dimethylation in models of atrophy characterized by the loss of innervation, including in muscle biopsies from patients with myotrophic lateral sclerosis (ALS). Mass spectrometry-based quantification of the proteome and asymmetric arginine dimethylome of skeletal muscle from individuals with ALS revealed the largest compendium of protein changes with the identification of 793 regulated proteins, and novel site-specific changes in asymmetric dimethyl arginine (aDMA) of key sarcomeric and cytoskeletal proteins. Finally, we show that in vivo overexpression of PRMT1 and aDMA resulted in increased fatigue resistance and functional recovery in mice. Our study provides evidence for asymmetric dimethylation as a regulator of muscle pathophysiology and presents a valuable proteomics resource and rationale for numerous methylated and nonmethylated proteins, including PRMT1, to be pursued for therapeutic development in ALS.
    Keywords:  amyotrophic lateral sclerosis; arginine dimethylation; arginine methylation; proteomics; skeletal muscle
    DOI:  https://doi.org/10.1096/fj.202400045R
  2. Proc Natl Acad Sci U S A. 2024 May 28. 121(22): e2405123121
    CISD3/MiNT is required for complex I function, mitochondrial integrity, and skeletal muscle maintenance.
    Rachel Nechushtai, Linda Rowland, Ola Karmi, Henri-Baptiste Marjault, Thi Thao Nguyen, Shubham Mittal, Raheel S Ahmed, DeAna Grant, Camila Manrique-Acevedo, Faruck Morcos, José N Onuchic, Ron Mittler.
      Mitochondria play a central role in muscle metabolism and function. A unique family of iron-sulfur proteins, termed CDGSH Iron Sulfur Domain-containing (CISD/NEET) proteins, support mitochondrial function in skeletal muscles. The abundance of these proteins declines during aging leading to muscle degeneration. Although the function of the outer mitochondrial CISD/NEET proteins, CISD1/mitoNEET and CISD2/NAF-1, has been defined in skeletal muscle cells, the role of the inner mitochondrial CISD protein, CISD3/MiNT, is currently unknown. Here, we show that CISD3 deficiency in mice results in muscle atrophy that shares proteomic features with Duchenne muscular dystrophy. We further reveal that CISD3 deficiency impairs the function and structure of skeletal muscles, as well as their mitochondria, and that CISD3 interacts with, and donates its [2Fe-2S] clusters to, complex I respiratory chain subunit NADH Ubiquinone Oxidoreductase Core Subunit V2 (NDUFV2). Using coevolutionary and structural computational tools, we model a CISD3-NDUFV2 complex with proximal coevolving residue interactions conducive of [2Fe-2S] cluster transfer reactions, placing the clusters of the two proteins 10 to 16 Å apart. Taken together, our findings reveal that CISD3/MiNT is important for supporting the biogenesis and function of complex I, essential for muscle maintenance and function. Interventions that target CISD3 could therefore impact different muscle degeneration syndromes, aging, and related conditions.
    Keywords:  Duchenne muscular dystrophy; NDUFV2; NEET/CISD proteins; complex I; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2405123121
  3. Heliyon. 2024 May 15. 10(9): e30640
    LncRNA 4930581F22Rik promotes myogenic differentiation by regulating the ERK/MAPK signaling pathway.
    Wei-Cai Chen, Wan-Xin Chen, Ye-Ya Tan, Ying-Jun Xu, Yi Luo, Shi-Yu Qian, Wan-Yi Xu, Meng-Chun Huang, Yan-Hua Guo, Zhi-Gang Zhou, Qi Zhang, Jian-Xi Lu, Shu-Juan Xie.
      The skeletal muscle is the largest organ in mammals and is the primary motor function organ of the body. Our previous research has shown that long non-coding RNAs (lncRNAs) are significant in the epigenetic control of skeletal muscle development. Here, we observed progressive upregulation of lncRNA 4930581F22Rik expression during skeletal muscle differentiation. Knockdown of lncRNA 4930581F22Rik hindered skeletal muscle differentiation and resulted in the inhibition of the myogenic markers MyHC and MEF2C. Furthermore, we found that lncRNA 4930581F22Rik regulates myogenesis via the ERK/MAPK signaling pathway, and this effect could be attenuated by the ERK-specific inhibitor PD0325901. Additionally, in vivo mice injury model results revealed that lncRNA 4930581F22Rik is involved in skeletal muscle regeneration. These results establish a theoretical basis for understanding the contribution of lncRNAs in skeletal muscle development and regeneration.
    Keywords:  Differentiation; ERK/MAPK signaling; Regeneration; Skeletal muscle; lncRNA 4930581F22Rik
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e30640
  4. Metabolites. 2024 May 06. pii: 262. [Epub ahead of print]14(5):
    Metabolome in Tibialis and Soleus Muscles in Wild-Type and Pin1 Knockout Mice through High-Resolution Magic Angle Spinning 1H Nuclear Magnetic Resonance Spectroscopy.
    Valeria Righi, Martina Grosso, Renata Battini, Takafumi Uchida, Anna Gambini, Susanna Molinari, Adele Mucci.
      Skeletal muscles are heterogenous tissues composed of different myofiber types that can be classified as slow oxidative, fast oxidative, and fast glycolytic which are distinguished on the basis of their contractile and metabolic properties. Improving oxidative metabolism in skeletal muscles can prevent metabolic diseases and plays a protective role against muscle wasting in a number of neuromuscular diseases. Therefore, achieving a detailed understanding of the factors that regulate myofiber metabolic properties might provide new therapeutic opportunities for these diseases. Here, we investigated whether peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) is involved in the control of myofiber metabolic behaviors. Indeed, PIN1 controls glucose and lipid metabolism in a number of tissues, and it is also abundant in adult skeletal muscles; however, its role in the control of energy homeostasis in this tissue is still to be defined. To start clarifying this topic, we compared the metabolome of the tibialis anterior muscle (mainly glycolytic) and soleus muscle (oxidative) in wild-type and Pin1 knockout mice with High-Resolution Magic Angle Spinning (HR-MAS) NMR on intact tissues. Our analysis reveals a clear demarcation between the metabolomes in the two types of muscles and allows us to decode a signature able to discriminate the glycolytic versus oxidative muscle phenotype. We also detected some changes in Pin1-depleted muscles that suggest a role for PIN1 in regulating the metabolic phenotype of skeletal muscles.
    Keywords:  HR-MAS NMR spectroscopy; Pin1 KO mice; biomarkers; metabolic profile; metabolomics; skeletal muscle; slow and fast myofibers
    DOI:  https://doi.org/10.3390/metabo14050262
  5. Front Cell Dev Biol. 2024 ;12 1411401
    Imaging analysis for muscle stem cells and regeneration.
    Smrithi Karthikeyan, Atsushi Asakura.
      Composed of a diverse variety of cells, the skeletal muscle is one of the body's tissues with the remarkable ability to regenerate after injury. One of the key players in the regeneration process is the muscle satellite cell (MuSC), a stem cell population for skeletal muscle, as it is the source of new myofibers. Maintaining MuSC quiescence during homeostasis involves complex interactions between MuSCs and other cells in their corresponding niche in adult skeletal muscle. After the injury, MuSCs are activated to enter the cell cycle for cell proliferation and differentiate into myotubes, followed by mature myofibers to regenerate muscle. Despite decades of research, the exact mechanisms underlying MuSC maintenance and activation remain elusive. Traditional methods of analyzing MuSCs, including cell cultures, animal models, and gene expression analyses, provide some insight into MuSC biology but lack the ability to replicate the 3-dimensional (3-D) in vivo muscle environment and capture dynamic processes comprehensively. Recent advancements in imaging technology, including confocal, intra-vital, and multi-photon microscopies, provide promising avenues for dynamic MuSC morphology and behavior to be observed and characterized. This chapter aims to review 3-D and live-imaging methods that have contributed to uncovering insights into MuSC behavior, morphology changes, interactions within the muscle niche, and internal signaling pathways during the quiescence to activation (Q-A) transition. Integrating advanced imaging modalities and computational tools provides a new avenue for studying complex biological processes in skeletal muscle regeneration and muscle degenerative diseases such as sarcopenia and Duchenne muscular dystrophy (DMD).
    Keywords:  Duchenne muscular dystrophy; endothelial cell; muscle regeneration; muscle stem cell; myogenesis; niche; satellite cell; skeletal muscle
    DOI:  https://doi.org/10.3389/fcell.2024.1411401
  6. Physiol Genomics. 2024 May 20.
    The interactive effect of sustained sleep restriction and resistance exercise on skeletal muscle transcriptomics in young females.
    Olivia E Knowles, Megan Soria, Nicholas J Saner, Adam J Trewin, Sarah E Alexander, Spencer S H Roberts, Danielle Hiam, Andrew P Garnham, Eric J Drinkwater, Brad Aisbett, Séverine Lamon.
      INTRODUCTION: Both sleep loss and exercise regulate gene expression in skeletal muscle, yet little is known about how the interaction of these stressors affects the muscle transcriptome. The aim of this study was to investigate the effect of nine nights of sleep restriction, with repeated resistance exercise (REx) sessions, on the skeletal muscle transcriptome of young, trained females.METHODS: Ten healthy females aged 18-35 years undertook a randomised cross-over study of nine nights' sleep restriction (SR; 5-h time in bed) and normal sleep (NS; ≥7 h time in bed) with a minimum 6-week washout. Participants completed four REx sessions per condition (day 3, 5, 7 and 9). Muscle biopsies were collected both pre- and post-REx on days 3 and 9. Gene and protein expression were assessed by RNA sequencing and Western Blot, respectively.
    RESULTS: Three or nine nights of sleep restriction had no effect on the muscle transcriptome independently of exercise. However, close to 3000 transcripts were differentially regulated (FDR < 0.05) 48 h post the completion of three resistance exercise sessions in both NS and SR conditions. Only 39% of downregulated and 18% of upregulated genes were common between both conditions, indicating a moderating effect of sleep restriction on the response to exercise.
    CONCLUSION: Sleep restriction and resistance exercise interacted to alter the enrichment of skeletal muscle transcriptomic pathways in young, resistance-trained females. Performing exercise when sleep restricted may not provide the same adaptive response for individuals as if they were fully rested.
    Keywords:  exercise; gene; sleep loss; transcriptome
    DOI:  https://doi.org/10.1152/physiolgenomics.00010.2024
  7. J Physiol. 2024 May 18.
    Differential impact of sex on regulation of skeletal muscle mitochondrial function and protein homeostasis by hypoxia-inducible factor-1α in normoxia.
    Nicole Welch, Saurabh Mishra, Annette Bellar, Pugazhendhi Kannan, Amrit Gopan, Maryam Goudarzi, Jasmine King, Mathew Luknis, Ryan Musich, Vandana Agrawal, James Bena, Cameron J Koch, Ling Li, Belinda Willard, Yatrik M Shah, Srinivasan Dasarathy.
      Hypoxia-inducible factor (HIF)-1α is continuously synthesized and degraded in normoxia. During hypoxia, HIF1α stabilization restricts cellular/mitochondrial oxygen utilization. Cellular stressors can stabilize HIF1α even during normoxia. However, less is known about HIF1α function(s) and sex-specific effects during normoxia in the basal state. Since skeletal muscle is the largest protein store in mammals and protein homeostasis has high energy demands, we determined HIF1α function at baseline during normoxia in skeletal muscle. Untargeted multiomics data analyses were followed by experimental validation in differentiated murine myotubes with loss/gain of function and skeletal muscle from mice without/with post-natal muscle-specific Hif1a deletion (Hif1amsd). Mitochondrial oxygen consumption studies using substrate, uncoupler, inhibitor, titration protocols; targeted metabolite quantification by gas chromatography-mass spectrometry; and post-mitotic senescence markers using biochemical assays were performed. Multiomics analyses showed enrichment in mitochondrial and cell cycle regulatory pathways in Hif1a deleted cells/tissue. Experimentally, mitochondrial oxidative functions and ATP content were higher with less mitochondrial free radical generation with Hif1a deletion. Deletion of Hif1a also resulted in higher concentrations of TCA cycle intermediates and HIF2α proteins in myotubes. Overall responses to Hif1amsd were similar in male and female mice, but changes in complex II function, maximum respiration, Sirt3 and HIF1β protein expression and muscle fibre diameter were sex-dependent. Adaptive responses to hypoxia are mediated by stabilization of constantly synthesized HIF1α. Despite rapid degradation, the presence of HIF1α during normoxia contributes to lower mitochondrial oxidative efficiency and greater post-mitotic senescence in skeletal muscle. In vivo responses to HIF1α in skeletal muscle were differentially impacted by sex. KEY POINTS: Hypoxia-inducible factor -1α (HIF1α), a critical transcription factor, undergoes continuous synthesis and proteolysis, enabling rapid adaptive responses to hypoxia by reducing mitochondrial oxygen consumption. In mammals, skeletal muscle is the largest protein store which is determined by a balance between protein synthesis and breakdown and is sensitive to mitochondrial oxidative function. To investigate the functional consequences of transient HIF1α expression during normoxia in the basal state, myotubes and skeletal muscle from male and female mice with HIF1α knockout were studied using complementary multiomics, biochemical and metabolite assays. HIF1α knockout altered the electron transport chain, mitochondrial oxidative function, signalling molecules for protein homeostasis, and post-mitotic senescence markers, some of which were differentially impacted by sex. The cost of rapid adaptive responses mediated by HIF1α is lower mitochondrial oxidative efficiency and post-mitotic senescence during normoxia.
    Keywords:  hypoxia inducible factor‐1 alpha; muscle‐specific deletion; normoxia; physiology; sex‐differences
    DOI:  https://doi.org/10.1113/JP285339
  8. Am J Physiol Cell Physiol. 2024 May 20.
    mTORC1 and BMP-Smad1/5 Regulation of Serum-Stimulated Myotube Hypertrophy: A Role for Autophagy.
    Quan Zhang, Jessica L Halle, Brittany R Counts, James A Carson.
      Protein synthesis regulation is critical for skeletal muscle hypertrophy; yet, other established cellular processes are necessary for growth-related cellular remodeling. Autophagy has a well-acknowledged role in muscle quality control, but evidence for its role in myofiber hypertrophy remains equivocal. Both mTORC1 and BMP-Smad1/5 signaling are reported regulators of myofiber hypertrophy; however, gaps remain in our understanding of how this regulation is integrated with the growth processes and autophagy regulation. Therefore, we investigated the mTORC1 and Smad1/5 regulation of protein synthesis and autophagy flux during serum-stimulated myotube growth. Chronic serum stimulation experiments were performed on day-5 differentiated C2C12 myotubes incubated in differentiation media (2%HS) or growth media (5%FBS) for 48 hours. Rapamycin or LDN193189 were dosed for 48 hours to inhibit mTORC1 and BMP-Smad1/5 signaling, respectively. Acute serum stimulation was examined in day-7 differentiated myotubes. Protein synthesis was measured by puromycin incorporation. Bafilomycin A1 and immunoblotting for LC3B were used to assess autophagy flux. Chronic serum stimulation increased myotube diameter 22%, total protein 21%, total RNA 100%, Smad1/5 phosphorylation 404%, and suppressed autophagy flux. Rapamycin, but not LDN193189, blocked serum-induced myotube hypertrophy and the increase in total RNA. Acute serum stimulation increased protein synthesis 111%, Smad1/5 phosphorylation 559%, rpS6 phosphorylation 117%, and suppressed autophagy flux. Rapamycin increased autophagy flux during acute serum stimulation. These results provide evidence for mTORC1, but not BMP-Smad1/5 signaling, being required for serum-induced myotube hypertrophy and autophagy flux by measuring LC3BII/I expression. Further investigation is warranted to examine the role of autophagy flux in myotube hypertrophy.
    Keywords:  C2C12 myotubes; cell growth; protein synthesis; rapamycin
    DOI:  https://doi.org/10.1152/ajpcell.00237.2024
  9. Skelet Muscle. 2024 May 21. 14(1): 11
    CaMKIIβ deregulation contributes to neuromuscular junction destabilization in Myotonic Dystrophy type I.
    Denis Falcetta, Sandrine Quirim, Ilaria Cocchiararo, Florent Chabry, Marine Théodore, Adeline Stiefvater, Shuo Lin, Lionel Tintignac, Robert Ivanek, Jochen Kinter, Markus A Rüegg, Michael Sinnreich, Perrine Castets.
      BACKGROUND: Myotonic Dystrophy type I (DM1) is the most common muscular dystrophy in adults. Previous reports have highlighted that neuromuscular junctions (NMJs) deteriorate in skeletal muscle from DM1 patients and mouse models thereof. However, the underlying pathomechanisms and their contribution to muscle dysfunction remain unknown.METHODS: We compared changes in NMJs and activity-dependent signalling pathways in HSALR and Mbnl1ΔE3/ΔE3 mice, two established mouse models of DM1.
    RESULTS: Muscle from DM1 mouse models showed major deregulation of calcium/calmodulin-dependent protein kinases II (CaMKIIs), which are key activity sensors regulating synaptic gene expression and acetylcholine receptor (AChR) recycling at the NMJ. Both mouse models exhibited increased fragmentation of the endplate, which preceded muscle degeneration. Endplate fragmentation was not accompanied by changes in AChR turnover at the NMJ. However, the expression of synaptic genes was up-regulated in mutant innervated muscle, together with an abnormal accumulation of histone deacetylase 4 (HDAC4), a known target of CaMKII. Interestingly, denervation-induced increase in synaptic gene expression and AChR turnover was hampered in DM1 muscle. Importantly, CaMKIIβ/βM overexpression normalized endplate fragmentation and synaptic gene expression in innervated Mbnl1ΔE3/ΔE3 muscle, but it did not restore denervation-induced synaptic gene up-regulation.
    CONCLUSIONS: Our results indicate that CaMKIIβ-dependent and -independent mechanisms perturb synaptic gene regulation and muscle response to denervation in DM1 mouse models. Changes in these signalling pathways may contribute to NMJ destabilization and muscle dysfunction in DM1 patients.
    Keywords:  CaMKII; Fibre type; Myotonic dystrophy; Neuromuscular junctions; Synaptic genes
    DOI:  https://doi.org/10.1186/s13395-024-00345-3
  10. Mol Aspects Med. 2024 May 23. pii: S0098-2997(24)00036-0. [Epub ahead of print]97 101277
    Fibro-adipogenic progenitors in physiological adipogenesis and intermuscular adipose tissue remodeling.
    Marcelo Flores-Opazo, Daniel Kopinke, Françoise Helmbacher, Rodrigo Fernández-Verdejo, Mauro Tuñón-Suárez, Gordon S Lynch, Osvaldo Contreras.
      Excessive accumulation of intermuscular adipose tissue (IMAT) is a common pathological feature in various metabolic and health conditions and can cause muscle atrophy, reduced function, inflammation, insulin resistance, cardiovascular issues, and unhealthy aging. Although IMAT results from fat accumulation in muscle, the mechanisms underlying its onset, development, cellular components, and functions remain unclear. IMAT levels are influenced by several factors, such as changes in the tissue environment, muscle type and origin, extent and duration of trauma, and persistent activation of fibro-adipogenic progenitors (FAPs). FAPs are a diverse and transcriptionally heterogeneous population of stromal cells essential for tissue maintenance, neuromuscular stability, and tissue regeneration. However, in cases of chronic inflammation and pathological conditions, FAPs expand and differentiate into adipocytes, resulting in the development of abnormal and ectopic IMAT. This review discusses the role of FAPs in adipogenesis and how they remodel IMAT. It highlights evidence supporting FAPs and FAP-derived adipocytes as constituents of IMAT, emphasizing their significance in adipose tissue maintenance and development, as well as their involvement in metabolic disorders, chronic pathologies and diseases. We also investigated the intricate molecular pathways and cell interactions governing FAP behavior, adipogenesis, and IMAT accumulation in chronic diseases and muscle deconditioning. Finally, we hypothesize that impaired cellular metabolic flexibility in dysfunctional muscles impacts FAPs, leading to IMAT. A deeper understanding of the biology of IMAT accumulation and the mechanisms regulating FAP behavior and fate are essential for the development of new therapeutic strategies for several debilitating conditions.
    Keywords:  Adipocytes; Adipogenesis; FAPs; IMAT; Metabolism; Obesity; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.mam.2024.101277
  11. Acta Neuropathol Commun. 2024 May 24. 12(1): 80
    Aberrant myonuclear domains and impaired myofiber contractility despite marked hypertrophy in MYMK-related, Carey-Fineman-Ziter Syndrome.
    Hannah F Dugdale, Yotam Levy, Heinz Jungbluth, Anders Oldfors, Julien Ochala.
      Carey Fineman Ziter Syndrome (CFZS) is a rare autosomal recessive disease caused by mutations in the MYMK locus which encodes the protein, myomaker. Myomaker is essential for fusion and concurrent myonuclei donation of muscle progenitors during growth and development. Strikingly, in humans, MYMK mutations appear to prompt myofiber hypertrophy but paradoxically, induce generalised muscle weakness. As the underlying cellular mechanisms remain unexplored, the present study aimed to gain insights by combining myofiber deep-phenotyping and proteomic profiling. Hence, we isolated individual muscle fibers from CFZS patients and performed mechanical, 3D morphological and proteomic analyses. Myofibers from CFZS patients were ~ 4x larger than controls and possessed ~ 2x more myonuclei than those from healthy subjects, leading to disproportionally larger myonuclear domain volumes. These greater myonuclear domain sizes were accompanied by smaller intrinsic cellular force generating-capacities in myofibers from CFZS patients than in control muscle cells. Our complementary proteomic analyses indicated remodelling in 233 proteins particularly those associated with cellular respiration. Overall, our findings suggest that myomaker is somewhat functional in CFZS patients, but the associated nuclear accretion may ultimately lead to non-functional hypertrophy and altered energy-related mechanisms in CFZS patients. All of these are likely contributors of the muscle weakness experienced by CFZS patients.
    Keywords:   MYMK gene; Carey-Fineman-Ziter Syndrome; Myomaker; Myonuclear domain; Single myofiber; Skeletal muscle
    DOI:  https://doi.org/10.1186/s40478-024-01783-2
  12. J Appl Physiol (1985). 2024 May 23.
    Sexual Dimorphisms in Skeletal Muscle: Current Concepts and Research Horizons.
    Marianne E Emmert, Andrew S Emmert, Qingnian Goh, Roger Cornwall.
      The complex compositional and functional nature of skeletal muscle makes this organ an essential topic of study for biomedical researchers and clinicians. An additional layer of complexity is added with the consideration of sex as a biological variable. Recent research advances have revealed sexual dimorphisms in developmental biology, muscle homeostasis, adaptive responses, and disorders relating to skeletal muscle. Many of the observed sex differences have hormonal and molecular mechanistic underpinnings, while others have yet to be elucidated. Future research is needed to investigate the mechanisms dictating sex-based differences in the various aspects of skeletal muscle. As such, it is necessary that skeletal muscle biologists ensure that both female and male subjects are represented in biomedical and clinical studies to facilitate the successful testing and development of therapeutics for all patients.
    Keywords:  Muscle adaptation; Muscle disease; Muscle growth; Sexual dimorphisms; Skeletal muscle
    DOI:  https://doi.org/10.1152/japplphysiol.00529.2023
  13. Front Physiol. 2024 ;15 1352242
    High nitrate levels in skeletal muscle contribute to nitric oxide generation via a nitrate/nitrite reductive pathway in mice that lack the nNOS enzyme.
    Supranee Upanan, Jeeyoung Lee, Khalid J Tunau-Spencer, Praveen K Rajvanshi, Elizabeth C Wright, Constance T Noguchi, Alan N Schechter.
      Introduction: Nitric oxide (NO) is a vasodilator gas that plays a critical role in mitochondrial respiration and skeletal muscle function. NO is endogenously generated by NO synthases: neuronal NO synthase (nNOS), endothelial NO synthase (eNOS), or inducible NO synthase (iNOS). NO in skeletal muscle is partly generated by nNOS, and nNOS deficiency can contribute to muscular dystrophic diseases. However, we and others discovered an alternative nitrate/nitrite reductive pathway for NO generation: nitrate to nitrite to NO. We hypothesized that nitrate supplementation would increase nitrate accumulation in skeletal muscle and promote a nitrate/nitrite reductive pathway for NO production to compensate for the loss of nNOS in skeletal muscle.Methods: Wild-type (WT) and genetic nNOS knockout (nNOS-/-) mice were fed normal chow (386.9 nmol/g nitrate) and subjected to three treatments: high-nitrate water (1 g/L sodium nitrate for 7 days), low-nitrate diet (46.8 nmol/g nitrate for 7 days), and low-nitrate diet followed by high-nitrate water for 7 days each.
    Results: High-nitrate water supplementation exhibited a greater and more significant increase in nitrate levels in skeletal muscle and blood in nNOS-/- mice than in WT mice. A low-nitrate diet decreased blood nitrate and nitrite levels in both WT and nNOS-/- mice. WT and nNOS-/- mice, treated with low-nitrate diet, followed by high-nitrate water supplementation, showed a significant increase in nitrate levels in skeletal muscle and blood, analogous to the increases observed in nNOS-/- mice supplemented with high-nitrate water. In skeletal muscle of nNOS-/- mice on high-nitrate water supplementation, on low-nitrate diet, and in low-high nitrate treatment, the loss of nNOS resulted in a corresponding increase in the expression of nitrate/nitrite reductive pathway-associated nitrate transporters [sialin and chloride channel 1 (CLC1)] and nitrate/nitrite reductase [xanthine oxidoreductase (XOR)] but did not show a compensatory increase in iNOS or eNOS protein and eNOS activation activity [p-eNOS (Ser1177)].
    Discussion: These findings suggest that a greater increase in nitrate levels in skeletal muscle of nNOS-/- mice on nitrate supplementation results from reductive processes to increase NO production with the loss of nNOS in skeletal muscle.
    Keywords:  neuronal nitric oxide synthase; neuronal nitric oxide synthase knockout mice (nNOS−/−); nitrate; nitrate/nitrite reductive pathway; nitric oxide; nitric oxide synthases; skeletal muscle; xanthine oxidoreductase
    DOI:  https://doi.org/10.3389/fphys.2024.1352242
  14. J Physiol. 2024 May 19.
    Piperine enhances contractile force in slow- and fast-twitch muscle.
    Jon Herskind, Niels Ørtenblad, Arthur J Cheng, Peter Pedersen, Kristian Overgaard.
      Piperine has been shown to bind to myosin and shift the distribution of conformational states of myosin molecules from the super-relaxed state to the disordered relaxed state. However, little is known about the implications for muscle force production and potential underlying mechanisms. Muscle contractility experiments were performed using isolated muscles and single fibres from rats and mice. The dose-response effect of piperine on muscle force was assessed at several stimulation frequencies. The potentiation of muscle force was also tested in muscles fatigued by eccentric contractions. Potential mechanisms of force potentiation were assessed by measuring Ca2+ levels during stimulation in enzymatically dissociated muscle fibres, while myofibrillar Ca2+ sensitivity was assessed in chemically skinned muscle fibres. Piperine caused a dose-dependent increase in low-frequency force with no effect on high-frequency force in both slow- and fast-twitch muscle, with similar relative increases in twitch force, rate of force development and relaxation rate. The potentiating effect of piperine on low-frequency force was reversible, and piperine partially recovered low-frequency force in fatigued muscle. Piperine had no effect on myoplasmic free [Ca2+] levels in mouse muscle fibres, whereas piperine substantially augmented the force response to submaximal levels of [Ca2+] in rat MyHCII fibres and MyHCI fibres along with a minor increase in maximum Ca2+-activated force. Piperine enhances low-frequency force production in both fast- and slow-twitch muscle. The effects are reversible and can counteract muscle fatigue. The primary underlying mechanism appears to be an increase in Ca2+ sensitivity. KEY POINTS: Piperine is a plant alkaloid derived from black pepper. It is known to bind to skeletal muscle myosin and enhance resting ATP turnover but its effects on contractility are not well known. We showed for the first time a piperine-induced force potentiation that was pronounced during low-frequency electrical stimulation of isolated muscles. The effect of piperine was observed in both slow and fast muscle types, was reversible, and could counteract the force decrements observed after fatiguing muscle contractions. Piperine treatment caused an increase in myofibrillar Ca2+ sensitivity in chemically skinned muscle fibres, while we observed no effect on intracellular Ca2+ concentrations during electrical stimulation in enzymatically dissociated muscle fibres.
    Keywords:  Ca2+ release; force potentiation; muscle contraction; prolonged low‐frequency force depression
    DOI:  https://doi.org/10.1113/JP285995
  15. Cell Death Discov. 2024 May 22. 10(1): 245
    Eliminating elevated p53 signaling fails to rescue skeletal muscle defects or extend survival in lamin A/C-deficient mice.
    Tyler J Kirby, Hind C Zahr, Ern Hwei Hannah Fong, Jan Lammerding.
      Lamins A and C, encoded by the LMNA gene, are nuclear intermediate filaments that provide structural support to the nucleus and contribute to chromatin organization and transcriptional regulation. LMNA mutations cause muscular dystrophies, dilated cardiomyopathy, and other diseases. The mechanisms by which many LMNA mutations result in muscle-specific diseases have remained elusive, presenting a major hurdle in the development of effective treatments. Previous studies using striated muscle laminopathy mouse models found that cytoskeletal forces acting on mechanically fragile Lmna-mutant nuclei led to transient nuclear envelope rupture, extensive DNA damage, and activation of DNA damage response (DDR) pathways in skeletal muscle cells in vitro and in vivo. Furthermore, hearts of Lmna mutant mice have elevated activation of the tumor suppressor protein p53, a central regulator of DDR signaling. We hypothesized that elevated p53 activation could present a pathogenic mechanism in striated muscle laminopathies, and that eliminating p53 activation could improve muscle function and survival in laminopathy mouse models. Supporting a pathogenic function of p53 activation in muscle, stabilization of p53 was sufficient to reduce contractility and viability in wild-type muscle cells in vitro. Using three laminopathy models, we found that increased p53 activity in Lmna-mutant muscle cells primarily resulted from mechanically induced damage to the myonuclei, and not from altered transcriptional regulation due to loss of lamin A/C expression. However, global deletion of p53 in a severe muscle laminopathy model did not reduce the disease phenotype or increase survival, indicating that additional drivers of disease must contribute to the disease pathogenesis.
    DOI:  https://doi.org/10.1038/s41420-024-01998-1
  16. Eur J Transl Myol. 2024 May 24.
    Proteomic reference map for sarcopenia research: mass spectrometric identification of key muscle proteins located in the sarcomere, cytoskeleton and the extracellular matrix.
    Paul Dowling, Stephen Gargan, Margit Zweyer, Michael Henry, Paula Meleady, Dieter Swandulla, Kay Ohlendieck.
      Sarcopenia of old age is characterized by the progressive loss of skeletal muscle mass and concomitant decrease in contractile strength. Age-related skeletal muscle dysfunctions play a key pathophysiological role in the frailty syndrome and can result in a drastically diminished quality of life in the elderly. Here we have used mass spectrometric analysis of the mouse hindlimb musculature to establish the muscle protein constellation at advanced age of a widely used sarcopenic animal model. Proteomic results were further analyzed by systems bioinformatics of voluntary muscles. In this report, the proteomic survey of aged muscles has focused on the expression patterns of proteins involved in the contraction-relaxation cycle, membrane cytoskeletal maintenance and the formation of the extracellular matrix. This includes proteomic markers of the fast versus slow phenotypes of myosin-containing thick filaments and actin-containing thin filaments, as well as proteins that are associated with the non-sarcomeric cytoskeleton and various matrisomal layers. The bioanalytical usefulness of the newly established reference map was demonstrated by the comparative screening of normal versus dystrophic muscles of old age, and findings were verified by immunoblot analysis.
    DOI:  https://doi.org/10.4081/ejtm.2024.12564
  17. Mol Biol Rep. 2024 May 23. 51(1): 667
    Time-course and muscle-specific gene expression of matrix metalloproteinases and inflammatory cytokines in response to acute treadmill exercise in rats.
    Ibrahim Turkel, Sema Tahtalioglu, Ertugrul Celik, Burak Yazgan, Gokhan Burcin Kubat, Berkay Ozerklig, Sukran Nazan Kosar.
      BACKGROUND: The extracellular matrix (ECM) of skeletal muscle plays a pivotal role in tissue repair and growth, and its remodeling tightly regulated by matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and inflammatory cytokines. This study aimed to investigate changes in the mRNA expression of MMPs (Mmp-2 and Mmp-14), TIMPs (Timp-1 and Timp-2), and inflammatory cytokines (Il-1β, Tnf-α, and Tgfβ1) in the soleus (SOL) and extensor digitorum longus (EDL) muscles of rats following acute treadmill exercise. Additionally, muscle morphology was examined using hematoxylin and eosin (H&E) staining.METHODS AND RESULTS: Male rats were subjected to acute treadmill exercise at 25 m/min for 60 min with a %0 slope. The mRNA expression of ECM components and muscle morphology in the SOL and EDL were assessed in both sedentary and exercise groups at various time points (immediately (0) and 1, 3, 6, 12, and 24 h post-exercise). Our results revealed a muscle-specific response, with early upregulation of the mRNA expression of Mmp-2, Mmp-14, Timp-1, Timp-2, Il-1β, and Tnf-α observed in the SOL compared to the EDL. A decrease in Tgfβ1 mRNA expression was evident in the SOL at all post-exercise time points. Conversely, Tgfβ1 mRNA expression increased at 0 and 3 h post-exercise in the EDL. Histological analysis also revealed earlier cell infiltration in the SOL than in the EDL following acute exercise.
    CONCLUSIONS: Our results highlight how acute exercise modulates ECM components and muscle structure differently in the SOL and EDL muscles, leading to distinct muscle-specific responses.
    Keywords:  Acute exercise; Gene expression; Inflammatory cytokines; Matrix metalloproteinases; Skeletal muscle
    DOI:  https://doi.org/10.1007/s11033-024-09637-9
  18. Am J Pathol. 2024 May 16. pii: S0002-9440(24)00174-3. [Epub ahead of print]
    Leucyl-tRNA synthetase contributes to muscle weakness through mTORC1 activation and autophagy suppression in a mouse model of Duchenne Muscular Dystrophy.
    Jae-Sung You, Kate Karaman, Adriana Reyes-Ordoñez, Soohyun Lee, Yongdeok Kim, Rashid Bashir, Jie Chen.
      Duchenne muscular dystrophy (DMD), caused by loss-of-function mutations in the dystrophin gene, results in progressive muscle weakness and early fatality. Impaired autophagy is one of the cellular hallmarks of DMD, contributing to the disease progression. Molecular mechanisms underlying the inhibition of autophagy in DMD are not well understood. In the current study the DMD mouse model mdx is used for the investigation of signaling pathways leading to suppression of autophagy. Mammalian target of rapamycin complex 1 (mTORC1) is found to be hyperactive in the DMD muscles, accompanying muscle weakness and autophagy impairment. Surprisingly, Akt, a well-known upstream regulator of mTORC1, is not responsible for mTORC1 activation or the dystrophic muscle phenotypes. Instead, leucyl-tRNA synthetase (LeuRS) is found to be overexpressed in mdx muscles compared to the wild-type. LeuRS is known to activate mTORC1 in a non-canonical mechanism that involves interaction with RagD, an activator of mTORC1. Disrupting LeuRS interaction with RagD by the small-molecule inhibitor BC-LI-0186 reduces mTORC1 activity, restores autophagy, and ameliorates myofiber damage in the mdx muscles. Furthermore, inhibition of LeuRS by BC-LI-0186 improves dystrophic muscle strength in an autophagy-dependent manner. Taken together, our findings uncover a non-canonical function of the house-keeping protein LeuRS as a potential therapeutic target in the treatment of DMD.
    Keywords:  Duchenne Muscular Dystrophy; autophagy; leucyl-tRNA synthetase; mTORC1; skeletal muscle weakness
    DOI:  https://doi.org/10.1016/j.ajpath.2024.04.006
  19. Int J Mol Sci. 2024 May 08. pii: 5117. [Epub ahead of print]25(10):
    Skeletal Muscle Injury in Chronic Kidney Disease-From Histologic Changes to Molecular Mechanisms and to Novel Therapies.
    Kylie Heitman, Matthew S Alexander, Christian Faul.
      Chronic kidney disease (CKD) is associated with significant reductions in lean body mass and in the mass of various tissues, including skeletal muscle, which causes fatigue and contributes to high mortality rates. In CKD, the cellular protein turnover is imbalanced, with protein degradation outweighing protein synthesis, leading to a loss of protein and cell mass, which impairs tissue function. As CKD itself, skeletal muscle wasting, or sarcopenia, can have various origins and causes, and both CKD and sarcopenia share common risk factors, such as diabetes, obesity, and age. While these pathologies together with reduced physical performance and malnutrition contribute to muscle loss, they cannot explain all features of CKD-associated sarcopenia. Metabolic acidosis, systemic inflammation, insulin resistance and the accumulation of uremic toxins have been identified as additional factors that occur in CKD and that can contribute to sarcopenia. Here, we discuss the elevation of systemic phosphate levels, also called hyperphosphatemia, and the imbalance in the endocrine regulators of phosphate metabolism as another CKD-associated pathology that can directly and indirectly harm skeletal muscle tissue. To identify causes, affected cell types, and the mechanisms of sarcopenia and thereby novel targets for therapeutic interventions, it is important to first characterize the precise pathologic changes on molecular, cellular, and histologic levels, and to do so in CKD patients as well as in animal models of CKD, which we describe here in detail. We also discuss the currently known pathomechanisms and therapeutic approaches of CKD-associated sarcopenia, as well as the effects of hyperphosphatemia and the novel drug targets it could provide to protect skeletal muscle in CKD.
    Keywords:  chronic kidney disease; fibroblast growth factor 23; klotho; parathyroid hormone; phosphate; sarcopenia; skeletal muscle atrophy; vitamin D
    DOI:  https://doi.org/10.3390/ijms25105117
  20. Eur J Transl Myol. 2024 May 22.
    Dirk Pette, remembered for his pioneering muscle research.
    Kay Ohlendieck, Winfried Mayr, Helmut Kern, Carlo Reggiani, Giorgio Fanò-Illic, Ugo Carraro.
      It is with great sadness that we learned of the passing of Prof. Dr. Dr. h.c. Dirk Pette. He passed away suddenly and unexpectedly on June 4, 2022. Dirk was an outstanding professor of biochemistry at the University of Konstanz, Germany and an internationally renowned researcher in the field of skeletal muscle biology. His research on electrical stimulation has had a profound impact on our understanding of myofiber type specification and the enormous adaptive potential of skeletal muscle. Under Dirk's leadership, new biological questions in the field of neuromuscular biology have developed into multidisciplinary approaches using advanced physiological, cell biological, and biochemical techniques. Dirk's research laboratory was frequently visited by a large number of national and international collaborators who familiarized themselves with the technically demanding stimulation protocols and bioanalytical techniques to study the intricate details of the highly complex process of fast-to-slow muscle transitions. Importantly, fundamental studies on the physiological effects of changes in innervation patterns on muscle phenotype have provided the scientific evidence base for a variety of innovative clinical applications. The skeletal muscle research community has lost one of its leading figures and an outstanding teacher of protein biochemistry. He leaves an inspiring legacy in the field of basic and applied myology. Dirk will be missed by his colleagues and by many students of neuromuscular biology and beyond.
    DOI:  https://doi.org/10.4081/ejtm.2024.12681
  21. PLoS One. 2024 ;19(5): e0303448
    Targeting skeletal muscle health with exercise in people with type 1 diabetes: A protocol for HOMET1D, a prospective observational trial with matched controls.
    Irena A Rebalka, Kenneth S Noguchi, Kayla R Bulyovsky, Matthew I Badour, Emma S Juracic, Khandra Barrett, Aditya Brahmbhatt, Baraa Al-Khazraji, Zubin Punthakee, Christopher G R Perry, Dinesh A Kumbhare, Maureen J MacDonald, Thomas J Hawke.
      INTRODUCTION: Individuals with type 1 diabetes (T1D) experience a complex set of alterations to skeletal muscle metabolic, neuromuscular, and vascular health; collectively referred to as diabetic myopathy. While the full scope of diabetic myopathy is still being elucidated, evidence suggests that even when individuals with T1D are physically active, indices of myopathy still exist. As such, there is a question if adherence to current physical activity guidelines elicits improvements in skeletal muscle health indices similarly between individuals with and without T1D. The objectives of this trial are to: 1) compare baseline differences in skeletal muscle health between adults with and without T1D, 2) examine the association between participation in a home-based exercise program, detraining, and retraining, with changes in skeletal muscle health, and 3) examine the roles of age and sex on these associations.METHODS AND ANALYSIS: This will be a prospective interventional trial. Younger (18-30 years) and older (45-65 years) males and females with T1D and matched individuals without T1D will engage in a four-phase, 18-week study sequentially consisting of a one-week lead-in period, 12-week exercise training program, one-week detraining period, and four-week retraining period. The exercise program will consist of aerobic and resistance exercise based on current guidelines set by Diabetes Canada. Metabolic, neuromuscular, and vascular outcome measures will be assessed four times: at baseline, post-exercise program, post-detraining, and post-retraining. Differences in baseline metrics between those with and without T1D will be examined with independent sample t-tests, and with two-way analyses of variance for age- and sex-stratified analyses. Changes across the duration of the study will be examined using mixed-model analyses.
    DISSEMINATION: Findings from this research will be shared locally and internationally with research participants, clinicians, diabetes educators, and patient advocacy organizations via in-person presentations, social media, and scientific fora.
    TRIAL REGISTRATION NUMBER: NCT05740514.
    DOI:  https://doi.org/10.1371/journal.pone.0303448
  22. Molecules. 2024 May 09. pii: 2216. [Epub ahead of print]29(10):
    Deciphering the Therapeutic Role of Lactate in Combating Disuse-Induced Muscle Atrophy: An NMR-Based Metabolomic Study in Mice.
    Yu Zhou, Xi Liu, Zhen Qi, Longhe Yang, Caihua Huang, Donghai Lin.
      Disuse muscle atrophy (DMA) is a significant healthcare challenge characterized by progressive loss of muscle mass and function resulting from prolonged inactivity. The development of effective strategies for muscle recovery is essential. In this study, we established a DMA mouse model through hindlimb suspension to evaluate the therapeutic potential of lactate in alleviating the detrimental effects on the gastrocnemius muscle. Using NMR-based metabolomic analysis, we investigated the metabolic changes in DMA-injured gastrocnemius muscles compared to controls and evaluated the beneficial effects of lactate treatment. Our results show that lactate significantly reduced muscle mass loss and improved muscle function by downregulating Murf1 expression, decreasing protein ubiquitination and hydrolysis, and increasing myosin heavy chain levels. Crucially, lactate corrected perturbations in four key metabolic pathways in the DMA gastrocnemius: the biosynthesis of phenylalanine, tyrosine, and tryptophan; phenylalanine metabolism; histidine metabolism; and arginine and proline metabolism. In addition to phenylalanine-related pathways, lactate also plays a role in regulating branched-chain amino acid metabolism and energy metabolism. Notably, lactate treatment normalized the levels of eight essential metabolites in DMA mice, underscoring its potential as a therapeutic agent against the consequences of prolonged inactivity and muscle wasting. This study not only advances our understanding of the therapeutic benefits of lactate but also provides a foundation for novel treatment approaches aimed at metabolic restoration and muscle recovery in conditions of muscle wasting.
    Keywords:  NMR spectroscopy; disuse-induced muscle atrophy; lactate; metabolism; metabolomics
    DOI:  https://doi.org/10.3390/molecules29102216
  23. iScience. 2024 Jun 21. 27(6): 109816
    Eicosapentaenoic acid increases proportion of type 1 muscle fibers through PPARδ and AMPK pathways in rats.
    Yusuke Komiya, Yuka Sakazaki, Tsuyoshi Goto, Fuminori Kawabata, Takahiro Suzuki, Yusuke Sato, Shoko Sawano, Mako Nakamura, Ryuichi Tatsumi, Yoshihide Ikeuchi, Keizo Arihara, Wataru Mizunoya.
      Muscle fiber type composition (% slow-twitch and % fast-twitch fibers) is associated with metabolism, with increased slow-twitch fibers alleviating metabolic disorders. Previously, we reported that dietary fish oil intake induced a muscle fiber-type transition in a slower direction in rats. The aim of this study was to determine the functionality of eicosapentaenoic acid (EPA), a unique fatty acid in fish oil, to skeletal muscle fiber type and metabolism in rats. Here, we showed that dietary EPA promotes whole-body oxidative metabolism and improves muscle function by increasing proportion of slow-twitch type 1 fibers in rats. Transcriptomic and metabolomic analyses revealed that EPA supplementation activated the peroxisome proliferator-activated receptor δ (PPARδ) and AMP-activated protein kinase (AMPK) pathways in L6 myotube cultures, which potentially increasing slow-twitch fiber share. This highlights the role of EPA as an exercise-mimetic dietary component that improves metabolism and muscle function, with potential benefits for health and athletic performance.
    Keywords:  Dietary supplement; Metabolomics; Molecular biology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2024.109816
  24. Phytomedicine. 2024 May 15. pii: S0944-7113(24)00406-9. [Epub ahead of print]130 155747
    Wheat seedlings extract ameliorates sarcopenia in aged mice by regulating protein synthesis and degradation with anti-inflammatory and mitochondrial biogenesis effects.
    Ji-Won Han, Su-Kyung Shin, Heekyong R Bae, HanGyeol Lee, So Yeon Moon, Woo Duck Seo, Eun-Young Kwon.
      BACKGROUND: Chronic inflammation, which becomes more prevalent during aging, contributes to sarcopenia by reducing muscle mass and strength.PURPOSE: Wheat seedlings extract (WSE) is known for its various physiological activities, including anti-inflammation and antioxidant effects. However, its efficacy against sarcopenia is not well documented.
    STUDY DESIGN: 8-week-old and 50-week-old C57BL/6 J mice were used as young control (YC group) and aged controls (AC group), respectively. Then, aged mice were randomly divided into 5 groups (WSE100mg/kg, WSE200mg/kg, WSE400mg/kg, and schizandrin as a positive control) and fed each experimental diet for 10 weeks.
    METHOD: We investigated the effects of WSE on muscle quality and protein homeostasis pathways based on improvements in mitochondrial function and chronic inflammation. We then used TNFα-treated C2C12 to investigate the effects of isoorientin (ISO) and isoschaftoside (ISS), the active substances of WSE, on the myogenic pathway.
    RESULTS: We administered WSE to aging mice and observed an increase in muscle mass, thickness, protein content, and strength in mice treated with WSE at a dose of 200 mg/kg or 400 mg/kg. Furthermore, the administration of WSE led to a reduction in inflammatory factors (TNFα, IL-1, and IL-6) and an increase in mitochondrial biogenesis (p-AMPK/SIRT3/PGC1α) in muscle. This effect was also observed in TNFα-induced muscle atrophy in C2C12 cells, and we additionally identified the upregulation of myogenic regulatory factors, including Myf5, Myf6, MyoD, and myogenin, by WSE, ISO, and ISS.
    CONCLUSION: These findings suggest that WSE could function as a dietary anti-inflammatory factor and mitochondrial activator, potentially exerting modulatory effects on the metabolism and mechanical properties of skeletal muscles in the aging population. Furthermore, Our results demonstrate the potential value of ISO and ISS as functional food ingredients for preventing muscle atrophy.
    Keywords:  Aging; Inflammation; Mitochondrial biogenesis; Muscle atrophy; Sarcopenia; Wheat seedlings extract
    DOI:  https://doi.org/10.1016/j.phymed.2024.155747
  25. Commun Biol. 2024 May 20. 7(1): 604
    GDE5/Gpcpd1 activity determines phosphatidylcholine composition in skeletal muscle and regulates contractile force in mice.
    Rahmawati Aisyah, Noriyasu Ohshima, Daiki Watanabe, Yoshiko Nakagawa, Tetsushi Sakuma, Felix Nitschke, Minako Nakamura, Koji Sato, Kaori Nakahata, Chihiro Yokoyama, Charlotte R Marchioni, Thanutchaporn Kumrungsee, Takahiko Shimizu, Yusuke Sotomaru, Toru Takeo, Naomi Nakagata, Takashi Izumi, Shinji Miura, Berge A Minassian, Takashi Yamamoto, Masanobu Wada, Noriyuki Yanaka.
      Glycerophosphocholine (GPC) is an important precursor for intracellular choline supply in phosphatidylcholine (PC) metabolism. GDE5/Gpcpd1 hydrolyzes GPC into choline and glycerol 3-phosphate; this study aimed to elucidate its physiological function in vivo. Heterozygous whole-body GDE5-deficient mice reveal a significant GPC accumulation across tissues, while homozygous whole-body knockout results in embryonic lethality. Skeletal muscle-specific GDE5 deletion (Gde5 skKO) exhibits reduced passive force and improved fatigue resistance in electrically stimulated gastrocnemius muscles in vivo. GDE5 deficiency also results in higher glycolytic metabolites and glycogen levels, and glycerophospholipids alteration, including reduced levels of phospholipids that bind polyunsaturated fatty acids (PUFAs), such as DHA. Interestingly, this PC fatty acid compositional change is similar to that observed in skeletal muscles of denervated and Duchenne muscular dystrophy mouse models. These are accompanied by decrease of GDE5 expression, suggesting a regulatory role of GDE5 activity for glycerophospholipid profiles. Furthermore, a DHA-rich diet enhances contractile force and lowers fatigue resistance, suggesting a functional relationship between PC fatty acid composition and muscle function. Finally, skinned fiber experiments show that GDE5 loss increases the probability of the ryanodine receptor opening and lowers the maximum Ca2+-activated force. Collectively, GDE5 activity plays roles in PC and glucose/glycogen metabolism in skeletal muscle.
    DOI:  https://doi.org/10.1038/s42003-024-06298-z
  26. J R Soc Interface. 2024 May;21(214): 20230658
    The effect of muscle ultrastructure on the force, displacement and work capacity of skeletal muscle.
    Nihav Dhawale, David Labonte, Natalie C Holt.
      Skeletal muscle powers animal movement through interactions between the contractile proteins, actin and myosin. Structural variation contributes greatly to the variation in mechanical performance observed across muscles. In vertebrates, gross structural variation occurs in the form of changes in the muscle cross-sectional area : fibre length ratio. This results in a trade-off between force and displacement capacity, leaving work capacity unaltered. Consequently, the maximum work per unit volume-the work density-is considered constant. Invertebrate muscle also varies in muscle ultrastructure, i.e. actin and myosin filament lengths. Increasing actin and myosin filament lengths increases force capacity, but the effect on muscle fibre displacement, and thus work, capacity is unclear. We use a sliding-filament muscle model to predict the effect of actin and myosin filament lengths on these mechanical parameters for both idealized sarcomeres with fixed actin : myosin length ratios, and for real sarcomeres with known filament lengths. Increasing actin and myosin filament lengths increases stress without reducing strain capacity. A muscle with longer actin and myosin filaments can generate larger force over the same displacement and has a higher work density, so seemingly bypassing an established trade-off. However, real sarcomeres deviate from the idealized length ratio suggesting unidentified constraints or selective pressures.
    Keywords:  LAMSA; actin; invertebrate; muscle work density; musculoskeletal dynamics; myosin
    DOI:  https://doi.org/10.1098/rsif.2023.0658
  27. J Cell Physiol. 2024 May 21.
    Ablation of Sam50 is associated with fragmentation and alterations in metabolism in murine and human myotubes.
    Bryanna Shao, Mason Killion, Ashton Oliver, Chia Vang, Faben Zeleke, Kit Neikirk, Zer Vue, Edgar Garza-Lopez, Jian-Qiang Shao, Margaret Mungai, Jacob Lam, Qiana Williams, Christopher T Altamura, Aaron Whiteside, Kinuthia Kabugi, Jessica McKenzie, Maria Ezedimma, Han Le, Alice Koh, Estevão Scudese, Larry Vang, Andrea G Marshall, Amber Crabtree, Janelle I Tanghal, Dominique Stephens, Ho-Jin Koh, Brenita C Jenkins, Sandra A Murray, Anthonya T Cooper, Clintoria Williams, Steven M Damo, Melanie R McReynolds, Jennifer A Gaddy, Celestine N Wanjalla, Heather K Beasley, Antentor Hinton.
      The sorting and assembly machinery (SAM) Complex is responsible for assembling β-barrel proteins in the mitochondrial membrane. Comprising three subunits, Sam35, Sam37, and Sam50, the SAM complex connects the inner and outer mitochondrial membranes by interacting with the mitochondrial contact site and cristae organizing system complex. Sam50, in particular, stabilizes the mitochondrial intermembrane space bridging (MIB) complex, which is crucial for protein transport, respiratory chain complex assembly, and regulation of cristae integrity. While the role of Sam50 in mitochondrial structure and metabolism in skeletal muscle remains unclear, this study aims to investigate its impact. Serial block-face-scanning electron microscopy and computer-assisted 3D renderings were employed to compare mitochondrial structure and networking in Sam50-deficient myotubes from mice and humans with wild-type (WT) myotubes. Furthermore, autophagosome 3D structure was assessed in human myotubes. Mitochondrial metabolic phenotypes were assessed using Gas Chromatography-Mass Spectrometry-based metabolomics to explore differential changes in WT and Sam50-deficient myotubes. The results revealed increased mitochondrial fragmentation and autophagosome formation in Sam50-deficient myotubes compared to controls. Metabolomic analysis indicated elevated metabolism of propanoate and several amino acids, including ß-Alanine, phenylalanine, and tyrosine, along with increased amino acid and fatty acid metabolism in Sam50-deficient myotubes. Furthermore, impairment of oxidative capacity was observed upon Sam50 ablation in both murine and human myotubes, as measured with the XF24 Seahorse Analyzer. Collectively, these findings support the critical role of Sam50 in establishing and maintaining mitochondrial integrity, cristae structure, and mitochondrial metabolism. By elucidating the impact of Sam50-deficiency, this study enhances our understanding of mitochondrial function in skeletal muscle.
    Keywords:  3D reconstruction; MICOS; SAM complex; Sam50; mitochondria
    DOI:  https://doi.org/10.1002/jcp.31293
  28. J Cachexia Sarcopenia Muscle. 2024 May 19.
    Transcriptomics reveals transient and dynamic muscle fibrosis and atrophy differences following spinal cord injury in rats.
    Hui Jean Kok, Drew B Fletcher, Jacob C Oster, Christine F Conover, Elisabeth R Barton, Joshua F Yarrow.
      BACKGROUND: The rate and magnitude of skeletal muscle wasting after severe spinal cord injury (SCI) exceeds most other disuse conditions. Assessing the time course of molecular changes can provide insight into the progression of muscle wasting post-SCI. The goals of this study were (1) to identify potential targets that may prevent the pathologic features of SCI in soleus muscles and (2) to establish therapeutic windows for treating these pathologic changes.METHODS: Four-month-old Sprague-Dawley male rats received T9 laminectomy (SHAM surgery) or severe contusion SCI. Hindlimb locomotor function was assessed weekly, with soleus muscles obtained 1 week, 2 weeks, 1 month and 3 months post-surgery (n = 6-7 per group per timepoint). RNA was extracted from muscles for bulk RNA-sequencing analysis (n = 3-5 per group per timepoint). Differentially expressed genes (DEGs) were evaluated between age-matched SHAM and SCI animals. Myofiber size, muscle fibre type and fibrosis were assessed on contralateral muscles.
    RESULTS: SCI produced immediate and persistent hindlimb paralysis, with Basso-Beattie-Bresnahan locomotor scores remaining below 7 throughout the study, contributing to a progressive 25-50% lower soleus mass and myofiber atrophy versus SHAM (P < 0.05 at all timepoints). Transcriptional comparisons of SCI versus SHAM resulted in 184 DEGs (1 week), 436 DEGs (2 weeks), 133 DEGs (1 month) and 1200 DEGs (3 months). Upregulated atrophy-related genes included those associated with cell senescence, nuclear factor kappa B, ubiquitin proteasome and unfolded protein response pathways, along with upregulated genes that negatively influence muscle growth through the transforming growth factor beta pathway and inhibition of insulin-like growth factor-I/Akt/mechanistic target of rapamycin and p38/mitogen-activated protein kinase signalling. Genes associated with extracellular matrix (ECM), including collagens, collagen crosslinkers, proteoglycans and those regulating ECM integrity, were enriched within upregulated DEGs at 1 week but subsequently downregulated at 2 weeks and 3 months and were accompanied by >50% higher ECM areas and hydroxyproline levels in SCI muscles (P < 0.05). Myofiber remodelling genes were enriched in upregulated DEGs at 2 weeks and 1 month and were downregulated at 3 months. Genes that regulate neuromuscular junction remodelling were evident in muscles post-SCI, along with slow-to-fast fibre-type shifts: 1 week and 2 weeks SCI muscles were composed of 90% myosin heavy chain (MHC) type I fibres, which decreased to only 16% at 3 months and were accompanied by 50% fibres containing MHC IIX (P < 0.05). Metabolism genes were enriched in upregulated DEGs at 1 month and were further enriched at 3 months.
    CONCLUSIONS: Our results substantiate many known pathologic features of SCI-induced wasting in rat skeletal muscle and identify a progressive and dynamic transcriptional landscape within the post-SCI soleus. Future studies are warranted to consider these therapeutic treatment windows when countering SCI muscle pathology.
    Keywords:  RNA‐sequencing; disuse atrophy; extracellular matrix remodelling; muscle fibre‐type shift; soleus muscle wasting; spinal cord injury
    DOI:  https://doi.org/10.1002/jcsm.13476
  29. Genome Res. 2024 May 22. pii: gr.278717.123. [Epub ahead of print]
    Single-cell spatial transcriptomics reveals a dystrophic trajectory following a developmental bifurcation of myoblast cell fates in facioscapulohumeral muscular dystrophy.
    Lujia Chen, Xiangduo Kong, Kevin G Johnston, Ali Mortazavi, Todd C Holmes, Zhiqun Tan, Kyoko Yokomori, Xiangmin Xu.
      Facioscapulohumeral muscular dystrophy (FSHD) is linked to abnormal de-repression of the transcription activator DUX4. This effect is localized to a low percentage of cells, requiring single-cell analysis. However, single-cell/nucleus RNA-seq cannot fully capture the transcriptome of multinucleated large myotubes. To circumvent these issues, we use MERFISH (Multiplexed Error Robust Fluorescent In Situ Hybridization) spatial transcriptomics that allows profiling of RNA transcripts at a subcellular resolution. We simultaneously examined spatial distributions of 140 genes, including 24 direct DUX4 targets, in in vitro differentiated control, isogenic D4Z4 contraction mutant and FSHD patient myotubes and unfused mononuclear cells (MNCs), as well as the individual nuclei within them. We find myocyte nuclei segregate into 2 clusters defined by expression of DUX4 target genes, which is exclusively found in patient/mutant nuclei, while MNCs cluster based on developmental state. Patient/mutant myotubes are found in "FSHD-hi" and "FSHD-lo" states with the former signified by high DUX4 target expression and decreased muscle gene expression. Pseudotime analyses reveal a clear bifurcation of myoblast differentiation into control and FSHD-hi myotube branches, with variable numbers of DUX4 target expressing nuclei found in multinucleated FSHD-hi myotubes. Gene coexpression modules related to extracellular matrix and stress gene ontologies are significantly altered in patient/mutant myotubes compared to control. We also identify distinct subpathways within the DUX4 gene network that may differentially contribute to the disease transcriptomic phenotype. Taken together, our MERFISH-based study provides effective gene network profiling of multinucleated cells and identifies FSHD-induced transcriptomic alterations during myoblast differentiation.
    DOI:  https://doi.org/10.1101/gr.278717.123
  30. Biomolecules. 2024 May 13. pii: 573. [Epub ahead of print]14(5):
    Failure of Autophagy in Pompe Disease.
    Hung Do, Naresh K Meena, Nina Raben.
      Autophagy is an evolutionarily conserved lysosome-dependent degradation of cytoplasmic constituents. The system operates as a critical cellular pro-survival mechanism in response to nutrient deprivation and a variety of stress conditions. On top of that, autophagy is involved in maintaining cellular homeostasis through selective elimination of worn-out or damaged proteins and organelles. The autophagic pathway is largely responsible for the delivery of cytosolic glycogen to the lysosome where it is degraded to glucose via acid α-glucosidase. Although the physiological role of lysosomal glycogenolysis is not fully understood, its significance is highlighted by the manifestations of Pompe disease, which is caused by a deficiency of this lysosomal enzyme. Pompe disease is a severe lysosomal glycogen storage disorder that affects skeletal and cardiac muscles most. In this review, we discuss the basics of autophagy and describe its involvement in the pathogenesis of muscle damage in Pompe disease. Finally, we outline how autophagic pathology in the diseased muscles can be used as a tool to fast track the efficacy of therapeutic interventions.
    Keywords:  Pompe disease; autophagy; enzyme replacement therapy; glycogen degradation; lysosome; muscle
    DOI:  https://doi.org/10.3390/biom14050573
  31. Aging (Albany NY). 2024 May 17. 16
    Global consensus for sarcopenia.
    Ben Kirk, Peggy M Cawthon, Alfonso J Cruz-Jentoft.
      
    Keywords:  GLIS; global definition; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.18632/aging.205919
  32. Dis Model Mech. 2024 May 01. pii: dmm050397. [Epub ahead of print]17(5):
    The glucocorticoid receptor acts locally to protect dystrophic muscle and heart during disease.
    Trinitee Oliver, Nhu Y Nguyen, Christopher B Tully, Nikki M McCormack, Christina M Sun, Alyson A Fiorillo, Christopher R Heier.
      Absence of dystrophin results in muscular weakness, chronic inflammation and cardiomyopathy in Duchenne muscular dystrophy (DMD). Pharmacological corticosteroids are the DMD standard of care; however, they have harsh side effects and unclear molecular benefits. It is uncertain whether signaling by physiological corticosteroids and their receptors plays a modifying role in the natural etiology of DMD. Here, we knocked out the glucocorticoid receptor (GR, encoded by Nr3c1) specifically in myofibers and cardiomyocytes within wild-type and mdx52 mice to dissect its role in muscular dystrophy. Double-knockout mice showed significantly worse phenotypes than mdx52 littermate controls in measures of grip strength, hang time, inflammatory pathology and gene expression. In the heart, GR deletion acted additively with dystrophin loss to exacerbate cardiomyopathy, resulting in enlarged hearts, pathological gene expression and systolic dysfunction, consistent with imbalanced mineralocorticoid signaling. The results show that physiological GR functions provide a protective role during muscular dystrophy, directly contrasting its degenerative role in other disease states. These data provide new insights into corticosteroids in disease pathophysiology and establish a new model to investigate cell-autonomous roles of nuclear receptors and mechanisms of pharmacological corticosteroids.
    Keywords:  Heart; Inflammation; Mouse model; Muscle; Muscular dystrophy; Steroids
    DOI:  https://doi.org/10.1242/dmm.050397
  33. Cell Calcium. 2024 May 23. pii: S0143-4160(24)00065-4. [Epub ahead of print]121 102907
    Unravelling the complexity of the mitochondrial Ca2+ uniporter: regulation, tissue specificity, and physiological implications.
    Denis Vecellio Reane, Julian D C Serna, Anna Raffaello.
      Calcium (Ca2+) signalling acts a pleiotropic message within the cell that is decoded by the mitochondria through a sophisticated ion channel known as the Mitochondrial Ca2+ Uniporter (MCU) complex. Under physiological conditions, mitochondrial Ca2+ signalling is crucial for coordinating cell activation with energy production. Conversely, in pathological scenarios, it can determine the fine balance between cell survival and death. Over the last decade, significant progress has been made in understanding the molecular bases of mitochondrial Ca2+ signalling. This began with the elucidation of the MCU channel components and extended to the elucidation of the mechanisms that regulate its activity. Additionally, increasing evidence suggests molecular mechanisms allowing tissue-specific modulation of the MCU complex, tailoring channel activity to the specific needs of different tissues or cell types. This review aims to explore the latest evidence elucidating the regulation of the MCU complex, the molecular factors controlling the tissue-specific properties of the channel, and the physiological and pathological implications of mitochondrial Ca2+ signalling in different tissues.
    Keywords:  Brain; Calcium signalling; Heart; Liver; MCU regulation; Mitochondrial calcium uniporter; Skeletal Muscle; tissue-specific modulation
    DOI:  https://doi.org/10.1016/j.ceca.2024.102907
  34. Am J Clin Nutr. 2024 May 16. pii: S0002-9165(24)00472-6. [Epub ahead of print]
    The effects of whey, pea, and collagen protein supplementation beyond the recommended dietary allowance on integrated myofibrillar protein synthetic rates in older males: a randomized controlled trial.
    James McKendry, Caroline V Lowisz, Arraksana Nanthakumar, Meaghan MacDonald, Changhyun Lim, Brad S Currier, Stuart M Phillips.
      BACKGROUND: Skeletal muscle mass is determined predominantly by feeding- and activity-induced fluctuations in muscle protein synthesis (MPS). Older individuals display a diminished MPS response to protein ingestion, referred to as age-related anabolic resistance, that contributes to the progression of age-related muscle loss - sarcopenia.OBJECTIVE: We aimed to determine the impact of consuming higher- versus lower-quality protein supplements above the recommended dietary allowance (RDA) on integrated MPS rates. We hypothesized that increasing total protein intake above the RDA, regardless of the source, would support higher integrated rates of myofibrillar protein synthesis.
    METHODS: Thirty-one healthy older males (72 ± 4 y) underwent a controlled diet with protein intake set at the RDA - control phase (CON; days 1-7). In a double-blind, randomized controlled fashion, participants were assigned to consume an additional 50g (2x25g) of Whey (WHEY, n=10), Pea (PEA, n=11), or collagen (COLL, n=10) protein each day (25 g at breakfast and lunch) during the supplemental phase (SUPP; days 8-15). Deuterated water ingestion and muscle biopsies assessed integrated MPS and acute anabolic signaling. Postprandial blood samples were collected to determine feeding-induced aminoacidemia.
    RESULTS: Integrated-MPS was increased during SUPP with WHEY (1.59 ± 0.11 %/d, p<0.001) and PEA (1.59 ± 0.14 %/d, p<0.001) when compared with RDA (1.46 ± 0.09 %/d WHEY; 1.46 ± 0.10 %/d PEA); however, it remained unchanged with COLL. Supplemental protein was sufficient to overcome anabolic signaling deficits (mTORC1 and rpS6), corroborating the greater postprandial aminoacidemia.
    CONCLUSIONS: Our findings demonstrate that supplemental protein provided at breakfast and lunch over the current RDA enhanced anabolic signaling and integrated MPS in older males; however, the source of additional protein may be an important consideration in overcoming age-related anabolic resistance. Clinical Trial Registry number and website where it was obtained This trial (NCT04026607) was registered clinicaltrials.gov.
    Keywords:  aging; muscle anabolism; nutrient requirements; plant-based protein; protein nutrition; sarcopenia; stable isotope tracers
    DOI:  https://doi.org/10.1016/j.ajcnut.2024.05.009
  35. J Cell Biol. 2024 Aug 05. pii: e202402046. [Epub ahead of print]223(8):
    Proteasome gene expression is controlled by coordinated functions of multiple transcription factors.
    Jennifer E Gilda, Asrafun Nahar, Dharanibalan Kasiviswanathan, Nadav Tropp, Tamar Gilinski, Tamar Lahav, Dina Alexandrovich, Yael Mandel-Gutfreund, Soyeon Park, Shenhav Shemer.
      Proteasome activity is crucial for cellular integrity, but how tissues adjust proteasome content in response to catabolic stimuli is uncertain. Here, we demonstrate that transcriptional coordination by multiple transcription factors is required to increase proteasome content and activate proteolysis in catabolic states. Using denervated mouse muscle as a model system for accelerated proteolysis in vivo, we reveal that a two-phase transcriptional program activates genes encoding proteasome subunits and assembly chaperones to boost an increase in proteasome content. Initially, gene induction is necessary to maintain basal proteasome levels, and in a more delayed phase (7-10 days after denervation), it stimulates proteasome assembly to meet cellular demand for excessive proteolysis. Intriguingly, the transcription factors PAX4 and α-PALNRF-1 control the expression of proteasome among other genes in a combinatorial manner, driving cellular adaptation to muscle denervation. Consequently, PAX4 and α-PALNRF-1 represent new therapeutic targets to inhibit proteolysis in catabolic diseases (e.g., type-2 diabetes, cancer).
    DOI:  https://doi.org/10.1083/jcb.202402046
  36. J Clin Endocrinol Metab. 2024 May 23. pii: dgae350. [Epub ahead of print]
    Characterising 24-h skeletal muscle gene expression alongside metabolic & endocrine responses under diurnal conditions.
    Harry A Smith, Iain Templeman, Max Davis, Tommy Slater, David J Clayton, Ian Varley, Lewis J James, Benita Middleton, Jonathan D Johnston, Leonidas G Karagounis, Kostas Tsintzas, Dylan Thompson, Javier T Gonzalez, Jean-Philippe Walhin, James A Betts.
      CONTEXT: Skeletal muscle plays a central role in the storage, synthesis, and breakdown of nutrients, yet little research has explored temporal responses of this human tissue, especially with concurrent measures of systemic biomarkers of metabolism.OBJECTIVE: To characterise temporal profiles in skeletal muscle expression of genes involved in carbohydrate metabolism, lipid metabolism, circadian clocks, and autophagy and descriptively relate them to systemic metabolites and hormones during a controlled laboratory protocol.
    METHODS: Ten healthy adults (9M/1F, mean ± SD: age: 30 ± 10 y; BMI: 24.1 ± 2.7 kg·m-2) rested in the laboratory for 37 hours with all data collected during the final 24 hours of this period (i.e., 0800-0800 h). Participants ingested hourly isocaloric liquid meal replacements alongside appetite assessments during waking before a sleep opportunity from 2200-0700 h. Blood samples were collected hourly for endocrine and metabolite analyses, with muscle biopsies occurring every 4 h from 1200 h to 0800 h the following day to quantify gene expression.
    RESULTS: Plasma insulin displayed diurnal rhythmicity peaking at 1804 h. Expression of skeletal muscle genes involved in carbohydrate metabolism (Name - Acrophase; GLUT4 - 1440 h; PPARGC1A -1613 h; HK2 - 1824 h) and lipid metabolism (FABP3 - 1237 h; PDK4 - 0530 h; CPT1B - 1258 h) displayed 24 h rhythmicity that reflected the temporal rhythm of insulin. Equally, circulating glucose (0019 h), NEFA (0456 h), glycerol (0432 h), triglyceride (2314 h), urea (0046 h), CTX (0507 h) and cortisol concentrations (2250 h) also all displayed diurnal rhythmicity.
    CONCLUSION: Diurnal rhythms were present in human skeletal muscle gene expression as well systemic metabolites and hormones under controlled diurnal conditions. The temporal patterns of genes relating to carbohydrate and lipid metabolism alongside circulating insulin are consistent with diurnal rhythms being driven in part by the diurnal influence of cyclic feeding and fasting.
    Keywords:  Circadian rhythms; Diurnal; Gene expression; Glucose; Lipids; Skeletal muscle
    DOI:  https://doi.org/10.1210/clinem/dgae350
  37. Cancers (Basel). 2024 May 18. pii: 1921. [Epub ahead of print]16(10):
    Influence of Amino Acids and Exercise on Muscle Protein Turnover, Particularly in Cancer Cachexia.
    Rashmita Pradhan, Walburga Dieterich, Anirudh Natarajan, Raphaela Schwappacher, Dejan Reljic, Hans J Herrmann, Markus F Neurath, Yurdagül Zopf.
      Cancer cachexia is a multifaceted syndrome that impacts individuals with advanced cancer. It causes numerous pathological changes in cancer patients, such as inflammation and metabolic dysfunction, which further diminish their quality of life. Unfortunately, cancer cachexia also increases the risk of mortality in affected individuals, making it an important area of focus for cancer research and treatment. Several potential nutritional therapies are being tested in preclinical and clinical models for their efficacy in improving muscle metabolism in cancer patients. Despite promising results, no special nutritional therapies have yet been validated in clinical practice. Multiple studies provide evidence of the benefits of increasing muscle protein synthesis through an increased intake of amino acids or protein. There is also increasing evidence that exercise can reduce muscle atrophy by modulating protein synthesis. Therefore, the combination of protein intake and exercise may be more effective in improving cancer cachexia. This review provides an overview of the preclinical and clinical approaches for the use of amino acids with and without exercise therapy to improve muscle metabolism in cachexia.
    Keywords:  amino acids; cancer cachexia; exercise; inflammation; oxidative stress
    DOI:  https://doi.org/10.3390/cancers16101921
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