bims-moremu 2024-06-30 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2024–06–30
33 papers selected by
Anna Vainshtein, Craft Science Inc.

Muscle weakness and mitochondrial stress occur before severe metastasis in a novel mouse model of ovarian cancer cachexia.
Aerobic exercise suppresses CCN2 secretion from senescent muscle stem cells and boosts muscle regeneration in aged mice.
The Influence of Aging on the Unfolded Protein Response in Human Skeletal Muscle at Rest and Following Acute Exercise.
The rRNA epitranscriptome and myonuclear SNORD landscape in skeletal muscle fibers contributes to ribosome heterogeneity and is altered by hypertrophic stimulus.
Myogenic microRNAs as Therapeutic Targets for Skeletal Muscle Mass Wasting in Breast Cancer Models.
BMAL1 and CLOCK proteins exhibit differential association with mitochondrial dynamics, protein synthesis pathways and muscle strength in human muscle.
Autophagic signaling promotes systems-wide remodeling in skeletal muscle upon oncometabolic stress by D2-HG.
Aging-associated Aberrant Mitochondrial Redox Signaling, Physical Activity, and Sarcopenia.
Transcriptome profiling of fast/glycolytic and slow/oxidative muscle fibers in aging and obesity.
Lactate transported by MCT1 plays an active role in promoting mitochondrial biogenesis and enhancing TCA flux in skeletal muscle.
Dual FKRP/FST gene therapy in a single AAV normalizes ambulation, increases muscle strength, decreases muscle pathology, and amplifies gene expression in the FKRPP448L model of LGMDR9.
Metformin treatment results in distinctive skeletal muscle mitochondrial remodeling in rats with different intrinsic aerobic capacities.
Investigating the Involvement of C-X-C Motif Chemokine 5 and P2X7 Purinoceptor in Ectopic Calcification in Mouse Models of Duchenne Muscular Dystrophy.
The Extract of Gloiopeltis tenax Enhances Myogenesis and Alleviates Dexamethasone-Induced Muscle Atrophy.
Oxidised Albumin Levels in Plasma and Skeletal Muscle as Biomarkers of Disease Progression and Treatment Efficacy in Dystrophic mdx Mice.
Acute and Chronic Changes in Muscle Androgen Receptor Markers Are Not Associated with Muscle Hypertrophy in Women and Men.
Mechanisms Underlying the Rarity of Skeletal Muscle Cancers.
PGAM5 interacts with and maintains BNIP3 to license cancer-associated muscle wasting.
The Neuromuscular Disorder Mediated by Extracellular Vesicles in Amyotrophic Lateral Sclerosis.
Thrombospondin-4 deletion does not exacerbate muscular dystrophy in β-sarcoglycan-deficient and laminin α2 chain-deficient mice.
The aging lipidome: exercise is medicine.
Whole-body metabolic rate is influenced by muscle fibre typology.
SIRT1 signaling pathways in sarcopenia: Novel mechanisms and potential therapeutic targets.
Mitochondrial puzzle in muscle: Linking the electron transport system to overweight.
Sunitinib-mediated inhibition of STAT3 in skeletal muscle and spinal cord does not affect the disease in a mouse model of ALS.
A Novel MAO-B/SSAO Inhibitor Improves Multiple Aspects of Dystrophic Phenotype in mdx Mice.
Proteomic profiling of polyglucosan bodies associated with glycogenin-1 deficiency in skeletal muscle.
Eugenol mimics exercise to promote skeletal muscle fiber remodeling and myokine IL-15 expression by activating TRPV1 channel.
ISOLATION OF A PERSISTENTLY QUIESCENT MUSCLE SATELLITE CELL POPULATION.
Muscle-Derived microRNAs Correlated with Thigh Lean Mass Gains during Progressive Resistance Training in Older Adults.
Aging and Autophagy: Roles in Musculoskeletal System Injury.
Sarcopenia-related changes in serum GLP-1 level affect myogenic differentiation.
Aged mice regain youthful muscles thanks to a compound that acts on the genes.

Mol Metab. 2024 Jun 24. pii: S2212-8778(24)00107-8. [Epub ahead of print] 101976

Muscle weakness and mitochondrial stress occur before severe metastasis in a novel mouse model of ovarian cancer cachexia.

Luca J Delfinis, Leslie M Ogilvie, Shahrzad Khajehzadehshoushtar, Shivam Gandhi, Madison C Garibotti, Arshdeep K Thuhan, Kathy Matuszewska, Madison Pereira, Ronald G Jones, Arthur J Cheng, Thomas J Hawke, Nicholas P Greene, Kevin A Murach, Jeremy A Simpson, Jim Petrik, Christopher G R Perry.

   OBJECTIVES: A high proportion of women with advanced epithelial ovarian cancer (EOC) experience weakness and cachexia. This relationship is associated with increased morbidity and mortality. EOC is the most lethal gynecological cancer, yet no preclinical cachexia model has demonstrated the combined hallmark features of metastasis, ascites development, muscle loss and weakness in adult immunocompetent mice.
METHODS: Here, we evaluated a new model of ovarian cancer-induced cachexia with the advantages of inducing cancer in adult immunocompetent C57BL/6J mice through orthotopic injections of EOC cells in the ovarian bursa. We characterized the development of metastasis, ascites, muscle atrophy, muscle weakness, markers of inflammation, and mitochondrial stress in the tibialis anterior (TA) and diaphragm ∼45, ∼75 and ∼90 days after EOC injection.
RESULTS: Primary ovarian tumour sizes were progressively larger at each time point while severe metastasis, ascites development, and reductions in body, fat and muscle weights occurred by 90 Days. There were no changes in certain inflammatory (TNFα), atrogene (MURF1 and Atrogin) or GDF15 markers within both muscles whereas IL-6 was increased at 45 and 90 Day groups in the diaphragm. TA weakness in 45 Day preceded atrophy and metastasis that were observed later (75 and 90 Day, respectively). The diaphragm demonstrated both weakness and atrophy in 45 Day. In both muscles, this pre-severe-metastatic muscle weakness corresponded with considerable reprogramming of gene pathways related to mitochondrial bioenergetics as well as reduced functional measures of mitochondrial pyruvate oxidation and creatine-dependent ADP/ATP cycling as well as increased reactive oxygen species emission (hydrogen peroxide). Remarkably, muscle force per unit mass at 90 days was partially restored in the TA despite the presence of atrophy and severe metastasis. In contrast, the diaphragm demonstrated progressive weakness. At this advanced stage, mitochondrial pyruvate oxidation in both muscles exceeded control mice suggesting an apparent metabolic super-compensation corresponding with restored indices of creatine-dependent adenylate cycling.
CONCLUSION: This mouse model demonstrates the concurrent development of cachexia and metastasis that occurs in women with EOC. The model provides physiologically relevant advantages of inducing tumour development within the ovarian bursa in immunocompetent adult mice. Moreover, the model reveals that muscle weakness in both TA and diaphragm precedes severe metastasis while weakness also precedes atrophy in the TA. An underlying mitochondrial bioenergetic stress corresponded with this early weakness. Collectively, these discoveries can direct new research towards the development of therapies that target pre-atrophy and pre-severe-metastatic weakness during EOC in addition to therapies targeting cachexia.

Keywords:  Ovarian cancer cachexia; metastasis; mitochondria; skeletal muscle

DOI:  https://doi.org/10.1016/j.molmet.2024.101976
J Cachexia Sarcopenia Muscle. 2024 Jun 26.

Aerobic exercise suppresses CCN2 secretion from senescent muscle stem cells and boosts muscle regeneration in aged mice.

Fan Li, Fulong Zhang, Haiwang Shi, Honglin Xia, Xiaobei Wei, Siqi Liu, Tao Wu, Yuecheng Li, Feng Shu, Mengjie Chen, Jie Li, Rui Duan.

   BACKGROUND: Aging negatively impacts tissue repair, particularly in skeletal muscle, where the regenerative capacity of muscle stem cells (MuSCs) diminishes with age. Although aerobic exercise is known to attenuate skeletal muscle atrophy, its specific impact on the regenerative and repair capacity of MuSCs remains unclear.
METHODS: Mice underwent moderate-intensity continuous training (MICT) from 9 months (aged + Ex-9M) or 20 months (aged + Ex-20M) to 25 months, with age-matched (aged) and adult controls. Histological examinations and MuSC transplantation assays assessed aerobic exercise effects on MuSC function and muscle regeneration. CCN2/connective tissue growth factor modulation (overexpression and knockdown) in MuSCs and AICAR supplementation effects were explored.
RESULTS: Aged mice displayed significantly reduced running duration (65.33 ± 4.32 vs. 161.9 ± 1.29 min, mean ± SD, P < 0.001) and distance (659.17 ± 103.64 vs. 3058.28 ± 46.26 m, P < 0.001) compared with adults. This reduction was accompanied by skeletal muscle weight loss and decreased myofiber cross-sectional area (CSA). However, MICT initiated at 9 or 20 months led to a marked increase in running duration (142.75 ± 3.14 and 133.86 ± 20.47 min, respectively, P < 0.001 compared with aged mice) and distance (2347.58 ± 145.11 and 2263 ± 643.87 m, respectively, P < 0.001). Additionally, MICT resulted in increased skeletal muscle weight and enhanced CSA. In a muscle injury model, aged mice exhibited fewer central nuclear fibres (CNFs; 266.35 ± 68.66/mm2), while adult, aged + Ex-9M and aged + Ex-20M groups showed significantly higher CNF counts (610.82 ± 46.76, 513.42 ± 47.19 and 548.29 ± 71.82/mm2, respectively; P < 0.001 compared with aged mice). MuSCs isolated from aged mice displayed increased CCN2 expression, which was effectively suppressed by MICT. Transplantation of MuSCs overexpressing CCN2 (Lenti-CCN2, Lenti-CON as control) into injured tibialis anterior muscle compromised regeneration capacity, resulting in significantly fewer CNFs in the Lenti-CCN2 group compared with Lenti-CON (488.07 ± 27.63 vs. 173.99 ± 14.28/mm2, P < 0.001) at 7 days post-injury (dpi). Conversely, knockdown of CCN2 (Lenti-CCN2shR, Lenti-NegsiR as control) in aged MuSCs improved regeneration capacity, significantly increasing the CNF count from 254.5 ± 26.36 to 560.39 ± 48.71/mm2. Lenti-CCN2 MuSCs also increased fibroblast proliferation and exacerbated skeletal muscle fibrosis, while knockdown of CCN2 in aged MuSCs mitigated this pattern. AICAR supplementation, mimicking exercise, replicated the beneficial effects of aerobic exercise by mitigating muscle weight decline, enhancing satellite cell activity and reducing fibrosis.
CONCLUSIONS: Aerobic exercise effectively reverses the decline in endurance capacity and mitigates muscle atrophy in aged mice. It inhibits CCN2 secretion from senescent MuSCs, thereby enhancing skeletal muscle regeneration and preventing fibrosis in aged mice. AICAR supplementation mimics the beneficial effects of aerobic exercise.

Keywords:  CCN2; MuSCs; aerobic exercise; aging; fibrosis; skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.13526
Med Sci Sports Exerc. 2024 Jun 27.

The Influence of Aging on the Unfolded Protein Response in Human Skeletal Muscle at Rest and Following Acute Exercise.

Kelly L Michie, Hawley E Kunz, Surendra Dasari, Ian R Lanza.

BACKGROUND: The unfolded protein response (UPR) is a proteostatic process that is activated in response to endoplasmic reticulum stress. It is currently unclear how aging influences the chronic and adaptive UPR in human skeletal muscle. Here we determined the effect of aging on UPR activation at rest, in response to exercise, and the associations with muscle function.
METHODS: Thirty young (20-35 yrs) and 50 older (65-85 yrs) individuals were enrolled. Vastus lateralis biopsies were performed at rest and 3 hrs and 48 hrs after a single bout of resistance exercise. The abundance of UPR-related transcripts and proteins were measured by RNA sequencing and Western blotting, respectively. Fractional synthetic rates (FSR) of muscle protein were determined by mass spectrometry following intravenous infusion of 13C6 phenylalanine.
RESULTS: Older adults demonstrated elevated transcriptional and proteomic markers of UPR activation in resting muscle. Resting UPR gene expression was negatively associated with muscle strength and power in older adults. The UPR is similarly activated by acute resistance exercise in young and older adults and positively associated with muscle function but not the anabolic response to exercise.
CONCLUSIONS: Skeletal muscle from older adults exhibits chronically activated UPR, which accompanies functional decline. The adaptive UPR is a proteostatic mechanism that is upregulated in response to exercise in young and older adults and positively associated with muscle function.

DOI: https://doi.org/10.1249/MSS.0000000000003508
Am J Physiol Cell Physiol. 2024 Jun 24.

The rRNA epitranscriptome and myonuclear SNORD landscape in skeletal muscle fibers contributes to ribosome heterogeneity and is altered by hypertrophic stimulus.

Minying Cui, Paulo Jannig, Maral Halladjian, Vandre C Figueiredo, Yuan Wen, Ivan J Vechetti, Nicolai Krogh, Baptiste Jude, Sebastian Edman, Johanna Lanner, John McCarthy, Kevin A Murach, Thomas Sejersen, Henrik Nielsen, Ferdinand von Walden.

  In cell biology, ribosomal RNA (rRNA) 2'O-methyl (2'-O-Me) is the most prevalent post-transcriptional chemical modification contributing to ribosome heterogeneity. The modification involves a family of small nucleolar RNAs (snoRNAs) and is specified by box C/D snoRNAs (SNORDs). Given the importance of ribosome biogenesis for skeletal muscle growth, we asked if rRNA 2'-O-Me in nascent ribosomes synthesized in response to a growth stimulus is an unrecognized mode of ribosome heterogeneity in muscle. To determine the pattern and dynamics of 2'-O-Me rRNA, we used a sequencing-based profiling method called RiboMeth-seq. We applied this method to tissue-derived rRNA of skeletal muscle and rRNA specifically from the muscle fiber using an inducible myofiber-specific RiboTag mouse in sedentary and mechanically overloaded conditions. These analyses were complemented by myonuclear-specific small RNA sequencing to profile SNORDs and link the rRNA epitranscriptome to known regulatory elements generated within the muscle fiber. We demonstrate for the first time that mechanical overload of skeletal muscle 1) induces decreased 2'-O-Me at a subset of skeletal muscle rRNAand 2) alters the SNORD profile in isolated myonuclei. These findings point to a transient diversification of the ribosome pool via 2'-O-Me during growth and adaptation in skeletal muscle. These findings suggest changes in ribosome heterogeneity at the 2'-O-Me level during muscle hypertrophy and lay the foundation for studies investigating the functional implications of these newly identified "growth-induced" ribosomes.

Keywords:  epitranscriptomics; hypertrophy; ribosome heterogeneity; skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00301.2024
Int J Mol Sci. 2024 Jun 18. pii: 6714. [Epub ahead of print]25(12):

Myogenic microRNAs as Therapeutic Targets for Skeletal Muscle Mass Wasting in Breast Cancer Models.

Macarena Artigas-Arias, Rui Curi, Gabriel Nasri Marzuca-Nassr.

  Breast cancer is the type of cancer with the highest prevalence in women worldwide. Skeletal muscle atrophy is an important prognostic factor in women diagnosed with breast cancer. This atrophy stems from disrupted skeletal muscle homeostasis, triggered by diminished anabolic signalling and heightened inflammatory conditions, culminating in an upregulation of skeletal muscle proteolysis gene expression. The importance of delving into research on modulators of skeletal muscle atrophy, such as microRNAs (miRNAs), which play a crucial role in regulating cellular signalling pathways involved in skeletal muscle protein synthesis and degradation, has been recognised. This holds true for conditions of homeostasis as well as pathologies like cancer. However, the determination of specific miRNAs that modulate skeletal muscle atrophy in breast cancer conditions has not yet been explored. In this narrative review, we aim to identify miRNAs that could directly or indirectly influence skeletal muscle atrophy in breast cancer models to gain an updated perspective on potential therapeutic targets that could be modulated through resistance exercise training, aiming to mitigate the loss of skeletal muscle mass in breast cancer patients.

Keywords:  breast cancer; microRNAs; muscle atrophy; myogenic miRNAs; myomirs; protein degradation; protein synthesis; skeletal muscle loss

DOI:  https://doi.org/10.3390/ijms25126714
J Physiol. 2024 Jun 26.

BMAL1 and CLOCK proteins exhibit differential association with mitochondrial dynamics, protein synthesis pathways and muscle strength in human muscle.

A M Figueroa-Toledo, J Gutiérrez-Pino, A Carriel-Nesvara, M Marchese-Bittencourt, H Zbinden-Foncea, M Castro-Sepúlveda.

  Murine models lacking CLOCK/BMAL1 proteins in skeletal muscle (SkM) present muscle deterioration and mitochondria abnormalities. It is unclear whether humans with lower levels of these proteins in the SkM have similar alterations. Here we evaluated the association between BMAL1 and CLOCK protein mass with mitochondrial dynamics parameters and molecular and functional SkM quality markers in males. SkM biopsies were taken from the vastus lateralis of 16 male (non-athletes, non-obese and non-diabetic) subjects (8-9 a.m.). The morphology of mitochondria and their interaction with the sarcoplasmic reticulum (mitochondria-SR) were determined using transmission electron microscopy images. Additionally, protein abundance of the OXPHOS complex, mitochondria fusion/fission regulators, mitophagy and signalling proteins related to muscle protein synthesis were measured. To evaluate the quality of SkM, the cross-sectional area and maximal SkM strength were also measured. The results showed that BMAL1 protein mass was positively associated with mitochondria-SR distance, mitochondria size, mitochondria cristae density and mTOR protein mass. On the other hand, CLOCK protein mass was negatively associated with mitochondria-SR interaction, but positively associated with mitochondria complex III, OPA1 and DRP1 protein mass. Furthermore, CLOCK protein mass was positively associated with the protein synthesis signalling pathway (total mTOR, AKT and P70S6K protein mass) and SkM strength. These findings suggest that the BMAL1 and CLOCK proteins play different roles in regulating mitochondrial dynamics and SkM function in males, and that modulation of these proteins could be a potential therapeutic target for treating muscle diseases. KEY POINTS: In murine models, reductions in BMAL1 and CLOCK proteins lead to changes in mitochondria biology and a decline in muscle function. However, this association has not been explored in humans. We found that in human skeletal muscle, a decrease in BMAL1 protein mass is linked to smaller intermyofibrillar mitochondria, lower mitochondria cristae density, higher interaction between mitochondria and sarcoplasmic reticulum, and reduced mTOR protein mass. Additionally, we found that a decrease in CLOCK protein mass is associated with a higher interaction between mitochondria and sarcoplasmic reticulum, lower protein mass of OPA1 and DRP1, which regulates mitochondria fusion and fission, lower protein synthesis signalling pathway (mTOR, AKT and P70S6K protein mass), and decreased skeletal muscle strength. According to our findings in humans, which are supported by previous studies in animals, the mitochondrial dynamics and skeletal muscle function could be regulated differently by BMAL1 and CLOCK proteins. As a result, targeting the modulation of these proteins could be a potential therapeutic approach for treating muscle diseases and metabolic disorders related to muscle.

Keywords:  circadian clock; mitochondria cristae density; mitochondria fusion and fission; mitochondria–sarcoplasmic reticulum interaction; mitophagy; muscle strength

DOI:  https://doi.org/10.1113/JP285955
Mol Metab. 2024 Jun 20. pii: S2212-8778(24)00100-5. [Epub ahead of print] 101969

Autophagic signaling promotes systems-wide remodeling in skeletal muscle upon oncometabolic stress by D2-HG.

Yaqi Gao, Kyoungmin Kim, Heidi Vitrac, Rebecca L Salazar, Benjamin D Gould, Daniel Soedkamp, Weston Spivia, Koen Raedschelders, An Q Dinh, Anna G Guzman, Lin Tan, Stavros Azinas, David J R Taylor, Walter Schiffer, Daniel McNavish, Helen B Burks, Roberta A Gottlieb, Philip L Lorenzi, Blake M Hanson, Jennifer E Van Eyk, Heinrich Taegtmeyer, Anja Karlstaedt.

   OBJECTIVES: Cachexia is a metabolic disorder and comorbidity with cancer and heart failure. The syndrome impacts more than thirty million people worldwide, accounting for 20% of all cancer deaths. In acute myeloid leukemia, somatic mutations of the metabolic enzyme isocitrate dehydrogenase 1 and 2 cause the production of the oncometabolite D2-hydroxyglutarate (D2-HG). Increased production of D2-HG is associated with heart and skeletal muscle atrophy, but the mechanistic links between metabolic and proteomic remodeling remain poorly understood. Therefore, we assessed how oncometabolic stress by D2-HG activates autophagy and drives skeletal muscle loss.
METHODS: We quantified genomic, metabolomic, and proteomic changes in cultured skeletal muscle cells and mouse models of IDH-mutant leukemia using RNA sequencing, mass spectrometry, and computational modeling.
RESULTS: D2-HG impairs NADH redox homeostasis in myotubes. Increased NAD+ levels drive activation of nuclear deacetylase Sirt1, which causes deacetylation and activation of LC3, a key regulator of autophagy. Using LC3 mutants, we confirm that deacetylation of LC3 by Sirt1 shifts its distribution from the nucleus into the cytosol, where it can undergo lipidation at pre-autophagic membranes. Sirt1 silencing or p300 overexpression attenuated autophagy activation in myotubes. In vivo, we identified increased muscle atrophy and reduced grip strength in response to D2-HG in male vs. female mice. In male mice, glycolytic intermediates accumulated, and protein expression of oxidative phosphorylation machinery was reduced. In contrast, female animals upregulated the same proteins, attenuating the phenotype in vivo. Network modeling and machine learning algorithms allowed us to identify candidate proteins essential for regulating oncometabolic adaptation in mouse skeletal muscle.
CONCLUSIONS: Our multi-omics approach exposes new metabolic vulnerabilities in response to D2-HG in skeletal muscle and provides a conceptual framework for identifying therapeutic targets in cachexia.

Keywords:  Autophagy; Cachexia; Oncometabolism; Systems Biology

DOI:  https://doi.org/10.1016/j.molmet.2024.101969
Curr Aging Sci. 2024 Jun 12.

Aging-associated Aberrant Mitochondrial Redox Signaling, Physical Activity, and Sarcopenia.

Mehmet Can Atayik, Erdem Atasever, Şeydanur Turgut, Ufuk Çakatay.

  Aging-related alteration of mitochondrial morphology, impairment in metabolic capacity, bioenergetics, and biogenesis are closely associated with loss of muscle mass and function. Mitochondrial Reactive Oxygen Species (ROS) stimulate muscular redox signaling mechanisms. Bioenergetic integrity of mitochondria and redox signaling dynamics deteriorates in aged skeletal muscle. Mitochondrial bioenergetic impairment leads to excessive ROS levels and induces the generation of defective mitochondria. Higher ROS levels may induce senescence or apoptosis. It is not a resolved issue that mitochondrial dysfunction is either the sole reason or a consequence of muscle loss (or both). However, Increasing evidence emphasizes that dysregulated mitochondrial redox signaling has a central role in age-related muscle loss. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates redox signaling pathways with the expression of antioxidant genes. As the aberrant redox signaling mechanisms in aging skeletal muscle become clearer, new natural and synthetic Nrf2-modulating substances and integrated daily physical activity alternatives are coming into view for preventing muscle loss in the elderly. A comprehensive understanding of the relationship between redox signaling pathways and age-related sarcopenia can help us to prevent sarcopenia and its frailty effects with an optimized exercise program as an innovative non-pharmacological therapeutic approach. A further aspect is necessary to consider both individualized physical training options and alternative Nrf2 signaling modulators. Ameliorating the redox signaling with physical activity and pharmacological interventions may help to prevent sarcopenia and its frailty effects.

Keywords:  Aging; exercise; mitochondria; reactive oxygen species; redox signaling; sarcopenia\

DOI:  https://doi.org/10.2174/0118746098315667240606052523
Cell Death Dis. 2024 Jun 28. 15(6): 459

Transcriptome profiling of fast/glycolytic and slow/oxidative muscle fibers in aging and obesity.

Feng-Min Zhang, Hao-Fan Wu, Ke-Fan Wang, Ding-Ye Yu, Xian-Zhong Zhang, Qi Ren, Wei-Zhe Chen, Feng Lin, Zhen Yu, Cheng-Le Zhuang.

Aging and obesity pose significant threats to public health and are major contributors to muscle atrophy. The trends in muscle fiber types under these conditions and the transcriptional differences between different muscle fiber types remain unclear. Here, we demonstrate distinct responses of fast/glycolytic fibers and slow/oxidative fibers to aging and obesity. We found that in muscles dominated by oxidative fibers, the proportion of oxidative fibers remains unchanged during aging and obesity. However, in muscles dominated by glycolytic fibers, despite the low content of oxidative fibers, a significant decrease in proportion of oxidative fibers was observed. Consistently, our study uncovered that during aging and obesity, fast/glycolytic fibers specifically increased the expression of genes associated with muscle atrophy and inflammation, including Dkk3, Ccl8, Cxcl10, Cxcl13, Fbxo32, Depp1, and Chac1, while slow/oxidative fibers exhibit elevated expression of antioxidant protein Nqo-1 and downregulation of Tfrc. Additionally, we noted substantial differences in the expression of calcium-related signaling pathways between fast/glycolytic fibers and slow/oxidative fibers in response to aging and obesity. Treatment with a calcium channel inhibitor thapsigargin significantly increased the abundance of oxidative fibers. Our study provides additional evidence to support the transcriptomic differences in muscle fiber types under pathophysiological conditions, thereby establishing a theoretical basis for modulating muscle fiber types in disease treatment.

DOI: https://doi.org/10.1038/s41419-024-06851-y
Sci Adv. 2024 Jun 28. 10(26): eadn4508

Lactate transported by MCT1 plays an active role in promoting mitochondrial biogenesis and enhancing TCA flux in skeletal muscle.

Lingling Zhang, Chenhao Xin, Shuo Wang, Shixuan Zhuo, Jing Zhu, Zi Li, Yuyi Liu, Lifeng Yang, Yan Chen.

Once considered as a "metabolic waste," lactate is now recognized as a major fuel for tricarboxylic acid (TCA) cycle. Our metabolic flux analysis reveals that skeletal muscle mainly uses lactate to fuel TCA cycle. Lactate is transported through the cell membrane via monocarboxylate transporters (MCTs) in which MCT1 is highly expressed in the muscle. We analyzed how MCT1 affects muscle functions using mice with specific deletion of MCT1 in skeletal muscle. MCT1 deletion enhances running performance, increases oxidative fibers while decreasing glycolytic fibers, and enhances flux of glucose to TCA cycle. MCT1 deficiency increases the expression of mitochondrial proteins, augments cell respiration rate, and elevates mitochondrial activity in the muscle. Mechanistically, the protein level of PGC-1α, a master regulator of mitochondrial biogenesis, is elevated upon loss of MCT1 via increases in cellular NAD+ level and SIRT1 activity. Collectively, these results demonstrate that MCT1-mediated lactate shuttle plays a key role in regulating muscle functions by modulating mitochondrial biogenesis and TCA flux.

DOI: https://doi.org/10.1126/sciadv.adn4508
Mol Ther. 2024 Jun 22. pii: S1525-0016(24)00411-8. [Epub ahead of print]

Dual FKRP/FST gene therapy in a single AAV normalizes ambulation, increases muscle strength, decreases muscle pathology, and amplifies gene expression in the FKRPP448L model of LGMDR9.

Patricia Lam, Deborah A Zygmunt, Anna Ashbrook, Macey Bennett, Tatyana A Vetter, Paul T Martin.

Recent clinical studies of single gene replacement therapy for neuromuscular disorders have shown they can slow or stop disease progression, but such therapies have had little impact on reversing muscle disease that was already present. In order to reverse disease in patients with muscular dystrophy, new muscle mass and strength must be rebuilt at the same time that gene replacement prevents subsequent disease. Here, we show that treatment of FKRPP448L mice with a dual FKRP/FST gene therapy packaged into a single AAV vector can build muscle strength and mass that exceed levels found in wild-type mice and can induce normal ambulation endurance in a one-hour walk test. Dual FKRP/FST therapy also showed more even increases in muscle mass and amplified muscle expression of both genes relative to either single gene therapy alone. These data suggest that treatment with a single AAV bearing dual FKRP/FST gene therapies can overcome loss of ambulation by improving muscle strength at the same time it prevents subsequent muscle damage. This design platform could be used to create therapies for other forms of muscular dystrophy that may improve patient outcomes.

DOI: https://doi.org/10.1016/j.ymthe.2024.06.028
Aging Cell. 2024 Jun 24. e14235

Metformin treatment results in distinctive skeletal muscle mitochondrial remodeling in rats with different intrinsic aerobic capacities.

Matthew P Bubak, Arik Davidyan, Colleen L O'Reilly, Samim A Mondal, Jordan Keast, Stephen M Doidge, Agnieszka K Borowik, Michael E Taylor, Evelina Volovičeva, Michael T Kinter, Steven L Britton, Lauren G Koch, Michael B Stout, Tommy L Lewis, Benjamin F Miller.

  The rationale for the use of metformin as a treatment to slow aging was largely based on data collected from metabolically unhealthy individuals. For healthspan extension metformin will also be used in periods of good health. To understand the potential context specificity of metformin treatment on skeletal muscle, we used a rat model (high-capacity runner/low-capacity runner [HCR/LCR]) with a divide in intrinsic aerobic capacity. Outcomes of metformin treatment differed based on baseline intrinsic mitochondrial function, oxidative capacity of the muscle (gastroc vs soleus), and the mitochondrial population (intermyofibrillar vs. subsarcolemmal). Metformin caused lower ADP-stimulated respiration in LCRs, with less of a change in HCRs. However, a washout of metformin resulted in an unexpected doubling of respiratory capacity in HCRs. These improvements in respiratory capacity were accompanied by mitochondrial remodeling that included increases in protein synthesis and changes in morphology. Our findings raise questions about whether the positive findings of metformin treatment are broadly applicable.

Keywords:  deuterium oxide; geroscience; healthspan; protein synthesis; proteomics

DOI:  https://doi.org/10.1111/acel.14235
J Cell Biochem. 2024 Jun 25. e30617

Investigating the Involvement of C-X-C Motif Chemokine 5 and P2X7 Purinoceptor in Ectopic Calcification in Mouse Models of Duchenne Muscular Dystrophy.

Robin M H Rumney, Joanna Pomeroy, Dariusz C Górecki.

  Ectopic calcification of myofibers is an early pathogenic feature in patients and animal models of Duchenne muscular dystrophy (DMD). In previous studies using the Dmdmdx-βgeo mouse model, we found that the dystrophin-null phenotype exacerbates this abnormality and that mineralised myofibers are surrounded by macrophages. Furthermore, the P2X7 purinoceptor, functioning in immune cells offers protection against dystrophic calcification. In the present study, by exploring transcriptomic data from Dmdmdx mice, we hypothesised these effects to be mediated by C-X-C motif chemokine 5 (CXCL5) downstream of P2X7 activation. We found that CXCL5 is upregulated in the quadriceps muscles of Dmdmdx-βgeo mice compared to wild-type controls. In contrast, at the cell level, dystrophic (SC5) skeletal muscle cells secreted less CXCL5 chemokine than wild-type (IMO) controls. Although release from IMO cells was increased by P2X7 activation, this could not explain the elevated CXCL5 levels observed in dystrophic muscle tissue. Instead, we found that CXCL5 is released by dystrophin-null macrophages in response to P2X7 activation, suggesting that macrophages are the source of CXCL5 in dystrophic muscles. The effects of CXCL5 upon mineralisation were investigated using the Alizarin Red assay to quantify calcium deposition in vitro. In basal (low phosphate) media, CXCL5 increased calcification in IMO but not SC5 myoblasts. However, in cultures treated in high phosphate media, to mimic dysregulated phosphate metabolism occurring in DMD, CXCL5 decreased calcification in both IMO and SC5 cells. These data indicate that CXCL5 is part of a homoeostatic mechanism regulating intracellular calcium, that CXCL5 can be released by macrophages in response to the extracellular ATP damage-associated signal, and that CXCL5 can be part of a damage response to protect against ectopic calcification. This mechanism is affected by DMD gene mutations.

Keywords:  CXCL5; Duchenne muscular dystrophy; P2X7; ectopic calcification; macrophage

DOI:  https://doi.org/10.1002/jcb.30617
Int J Mol Sci. 2024 Jun 20. pii: 6806. [Epub ahead of print]25(12):

The Extract of Gloiopeltis tenax Enhances Myogenesis and Alleviates Dexamethasone-Induced Muscle Atrophy.

Si-Hyung Kim, Young-Eun Leem, Hye Eun Park, Hae-In Jeong, Jihye Lee, Jong-Sun Kang.

  The decline in the function and mass of skeletal muscle during aging or other pathological conditions increases the incidence of aging-related secondary diseases, ultimately contributing to a decreased lifespan and quality of life. Much effort has been made to surmise the molecular mechanisms underlying muscle atrophy and develop tools for improving muscle function. Enhancing mitochondrial function is considered critical for increasing muscle function and health. This study is aimed at evaluating the effect of an aqueous extract of Gloiopeltis tenax (GTAE) on myogenesis and muscle atrophy caused by dexamethasone (DEX). The GTAE promoted myogenic differentiation, accompanied by an increase in peroxisome proliferator-activated receptor γ coactivator α (PGC-1α) expression and mitochondrial content in myoblast cell culture. In addition, the GTAE alleviated the DEX-mediated myotube atrophy that is attributable to the Akt-mediated inhibition of the Atrogin/MuRF1 pathway. Furthermore, an in vivo study using a DEX-induced muscle atrophy mouse model demonstrated the efficacy of GTAE in protecting muscles from atrophy and enhancing mitochondrial biogenesis and function, even under conditions of atrophy. Taken together, this study suggests that the GTAE shows propitious potential as a nutraceutical for enhancing muscle function and preventing muscle wasting.

Keywords:  Gloiopeltis tenax; PGC-1α; mitochondria; muscle atrophy; red algae

DOI:  https://doi.org/10.3390/ijms25126806
Antioxidants (Basel). 2024 Jun 13. pii: 720. [Epub ahead of print]13(6):

Oxidised Albumin Levels in Plasma and Skeletal Muscle as Biomarkers of Disease Progression and Treatment Efficacy in Dystrophic mdx Mice.

Jessica R Terrill, Angelo Patrick R Bautista, Irene Tsioutsias, Miranda D Grounds, Peter G Arthur.

  Redox modifications to the plasma protein albumin have the potential to be used as biomarkers of disease progression and treatment efficacy in pathologies associated with inflammation and oxidative stress. One such pathology is Duchenne muscular dystrophy (DMD), a fatal childhood disease characterised by severe muscle wasting. We have previously shown in the mdx mouse model of DMD that plasma albumin thiol oxidation is increased; therefore, the first aim of this paper was to establish that albumin thiol oxidation in plasma reflects levels within mdx muscle tissue. We therefore developed a method to measure tissue albumin thiol oxidation. We show that albumin thiol oxidation was increased in both mdx muscle and plasma, with levels correlated with measures of dystropathology. In dystrophic muscle, albumin content was associated with areas of myonecrosis. The second aim was to test the ability of plasma thiol oxidation to track acute changes in dystropathology: we therefore subjected mdx mice to a single treadmill exercise session (known to increase myonecrosis) and took serial blood samples. This acute exercise caused a transient increase in total plasma albumin oxidation and measures of dystropathology. Together, these data support the use of plasma albumin thiol oxidation as a biomarker to track active myonecrosis in DMD.

Keywords:  Duchenne muscular dystrophy; albumin; albumin oxidation; biomarkers; mdx mice; redox modifications; taurine

DOI:  https://doi.org/10.3390/antiox13060720
Med Sci Sports Exerc. 2024 Jun 27.

Acute and Chronic Changes in Muscle Androgen Receptor Markers Are Not Associated with Muscle Hypertrophy in Women and Men.

João G A Bergamasco, Maíra C Scarpelli, Joshua S Godwin, Paulo H C Mesquita, Talisson S Chaves, Deivid G Silva, Diego Bittencourt, Nathalia F Dias, Ricardo A Medalha Junior, Paulo C Carello Filho, Vitor Angleri, Luiz A R Costa, J Max Michel, Felipe C Vechin, Andreas N Kavazis, Carlos Ugrinowitsch, Michael D Roberts, Cleiton A Libardi.

PURPOSE: Androgen receptor (AR) expression and signaling has been regarded as a mechanism for regulating muscle hypertrophy. However, little is known about the associations between acute and chronic changes in skeletal muscle total AR, cytoplasmic AR (cAR), nuclear AR (nAR) and AR DNA-binding (AR-DNA) induced by resistance training (RT) and hypertrophy outcomes in women and men. This study aimed to investigate the acute and chronic effects of RT on skeletal muscle total AR, cAR, nAR contents and AR-DNA in women and men. Additionally, we investigated whether these acute and chronic changes in these markers were associated with muscle hypertrophy in both sexes.
METHODS: Nineteen women and 19 men underwent 10 weeks of RT. Muscle biopsies were performed at baseline, 24 h after the first RT session and 96-120 h after the last session. AR, cAR and nAR were analyzed using Western blotting, and AR-DNA using an ELISA-oligonucleotide assay. Fiber cross-sectional area (fCSA) was analyzed through immunohistochemistry and muscle cross-sectional area (mCSA) by ultrasound.
RESULTS: At baseline, men demonstrated greater nAR than women. Baseline cAR was significantly associated with type II fCSA hypertrophy in men. Acutely, both sexes decreased AR and cAR, whereas men demonstrated greater decreases in nAR. After 10 weeks of RT, AR and nAR remained unchanged, men demonstrated greater cAR compared to women, and both sexes decreased AR-DNA activity. Acute and chronic changes in AR markers did not correlate with muscle hypertrophy (type I/II fCSA and mCSA) in women or men.
CONCLUSIONS: Baseline cAR content may influence hypertrophy in men, while neither RT-induced acute nor chronic changes in AR, cAR, nAR, and AR-DNA are associated with muscle hypertrophy in women or men.

DOI: https://doi.org/10.1249/MSS.0000000000003509
Int J Mol Sci. 2024 Jun 12. pii: 6480. [Epub ahead of print]25(12):

Mechanisms Underlying the Rarity of Skeletal Muscle Cancers.

David S Kump.

  Skeletal muscle (SKM), despite comprising ~40% of body mass, rarely manifests cancer. This review explores the mechanisms that help to explain this rarity, including unique SKM architecture and function, which prohibits the development of new cancer as well as negates potential metastasis to SKM. SKM also presents a unique immune environment that may magnify the anti-tumorigenic effect. Moreover, the SKM microenvironment manifests characteristics such as decreased extracellular matrix stiffness and altered lactic acid, pH, and oxygen levels that may interfere with tumor development. SKM also secretes anti-tumorigenic myokines and other molecules. Collectively, these mechanisms help account for the rarity of SKM cancer.

Keywords:  cancer; epidemiology; immune; incidence; metastasis; microenvironment; myokine; prevention; skeletal muscle

DOI:  https://doi.org/10.3390/ijms25126480
Autophagy. 2024 Jun 26. 1-16

PGAM5 interacts with and maintains BNIP3 to license cancer-associated muscle wasting.

Qingyuan Zhang, Chunhui Chen, Ye Ma, Xinyi Yan, Nianhong Lai, Hao Wang, Baogui Gao, Anna Meilin Gu, Qinrui Han, Qingling Zhang, Lei La, Xuegang Sun.

  Regressing the accelerated degradation of skeletal muscle protein is a significant goal for cancer cachexia management. Here, we show that genetic deletion of Pgam5 ameliorates skeletal muscle atrophy in various tumor-bearing mice. pgam5 ablation represses excessive myoblast mitophagy and effectively suppresses mitochondria meltdown and muscle wastage. Next, we define BNIP3 as a mitophagy receptor constitutively associating with PGAM5. bnip3 deletion restricts body weight loss and enhances the gastrocnemius mass index in the age- and tumor size-matched experiments. The NH2-terminal region of PGAM5 binds to the PEST motif-containing region of BNIP3 to dampen the ubiquitination and degradation of BNIP3 to maintain continuous mitophagy. Finally, we identify S100A9 as a pro-cachectic chemokine via activating AGER/RAGE. AGER deficiency or S100A9 inhibition restrains skeletal muscle loss by weakening the interaction between PGAM5 and BNIP3. In conclusion, the AGER-PGAM5-BNIP3 axis is a novel but common pathway in cancer-associated muscle wasting that can be targetable. Abbreviation: AGER/RAGE: advanced glycation end-product specific receptor; BA1: bafilomycin A1; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; Ckm-Cre: creatinine kinase, muscle-specific Cre; CM: conditioned medium; CON/CTRL: control; CRC: colorectal cancer; FUNDC1: FUN14 domain containing 1; MAP1LC3A/LC3A: microtubule associated protein 1 light chain 3 alpha; PGAM5: PGAM family member 5, mitochondrial serine/threonine protein phosphatase; S100A9: S100 calcium binding protein A9; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TIMM23: translocase of inner mitochondrial membrane 23; TSKO: tissue-specific knockout; VDAC1: voltage dependent anion channel 1.

Keywords:  AGER; S100A9; cachexia; cancer; mitophagy; muscle atrophy

DOI:  https://doi.org/10.1080/15548627.2024.2360340
Curr Issues Mol Biol. 2024 Jun 14. 46(6): 5999-6017

The Neuromuscular Disorder Mediated by Extracellular Vesicles in Amyotrophic Lateral Sclerosis.

Elisabetta Carata, Marco Muci, Simona Di Giulio, Tiziano Di Giulio, Stefania Mariano, Elisa Panzarini.

  Amyotrophic lateral sclerosis (ALS) represents a neurodegenerative disorder characterized by the progressive loss of both upper and lower motor neurons, resulting in muscular atrophy and eventual paralysis. While much research has concentrated on investigating the impact of major mutations associated with ALS on motor neurons and central nervous system (CNS) cells, recent studies have unveiled that ALS pathogenesis extends beyond CNS imbalances, encompassing dysregulation in other tissues such as skeletal muscle. Evidence from animal models and patients supports this broader perspective. Skeletal muscle, once considered solely as an effector organ, is now recognized as possessing significant secretory activity capable of influencing motor neuron survival. However, the precise cellular and molecular mechanisms underlying the detrimental effects observed in muscle and its associated structures in ALS remain poorly understood. Additionally, emerging data suggest that extracellular vesicles (EVs) may play a role in the establishment and function of the neuromuscular junction (NMJ) under both physiological and pathological conditions and in wasting and regeneration of skeletal muscles, particularly in neurodegenerative diseases like ALS. This review aims to explore the key findings about skeletal muscle involvement in ALS, shedding light on the potential underlying mechanisms and contributions of EVs and their possible application for the design of biosensors.

Keywords:  amyotrophic lateral sclerosis; biosensors; extracellular vesicles; miRNA; skeletal muscle

DOI:  https://doi.org/10.3390/cimb46060358
Sci Rep. 2024 06 26. 14(1): 14757

Thrombospondin-4 deletion does not exacerbate muscular dystrophy in β-sarcoglycan-deficient and laminin α2 chain-deficient mice.

Paula Zarén, Kinga I Gawlik.

Muscular dystrophy is a group of genetic disorders that lead to muscle wasting and loss of muscle function. Identifying genetic modifiers that alleviate symptoms or enhance the severity of a primary disease helps to understand mechanisms behind disease pathology and facilitates discovery of molecular targets for therapy. Several muscular dystrophies are caused by genetic defects in the components of the dystrophin-glycoprotein adhesion complex (DGC). Thrombospondin-4 overexpression has been shown to mitigate dystrophic disease in mouse models for Duchenne muscular dystrophy (dystrophin deficiency) and limb-girdle muscular dystrophy type 2F (LGMD2F, δ-sarcoglycan deficiency), while deletion of the thrombospondin-4 gene exacerbated the diseases. Hence, thrombospondin-4 has been considered a candidate molecule for therapy of muscular dystrophies involving the DGC. We have investigated whether thrombospondin-4 could act as a genetic modifier for other DGC-associated diseases: limb-girdle muscular dystrophy type 2E (LGMD2E, β-sarcoglycan deficiency) and laminin α2 chain-deficient muscular dystrophy (LAMA2-RD). Deletion of the thrombospondin-4 gene in mouse models for LGMD2E and LAMA2-RD, respectively, did not result in worsening of the dystrophic phenotype. Loss of thrombospondin-4 did not enhance sarcolemma damage and did not impair trafficking of transmembrane receptors integrin α7β1 and dystroglycan in double knockout muscles. Our results suggest that thrombospondin-4 might not be a relevant therapeutic target for all muscular dystrophies involving the DGC. This data also demonstrates that molecular pathology between very similar diseases like LGMD2E and 2F can differ significantly.

DOI: https://doi.org/10.1038/s41598-024-65473-8
Trends Mol Med. 2024 Jun 24. pii: S1471-4914(24)00164-3. [Epub ahead of print]

The aging lipidome: exercise is medicine.

Abel Plaza-Florido, Inmaculada Pérez-Prieto, Alejandro Lucia.

  The molecular mechanisms behind the potential 'anti-aging' effects of exercise remain to be elucidated. Janssens et al. studied the lipidome of different mouse tissues and human skeletal muscle. They identified an evolutionary conserved 'lipid aging' signature, characterized by bis(monoacylglycero)phosphate accumulation, which, at the muscle level, can be attenuated by exercise.

Keywords:  lipidomics; older adults; omics; physical activity

DOI:  https://doi.org/10.1016/j.molmed.2024.06.006
J Physiol. 2024 Jun 25.

Whole-body metabolic rate is influenced by muscle fibre typology.

Sydney L Poulsen, Ashley R Lovell, Lindsey P Stallworth, Samuel F Packer.



Keywords:  carnosine; endurance; exercise physiology; locomotion; metabolic rate; skeletal fibre type; triceps surare; typology

DOI:  https://doi.org/10.1113/JP286853
Biomed Pharmacother. 2024 Jun 21. pii: S0753-3322(24)00801-1. [Epub ahead of print]177 116917

SIRT1 signaling pathways in sarcopenia: Novel mechanisms and potential therapeutic targets.

Luning Yang, Di Liu, Shide Jiang, Hengzhen Li, Lin Chen, Yuxiang Wu, Anko Elijah Essien, Michael Opoku, Shinen Naranmandakh, ShuGuang Liu, Qin Ru, Yusheng Li.

  Sarcopenia is an aging-related skeletal disease characterized by decreased muscle mass, strength, and physical function, severely affecting the quality of life (QoL) of the elderly population. Sirtuin 1 (SIRT1), as a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases, has been reported to participate in various aging-related signaling pathways and exert protective effect on many human diseases. SIRT1 functioned as an important role in the occurrence and progression of sarcopenia through regulating key pathways related to protein homeostasis, apoptosis, mitochondrial dysfunction, insulin resistance and autophagy in skeletal muscle, including SIRT1/Forkhead Box O (FoxO), AMP-activated protein kinase (AMPK)/SIRT1/nuclear factor κB (NF-κB), SIRT1/p53, AMPK/SIRT1/peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), and SIRT1/live kinase B1 (LKB1)/AMPK pathways. However, the specific mechanisms of these processes have not been fully illuminated. Currently, several SIRT1-mediated interventions on sarcopenia have been preliminarily developed, such as SIRT1 activator polyphenolic compounds, exercising and calorie restriction. In this review, we summarized the predominant mechanisms of SIRT1 involved in sarcopenia and therapeutic modalities targeting the SIRT1 signaling pathways for the prevention and prognosis of sarcopenia.

Keywords:  Aging; Prevention; Sarcopenia; Sirtuin 1

DOI:  https://doi.org/10.1016/j.biopha.2024.116917
Obes Rev. 2024 Jun 24. e13794

Mitochondrial puzzle in muscle: Linking the electron transport system to overweight.

Rafael A Casuso.

  Human skeletal muscle mitochondria regulate energy expenditure. Research has shown that the functionality of muscle mitochondria is altered in subjects with overweight, as well as in response to nutrient excess and calorie restriction. Two metabolic features of obesity and overweight are (1) incomplete muscular fatty acid oxidation and (2) increased circulating lactate levels. In this study, I propose that these metabolic disturbances may originate from a common source within the muscle mitochondrial electron transport system. Specifically, a reorganization of the supramolecular structure of the electron transport chain could facilitate the maintenance of readily accessible coenzyme Q pools, which are essential for metabolizing lipid substrates. This approach is expected to maintain effective electron transfer, provided that there is sufficient complex III to support the Q-cycle. Such an adaptation could enhance fatty acid oxidation and prevent mitochondrial overload, thereby reducing lactate production. These insights advance our understanding of the molecular mechanisms underpinning metabolic dysregulation in overweight states. This provides a basis for targeted interventions in the quest for metabolic health.

Keywords:  coenzyme Q; electron transport chain; metabolism; obesity; respiratory supercomplexes; skeletal muscle

DOI:  https://doi.org/10.1111/obr.13794
Neurobiol Dis. 2024 Jun 22. pii: S0969-9961(24)00176-1. [Epub ahead of print]199 106576

Sunitinib-mediated inhibition of STAT3 in skeletal muscle and spinal cord does not affect the disease in a mouse model of ALS.

Massimo Tortarolo, Andrea David Re Cecconi, Laura Camporeale, Cassandra Margotta, Giovanni Nardo, Laura Pasetto, Valentina Bonetto, Mariarita Galbiati, Valeria Crippa, Angelo Poletti, Rosanna Piccirillo, Caterina Bendotti.

  Variability in disease onset and progression is a hallmark of amyotrophic lateral sclerosis (ALS), both in sporadic and genetic forms. Recently, we found that SOD1-G93A transgenic mice expressing the same amount of mutant SOD1 but with different genetic backgrounds, C57BL/6JOlaHsd and 129S2/SvHsd, show slow and rapid muscle wasting and disease progression, respectively. Here, we investigated the different molecular mechanisms underlying muscle atrophy. Although both strains showed similar denervation-induced degradation of muscle proteins, only the rapidly progressing mice exhibited early and sustained STAT3 activation that preceded atrophy in gastrocnemius muscle. We therefore investigated the therapeutic potential of sunitinib, a tyrosine kinase inhibitor known to inhibit STAT3 and prevent cancer-induced muscle wasting. Although sunitinib treatment reduced STAT3 activation in the gastrocnemius muscle and lumbar spinal cord, it did not preserve spinal motor neurons, improve neuromuscular impairment, muscle atrophy and disease progression in the rapidly progressing SOD1-G93A mice. Thus, the effect of sunitinib is not equally positive in different diseases associated with muscle wasting. Moreover, given the complex role of STAT3 in the peripheral and central compartments of the neuromuscular system, the present study suggests that its broad inhibition may lead to opposing effects, ultimately preventing a potential positive therapeutic action in ALS.

Keywords:  Amyotrophic lateral sclerosis; Atrogenes; Disease progression; Genetic background; SOD1; STAT3, muscle atrophy; Spinal cord; Sunitinib

DOI:  https://doi.org/10.1016/j.nbd.2024.106576
Antioxidants (Basel). 2024 May 21. pii: 622. [Epub ahead of print]13(6):

A Novel MAO-B/SSAO Inhibitor Improves Multiple Aspects of Dystrophic Phenotype in mdx Mice.

Francesca Gasparella, Leonardo Nogara, Elena Germinario, Lucia Tibaudo, Stefano Ciciliot, Giorgia Piccoli, Francisca Carolina Venegas, Francesca Fontana, Gabriele Sales, Daniele Sabbatini, Jonathan Foot, Wolfgang Jarolimek, Bert Blaauw, Marcella Canton, Libero Vitiello.

  Duchenne muscular dystrophy (DMD) is one of the most frequent and severe childhood muscle diseases. Its pathophysiology is multifaceted and still incompletely understood, but we and others have previously shown that oxidative stress plays an important role. In particular, we have demonstrated that inhibition of mitochondrial monoamine oxidases could improve some functional and biohumoral markers of the pathology. In the present study we report the use of dystrophic mdx mice to evaluate the efficacy of a dual monoamine oxidase B (MAO-B)/semicarbazide-sensitive amine oxidase (SSAO) inhibitor, PXS-5131, in reducing inflammation and fibrosis and improving muscle function. We found that a one-month treatment starting at three months of age was able to decrease reactive oxygen species (ROS) production, fibrosis, and inflammatory infiltrate in the tibialis anterior (TA) and diaphragm muscles. Importantly, we also observed a marked improvement in the capacity of the gastrocnemius muscle to maintain its force when challenged with eccentric contractions. Upon performing a bulk RNA-seq analysis, PXS-5131 treatment affected the expression of genes involved in inflammatory processes and tissue remodeling. We also studied the effect of prolonged treatment in older dystrophic mice, and found that a three-month administration of PXS-5131 was able to greatly reduce the progression of fibrosis not only in the diaphragm but also in the heart. Taken together, these results suggest that PXS-5131 is an effective inhibitor of fibrosis and inflammation in dystrophic muscles, a finding that could open a new therapeutic avenue for DMD patients.

Keywords:  Duchenne muscular dystrophy; MAO-B; SSAO; fibrosis; heart; inflammation; mdx mice; osteopontin; oxidative stress; skeletal muscle

DOI:  https://doi.org/10.3390/antiox13060622
Neuropathol Appl Neurobiol. 2024 Jun;50(3): e12995

Proteomic profiling of polyglucosan bodies associated with glycogenin-1 deficiency in skeletal muscle.

Kittichate Visuttijai, Carola Hedberg-Oldfors, Daniel J Costello, Niamh Bermingham, Anders Oldfors.

   AIMS: Polyglucosan storage disorders represent an emerging field within neurodegenerative and neuromuscular conditions, including Lafora disease (EPM2A, EPM2B), adult polyglucosan body disease (APBD, GBE1), polyglucosan body myopathies associated with RBCK1 deficiency (PGBM1, RBCK1) or glycogenin-1 deficiency (PGBM2, GYG1). While the storage material primarily comprises glycans, this study aimed to gain deeper insights into the protein components by proteomic profiling of the storage material in glycogenin-1 deficiency.
METHODS: We employed molecular genetic analyses, quantitative mass spectrometry of laser micro-dissected polyglucosan bodies and muscle homogenate, immunohistochemistry and western blot analyses in muscle tissue from a 45-year-old patient with proximal muscle weakness from late teenage years due to polyglucosan storage myopathy.
RESULTS: The muscle tissue exhibited a complete absence of glycogenin-1 due to a novel homozygous deep intronic variant in GYG1 (c.7+992T>G), introducing a pseudo-exon causing frameshift and a premature stop codon. Accumulated proteins in the polyglucosan bodies constituted components of glycogen metabolism, protein quality control pathways and desmin. Muscle fibres containing polyglucosan bodies frequently exhibited depletion of normal glycogen.
CONCLUSIONS: The absence of glycogenin-1, a protein important for glycogen synthesis initiation, causes storage of polyglucosan that displays accumulation of several proteins, including those essential for glycogen synthesis, sequestosome 1/p62 and desmin, mirroring findings in RBCK1 deficiency. These results suggest shared pathogenic pathways across different diseases exhibiting polyglucosan storage. Such insights have implications for therapy in these rare yet devastating and presently untreatable disorders.

Keywords:  GYG1; PGBM2; glycogen storage disease XV; glycogenin‐1 deficiency; myopathy; polyglucosan body myopathy 2; proteomic profiling

DOI:  https://doi.org/10.1111/nan.12995
Elife. 2024 Jun 24. pii: RP90724. [Epub ahead of print]12

Eugenol mimics exercise to promote skeletal muscle fiber remodeling and myokine IL-15 expression by activating TRPV1 channel.

Tengteng Huang, Xiaoling Chen, Jun He, Ping Zheng, Yuheng Luo, Aimin Wu, Hui Yan, Bing Yu, Daiwen Chen, Zhiqing Huang.

  Metabolic disorders are highly prevalent in modern society. Exercise mimetics are defined as pharmacological compounds that can produce the beneficial effects of fitness. Recently, there has been increased interest in the role of eugenol and transient receptor potential vanilloid 1 (TRPV1) in improving metabolic health. The aim of this study was to investigate whether eugenol acts as an exercise mimetic by activating TRPV1. Here, we showed that eugenol improved endurance capacity, caused the conversion of fast-to-slow muscle fibers, and promoted white fat browning and lipolysis in mice. Mechanistically, eugenol promoted muscle fiber-type transformation by activating TRPV1-mediated CaN signaling pathway. Subsequently, we identified IL-15 as a myokine that is regulated by the CaN/nuclear factor of activated T cells cytoplasmic 1 (NFATc1) signaling pathway. Moreover, we found that TRPV1-mediated CaN/NFATc1 signaling, activated by eugenol, controlled IL-15 levels in C2C12 myotubes. Our results suggest that eugenol may act as an exercise mimetic to improve metabolic health via activating the TRPV1-mediated CaN signaling pathway.

Keywords:  C2C12 cell; cell biology; exercise; mouse; skeletal muscle

DOI:  https://doi.org/10.7554/eLife.90724
Am J Physiol Cell Physiol. 2024 Jun 24.

ISOLATION OF A PERSISTENTLY QUIESCENT MUSCLE SATELLITE CELL POPULATION.

Alexandra P Steele, Anika L Syroid, Cassandra Mombo, Shathana Raveetharan, Irena A Rebalka, Thomas J Hawke.

  While studies have identified characteristics of quiescent satellite cells, their isolation has been hampered by the fact that the isolation procedures result in the activation of these cells into their rapidly proliferating progeny (myoblasts). Thus, the use of myoblasts for therapeutic (regenerative medicine) or industrial applications (cellular agriculture) has been impeded by the limited proliferative and differentiative capacity of these myogenic progenitors. Here we identify a subpopulation of satellite cells isolated from mouse skeletal muscle using flow cytometry that are highly Pax7-positive, exhibit a very slow proliferation rate (7.7 ± 1.2 days/doubling), and are capable of being maintained in culture for at least three months without a change in phenotype. These cells can be activated from quiescence using a p38 inhibitor or by exposure to freeze-thaw cycles. Once activated, these cells proliferate rapidly (22.7 ± 0.2 hours/doubling), have reduced Pax7 expression (3-fold decrease in Pax7 fluorescence vs. quiescence) and differentiate into myotubes with a high efficiency. Furthermore, these cells withstand freeze-thawing readily without a significant loss of viability (83.1 ± 2.1% live). The results presented here provide researchers with a method to isolate quiescent satellite cells, allowing for more detailed examinations of the factors affecting satellite cell quiescence/activation and providing a cell source that has a unique potential in the regenerative medicine and cellular agriculture fields.

Keywords:  CD34; NCAM; Pax7; methodology; quiescent satellite cell

DOI:  https://doi.org/10.1152/ajpcell.00231.2024
J Appl Physiol (1985). 2024 Jun 27.

Muscle-Derived microRNAs Correlated with Thigh Lean Mass Gains during Progressive Resistance Training in Older Adults.

Samia M O'Bryan, Kaleen M Lavin, Zachary A Graham, Devin J Drummer, S Craig Tuggle, Kendall Van Keuren-Jensen, Rebecca Reiman, Eric Alsop, Madhavi P Kadakia, Michael P Craig, Jin Zhang, Marcas M Bamman.

  Resistance training (RT) remains the most effective treatment for age-related declines in muscle mass. However, many older adults experience attenuated muscle hypertrophy in response to RT when compared to younger adults. This may be attributed to underlying molecular processes that are dysregulated by aging and exacerbated by improperly prescribed RT weekly volume, intensity, and/or frequency doses. MicroRNA (miRNA) are key epigenetic regulators that impact signaling pathways and protein expression within cells, are dynamic and responsive to exercise stimuli, and are often dysregulated in diseases. In this study, we used untargeted miRNA-seq to examine miRNA in skeletal muscle and serum-derived exosomes of older adults (n = 18, 11M/7F, 66±1y) who underwent 3x/wk RT for 30 weeks [e.g., high intensity 3x/wk (HHH, n = 9) or alternating high-low-high intensity (HLH, n = 9)], after a standardized four-week wash-in. Within each tissue, miRNAs were clustered into modules based on pairwise correlation using Weighted Gene Correlation Network Analysis (WGCNA). Modules were tested for association with the magnitude of RT-induced thigh lean mass (TLM) change (as measured by DXA). While no modules were unique to training dose, we identified miRNA modules in skeletal muscle associated with TLM gains irrespective of exercise dose. Using miRNA-target interactions, we analyzed key miRNAs in significant modules for their potential regulatory involvement in biological pathways. Findings point toward potential miRNAs that may be informative biomarkers and could also be evaluated as potential therapeutic targets as an adjuvant to RT in order to maximize skeletal muscle mass accrual in older adults.

Keywords:  Aging; Exercise Physiology; Muscle Mass; Resistance Training

DOI:  https://doi.org/10.1152/japplphysiol.00680.2023
Aging Dis. 2024 Jun 07.

Aging and Autophagy: Roles in Musculoskeletal System Injury.

Haifeng Zhang, Wenhui Gu, Genbin Wu, Yinxian Yu.

Aging is a multifactorial process that ultimately leads to a decline in physiological function and a consequent reduction in the health span, and quality of life in elderly population. In musculoskeletal diseases, aging is often associated with a gradual loss of skeletal muscle mass and strength, resulting in reduced functional capacity and an increased risk of chronic metabolic diseases, leading to impaired function and increased mortality. Autophagy is a highly conserved physiological process by which cells, under the regulation of autophagy-related genes, degrade their own organelles and large molecules by lysosomal degradation. This process is unique to eukaryotic cells and is a strict regulator of homeostasis, the maintenance of energy and substance balance. Autophagy plays an important role in a wide range of physiological and pathological processes such as cell homeostasis, aging, immunity, tumorigenesis and neurodegenerative diseases. On the one hand, under mild stress conditions, autophagy mediates the restoration of homeostasis and proliferation, reduction of the rate of aging and delay of the aging process. On the other hand, under more intense stress conditions, an inadequate suppression of autophagy can lead to cellular aging. Conversely, autophagy activity decreases during aging. Due to the interrelationship between aging and autophagy, limited literature exists on this topic. Therefore, the objective of this review is to summarize the current concepts on aging and autophagy in the musculoskeletal system. The aim is to better understand the mechanisms of age-related changes in bone, joint and muscle, as well as the interaction relationship between autophagy and aging. Its goal is to provide a comprehensive perspective for the improvement of diseases of the musculoskeletal system.

DOI: https://doi.org/10.14336/AD.2024.0362
J Cachexia Sarcopenia Muscle. 2024 Jun 26.

Sarcopenia-related changes in serum GLP-1 level affect myogenic differentiation.

Hsien-Hao Huang, Yun-Jie Wang, Hui-Yu Jiang, Helen Wenshin Yu, Yin-Quan Chen, Arthur Chiou, Jean-Cheng Kuo.

   BACKGROUND: Sarcopenia, a group of muscle-related disorders, leads to the gradual decline and weakening of skeletal muscle over time. Recognizing the pivotal role of gastrointestinal conditions in maintaining metabolic homeostasis within skeletal muscle, we hypothesize that the effectiveness of the myogenic programme is influenced by the levels of gastrointestinal hormones in the bloodstream, and this connection is associated with the onset of sarcopenia.
METHODS: We first categorized 145 individuals from the Emergency Room of Taipei Veterans General Hospital into sarcopenia and non-sarcopenia groups, following the criteria established by the Asian Working Group for Sarcopenia. A thorough examination of specific gastrointestinal hormone levels in plasma was conducted to identify the one most closely associated with sarcopenia. Techniques, including immunofluorescence, western blotting, glucose uptake assays, seahorse real-time cell metabolic analysis, flow cytometry analysis, kinesin-1 activity assays and qPCR analysis, were applied to investigate its impacts and mechanisms on myogenic differentiation.
RESULTS: Individuals in the sarcopenia group exhibited elevated plasma levels of glucagon-like peptide 1 (GLP-1) at 1021.5 ± 313.5 pg/mL, in contrast to non-sarcopenic individuals with levels at 351.1 ± 39.0 pg/mL (P < 0.05). Although it is typical for GLP-1 levels to rise post-meal and subsequently drop naturally, detecting higher GLP-1 levels in starving individuals with sarcopenia raised the possibility of GLP-1 influencing myogenic differentiation in skeletal muscle. Further investigation using a cell model revealed that GLP-1 (1, 10 and 100 ng/mL) dose-dependently suppressed the expression of the myogenic marker, impeding myocyte fusion and the formation of polarized myotubes during differentiation. GLP-1 significantly inhibited the activity of the microtubule motor kinesin-1, interfering with the translocation of glucose transporter 4 (GLUT4) to the cell membrane and the dispersion of mitochondria. These impairments subsequently led to a reduction in glucose uptake to 0.81 ± 0.04 fold (P < 0.01) and mitochondrial adenosine triphosphate (ATP) production from 25.24 ± 1.57 pmol/min to 18.83 ± 1.11 pmol/min (P < 0.05). Continuous exposure to GLP-1, even under insulin induction, attenuated the elevated glucose uptake.
CONCLUSIONS: The elevated GLP-1 levels observed in individuals with sarcopenia are associated with a reduction in myogenic differentiation. The impact of GLP-1 on both the membrane translocation of GLUT4 and the dispersion of mitochondria significantly hinders glucose uptake and the production of mitochondrial ATP necessary for the myogenic programme. These findings point us towards strategies to establish the muscle-gut axis, particularly in the context of sarcopenia. Additionally, these results present the potential of identifying relevant diagnostic biomarkers.

Keywords:  ATP production; GLP‐1; Glucose uptake; Microtubule motor kinesin‐1; Sarcopenia

DOI:  https://doi.org/10.1002/jcsm.13524
Nature. 2024 Jun 26.

Aged mice regain youthful muscles thanks to a compound that acts on the genes.



Keywords:  Ageing

DOI:  https://doi.org/10.1038/d41586-024-02100-6