bims-moremu 2024-06-02 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2024–06–02
twenty-one papers selected by
Anna Vainshtein, Craft Science Inc.

Cystine/glutamate antiporter xCT controls skeletal muscle glutathione redox, bioenergetics and differentiation.
Loss of HNRNPU in Skeletal Muscle Increases Intramuscular Infiltration of Ly6C Positive Cells, leading to Muscle Atrophy through Activation of NF-κB Signaling.
Muscle-specific PGC-1α modulates mitochondrial oxidative stress in aged sarcopenia through regulating Nrf2.
Intrinsic skeletal muscle function and contraction-stimulated glucose uptake do not vary by time-of-day in mice.
Endothelin-1 impairs skeletal muscle myogenesis and development via ETB receptors and p38 MAPK signaling pathway.
Fast myosin binding protein C knockout in skeletal muscle alters length-dependent activation and myofilament structure.
Custom-made 3D-printed boot as a model of disuse-induced atrophy in murine skeletal muscle.
Functional role of myosin-binding protein H in thick filaments of developing vertebrate fast-twitch skeletal muscle.
Aging-dependent mitochondrial bioenergetic impairment in the skeletal muscle of NNT-deficient mice.
Effects of physical exercise on neuromuscular junction degeneration during ageing: A systematic review.
Physiological role for S-nitrosylation of RyR1 in skeletal muscle function and development.
EDA2R-NIK signaling in cancer cachexia.
Unresolved questions in the regulation of skeletal muscle insulin action by reactive oxygen species.
Brassinin alleviates cancer cachexia by suppressing diverse inflammatory mechanisms in mice.
Different roles of circulating and intramuscular GDF15 as markers of skeletal muscle health.
Exposome on skeletal muscle system: a mini-review.
Dexamethasone and Insulin Modulate Alanine Aminotransferase (ALT) Activity and Alanine Oxidation in C2C12 Cells in a Dose-Dependent Manner.
NMR-based comparative metabolomics of quiescent muscle cells.
Molecular insights of exercise therapy in disease prevention and treatment.
Macrophage scavenger receptor-A1 promotes skeletal muscle regeneration after hindlimb ischemia.
Studying intramuscular fat deposition and muscle regeneration: insights from a comparative analysis of mouse strains, injury models, and sex differences.

Redox Biol. 2024 May 25. pii: S2213-2317(24)00191-5. [Epub ahead of print]73 103213

Cystine/glutamate antiporter xCT controls skeletal muscle glutathione redox, bioenergetics and differentiation.

Michel N Kanaan, Chantal A Pileggi, Charbel Y Karam, Luke S Kennedy, Claire Fong-McMaster, Miroslava Cuperlovic-Culf, Mary-Ellen Harper.

  Cysteine, the rate-controlling amino acid in cellular glutathione synthesis is imported as cystine, by the cystine/glutamate antiporter, xCT, and subsequently reduced to cysteine. As glutathione redox is important in muscle regeneration in aging, we hypothesized that xCT exerts upstream control over skeletal muscle glutathione redox, metabolism and regeneration. Bioinformatic analyses of publicly available datasets revealed that expression levels of xCT and GSH-related genes are inversely correlated with myogenic differentiation genes. Muscle satellite cells (MuSCs) isolated from Slc7a11sut/sut mice, which harbour a mutation in the Slc7a11 gene encoding xCT, required media supplementation with 2-mercaptoethanol to support cell proliferation but not myotube differentiation, despite persistently lower GSH. Slc7a11sut/sut primary myotubes were larger compared to WT myotubes, and also exhibited higher glucose uptake and cellular oxidative capacities. Immunostaining of myogenic markers (Pax7, MyoD, and myogenin) in cardiotoxin-damaged tibialis anterior muscle fibres revealed greater MuSC activation and commitment to differentiation in Slc7a11sut/sut muscle compared to WT mice, culminating in larger myofiber cross-sectional areas at 21 days post-injury. Slc7a11sut/sut mice subjected to a 5-week exercise training protocol demonstrated enhanced insulin tolerance compared to WT mice, but blunted muscle mitochondrial biogenesis and respiration in response to exercise training. Our results demonstrate that the absence of xCT inhibits cell proliferation but promotes myotube differentiation by regulating cellular metabolism and glutathione redox. Altogether, these results support the notion that myogenesis is a redox-regulated process and may help inform novel therapeutic approaches for muscle wasting and dysfunction in aging and disease.

Keywords:  Glutathione; Glycolysis; Mitochondria; Myogenesis; Oxidative phosphorylation; Redox

DOI:  https://doi.org/10.1016/j.redox.2024.103213
Adv Biol (Weinh). 2024 May 26. e2400152

Loss of HNRNPU in Skeletal Muscle Increases Intramuscular Infiltration of Ly6C Positive Cells, leading to Muscle Atrophy through Activation of NF-κB Signaling.

Eun-Joo Lee, Julia F Charles, Indranil Sinha, Ronald L Neppl.

  Heterogeneous nuclear ribonucleoprotein U (hnRNPU) is known to play multiple biological roles by regulating transcriptional expression, RNA splicing, RNA stability, and chromatin structure in a tissue-dependent manner. The role of hnRNPU in skeletal muscle development and maintenance has not been previously evaluated. In this study, skeletal muscle specific hnRNPU knock out mice is utilized and evaluated skeletal muscle mass and immune cell infiltration through development. By 4 weeks, muscle-specific hnRNPU knockout mice revealed Ly6C+ monocyte infiltration into skeletal muscle, which preceded muscle atrophy. Canonical NF-kB signaling is activated in a myofiber-autonomous manner with hnRNPU repression. Inducible hnRNPU skeletal muscle knockout mice further demonstrated that deletion of hnRNPU in adulthood is sufficient to cause muscle atrophy, suggesting that hnRNPU's role in muscle maintenance is not during development alone. Treatment with salirasib, to inhibit proliferation of immune cells, prevents muscle atrophy in muscle-specific hnRNPU knock out mice, indicating that immune cell infiltration plays causal role in muscle atrophy of hnRNPU knock out mice. Overall, the findings suggest that loss of hnRNPU triggers muscle inflammation and activates NF-κB signaling in a cell-autonomous manner, culminating in muscle atrophy.

Keywords:  HnRNPU; Ly6C positive monocyte; canonical NF‐κB signaling; intramuscular inflammation; muscle atrophy

DOI:  https://doi.org/10.1002/adbi.202400152
Exp Gerontol. 2024 May 28. pii: S0531-5565(24)00110-4. [Epub ahead of print]193 112468

Muscle-specific PGC-1α modulates mitochondrial oxidative stress in aged sarcopenia through regulating Nrf2.

Lei Song, Jianfeng Xue, Lingfen Xu, Lin Cheng, Yongxia Zhang, Xiaojun Wang.

   BACKGROUND: Aged sarcopenia is characterized by loss of skeletal muscle mass and strength, and mitochondrial dysregulation in skeletal myocyte is considered as a major factor. Here, we aimed to analyze the effects of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) on mitochondrial reactive oxygen species (ROS) and nuclear factor erythroid 2-related factor 2 (Nrf2) in aged skeletal muscles.
METHODS: C2C12 cells were stimulated by 50 μM 7β-hydroxycholesterol (7β-OHC) to observe the changes of cellular ROS, mitochondrial ROS, and expression of PGC-1α and Nrf2. Different PGC-1α expression in cells was established by transfection with small interfering RNA (siRNA) or plasmids overexpressing PGC-1α (pEX-3-PGC-1α). The effects of different PGC-1α expression on cellular ROS, mitochondrial ROS and Nrf2 expression were measured in cells. Wild type (WT) mice and PGC-1α conditional knockout (CKO) mice were used to analyze the effects of PGC-1α on aged sarcopenia and expression of Nrf2 and CD38 in gastrocnemius muscles. Diethylmaleate, a Nrf2 activator, was used to analyze the connection between PGC-1α and Nrf2 in cells and in mice.
RESULTS: In C2C12 cells, the expressions of PGC-1α and Nrf2 were declined by the 7β-OHC treatment or PGC-1α silence. Moreover, PGC-1α silence increased the harmful ROS and decreased the Nrf2 protein expression in the 7β-OHC-treated cells. PGC-1α overexpression decreased the harmful ROS and increased the Nrf2 protein expression in the 7β-OHC-treated cells. Diethylmaleate treatment decreased the harmful ROS in the 7β-OHC-treated or PGC-1α siRNA-transfected cells. At the same age, muscle-specific PGC-1α deficiency aggravated aged sarcopenia, decreased Nrf2 expression and increased CD38 expression in gastrocnemius muscles compared with the WT mice. Diethylmaleate treatment improved the muscle function and decreased the CD38 expression in the old two genotypes.
CONCLUSIONS: Our study demonstrated that PGC-1α modulated mitochondrial oxidative stress in aged sarcopenia through regulating Nrf2.

Keywords:  7β-hydroxycholesterol (7β-OHC); C2C12 cells; CD38; PGC-1α conditional knockout (CKO) mice; PGC-1α siRNA

DOI:  https://doi.org/10.1016/j.exger.2024.112468
bioRxiv. 2024 May 18. pii: 2024.05.15.594323. [Epub ahead of print]

Intrinsic skeletal muscle function and contraction-stimulated glucose uptake do not vary by time-of-day in mice.

Liam S Fitzgerald, Shannon N Bremner, Samuel R Ward, Yoshitake Cho, Simon Schenk.

A growing body of data suggests that skeletal muscle contractile function and glucose metabolism vary by time-of-day, with chronobiological effects on intrinsic skeletal muscle properties being proposed as the underlying mediator. However, no studies have directly investigated intrinsic contractile function or glucose metabolism in skeletal muscle over a 24 h circadian cycle. To address this, we assessed intrinsic contractile function and endurance, as well as contraction-stimulated glucose uptake, in isolated extensor digitorum longus and soleus from female mice at four times-of-day (Zeitgeber Times 1, 7, 13, 19). Significantly, while both muscles demonstrated circadian-related changes in gene expression, intrinsic contractile function, endurance, and contraction-stimulated glucose uptake were not different between the four time points. Overall, these results demonstrate that time-of-day variation in exercise performance and the glycemia-reducing benefits of exercise are not due to chronobiological effects on intrinsic muscle function or contraction-stimulated glucose uptake.
Impact statement: Ex vivo testing demonstrates that there is no time-of-day variation in the intrinsic contractile properties of skeletal muscle (including no effect on force production or endurance) or contraction-stimulated glucose uptake.

DOI: https://doi.org/10.1101/2024.05.15.594323
Clin Sci (Lond). 2024 May 28. pii: CS20240341. [Epub ahead of print]

Endothelin-1 impairs skeletal muscle myogenesis and development via ETB receptors and p38 MAPK signaling pathway.

Shui-Yu Liu, Luei-Kui Chen, Yi-Ting Jhong, Chien-Wei Chen, Li-En Hsiao, Huei-Chi Ku, Pin-Hsuan Lee, Guey-Shyang Hwang, Chi-Chang Juan.

  Myopenia is a condition marked by progressive decline of muscle mass and strength and is associated with aging or obesity. It poses the risk of falling, with potential bone fractures, thereby also increasing the burden on family and society. Skeletal muscle wasting is characterized by a reduced number of myoblasts, impaired muscle regeneration and increased muscle atrophy markers (Atrogin-1, MuRF-1). Endotheline-1 (ET-1) is a potent vasoconstrictor peptide. Increased circulating levels of ET-1 is noted with aging and is associated with muscular fibrosis and decline of strength. However, the regulatory mechanism controlling its effect on myogenesis and atrophy remains unknown. In the present study, the effects of ET-1 on myoblast proliferation, differentiation and development were investigated in C2C12 cells and in ET-1-infused mice. The results show that ET-1, acting via ETB receptors, reduced insulin-stimulated cell proliferation, and also reduced MyoD, MyoG and MyHC expression in the differentiation processes of C2C12 myoblasts. ET-1 inhibited myoblast differentiation through ETB receptors and the p38 mitogen-activated protein kinase (MAPK)-dependent pathway. Additionally, ET-1 decreased MyHC expression in differentiated myotubes. Inhibition of proteasome activity by MG132 ameliorated the ET-1-stimulated protein degradation in differentiated C2C12 myotubes. Furthermore, chronic ET-1 infusion caused skeletal muscle atrophy and impaired exercise performance in mice. In conclusion, ET-1 inhibits insulin-induced cell proliferation, impairs myogenesis and induces muscle atrophy via ETB receptors and the p38 MAPK-dependent pathway.

Keywords:  atrophy; endothelin; myogenesis; p38 MAPK; proliferation

DOI:  https://doi.org/10.1042/CS20240341
Commun Biol. 2024 May 27. 7(1): 648

Fast myosin binding protein C knockout in skeletal muscle alters length-dependent activation and myofilament structure.

Anthony L Hessel, Michel N Kuehn, Seong-Won Han, Weikang Ma, Thomas C Irving, Brent A Momb, Taejeong Song, Sakthivel Sadayappan, Wolfgang A Linke, Bradley M Palmer.

In striated muscle, the sarcomeric protein myosin-binding protein-C (MyBP-C) is bound to the myosin thick filament and is predicted to stabilize myosin heads in a docked position against the thick filament, which limits crossbridge formation. Here, we use the homozygous Mybpc2 knockout (C2-/-) mouse line to remove the fast-isoform MyBP-C from fast skeletal muscle and then conduct mechanical functional studies in parallel with small-angle X-ray diffraction to evaluate the myofilament structure. We report that C2-/- fibers present deficits in force production and calcium sensitivity. Structurally, passive C2-/- fibers present altered sarcomere length-independent and -dependent regulation of myosin head conformations, with a shift of myosin heads towards actin. At shorter sarcomere lengths, the thin filament is axially extended in C2-/-, which we hypothesize is due to increased numbers of low-level crossbridges. These findings provide testable mechanisms to explain the etiology of debilitating diseases associated with MyBP-C.

DOI: https://doi.org/10.1038/s42003-024-06265-8
PLoS One. 2024 ;19(5): e0304380

Custom-made 3D-printed boot as a model of disuse-induced atrophy in murine skeletal muscle.

Giulio Masiero, Giulia Ferrarese, Eleonora Perazzolo, Martina Baraldo, Leonardo Nogara, Caterina Tezze.

Skeletal muscle atrophy is characterized by a decrease in muscle mass and strength caused by an imbalance in protein synthesis and degradation. This process naturally occurs upon reduced or absent physical activity, often related to illness, forced bed rest, or unhealthy lifestyles. Currently, no treatment is available for atrophy, and it can only be prevented by overloading exercise, causing severe problems for patients who cannot exercise due to chronic diseases, disabilities, or being bedridden. The two murine models commonly used to induce muscle atrophy are hindlimb suspension and ankle joint immobilization, both of which come with criticalities. The lack of treatments and the relevance of this atrophic process require a unilateral, safe, and robust model to induce muscle atrophy. In this work, we designed and developed a 3D-printed cast to be used for the study of disuse skeletal muscle atrophy. Applying two halves of the cast is non-invasive, producing little to no swelling or skin damage. The application of the cast induces, in 2-weeks immobilized leg, the activation of atrophy-related genes, causing a muscle weight loss up to 25% in the gastrocnemius muscle, and 31% in the soleus muscle of the immobilized leg compared to the control leg. The cross-sectional area of the fibers is decreased by 31% and 34% respectively, with a peculiar effect on fiber types. In the immobilized gastrocnemius, absolute muscle force is reduced by 38%, while normalized force is reduced by 16%. The contralateral leg did not show signs of overload or hypertrophy when compared to free roaming littermates, offering a good internal control over the immobilized limb. Upon removing the cast, the mice effectively recovered mass and force in 3 weeks.

DOI: https://doi.org/10.1371/journal.pone.0304380
bioRxiv. 2024 May 13. pii: 2024.05.10.593199. [Epub ahead of print]

Functional role of myosin-binding protein H in thick filaments of developing vertebrate fast-twitch skeletal muscle.

Andrew F Mead, Neil B Wood, Shane R Nelson, Bradley M Palmer, Lin Yang, Samantha Beck Previs, Angela Ploysangngam, Guy G Kennedy, Jennifer F McAdow, Sarah M Tremble, Marilyn J Cipolla, Alicia M Ebert, Aaron N Johnson, Christina A Gurnett, Michael J Previs, David M Warshaw.

Myosin-binding protein H (MyBP-H) is a component of the vertebrate skeletal muscle sarcomere with sequence and domain homology to myosin-binding protein C (MyBP-C). Whereas skeletal muscle isoforms of MyBP-C (fMyBP-C, sMyBP-C) modulate muscle contractility via interactions with actin thin filaments and myosin motors within the muscle sarcomere "C-zone," MyBP-H has no known function. This is in part due to MyBP-H having limited expression in adult fast-twitch muscle and no known involvement in muscle disease. Quantitative proteomics reported here reveal MyBP-H is highly expressed in prenatal rat fast-twitch muscles and larval zebrafish, suggesting a conserved role in muscle development, and promoting studies to define its function. We take advantage of the genetic control of the zebrafish model and a combination of structural, functional, and biophysical techniques to interrogate the role of MyBP-H. Transgenic, FLAG-tagged MyBP-H or fMyBP-C both localize to the C-zones in larval myofibers, whereas genetic depletion of endogenous MyBP-H or fMyBP-C leads to increased accumulation of the other, suggesting competition for C-zone binding sites. Does MyBP-H modulate contractility from the C-zone? Globular domains critical to MyBP-C's modulatory functions are absent from MyBP-H, suggesting MyBP-H may be functionally silent. However, our results suggest an active role. Small angle x-ray diffraction of intact larval tails revealed MyBP-H contributes to the compression of the myofilament lattice accompanying stretch or contraction, while in vitro motility experiments indicate MyBP-H shares MyBP-C's capacity as a molecular "brake". These results provide new insights and raise questions about the role of the C-zone during muscle development.

DOI: https://doi.org/10.1101/2024.05.10.593199
Exp Gerontol. 2024 May 25. pii: S0531-5565(24)00107-4. [Epub ahead of print]193 112465

Aging-dependent mitochondrial bioenergetic impairment in the skeletal muscle of NNT-deficient mice.

Claudia D C Navarro, Annelise Francisco, Ericka F D Costa, Ana P Dalla Costa, Marina R Sartori, Paulo F V Bizerra, Andréia R Salgado, Tiago R Figueira, Anibal E Vercesi, Roger F Castilho.

  Overall health relies on features of skeletal muscle that generally decline with age, partly due to mechanisms associated with mitochondrial redox imbalance and bioenergetic dysfunction. Previously, aged mice genetically devoid of the mitochondrial NAD(P)+ transhydrogenase (NNT, encoded by the nicotinamide nucleotide transhydrogenase gene), an enzyme involved in mitochondrial NADPH supply, were shown to exhibit deficits in locomotor behavior. Here, by using young, middle-aged, and older NNT-deficient (Nnt-/-) mice and age-matched controls (Nnt+/+), we aimed to investigate how muscle bioenergetic function and motor performance are affected by NNT expression and aging. Mice were subjected to the wire-hang test to assess locomotor performance, while mitochondrial bioenergetics was evaluated in fiber bundles from the soleus, vastus lateralis and plantaris muscles. An age-related decrease in the average wire-hang score was observed in middle-aged and older Nnt-/- mice compared to age-matched controls. Although respiratory rates in the soleus, vastus lateralis and plantaris muscles did not significantly differ between the genotypes in young mice, the rates of oxygen consumption did decrease in the soleus and vastus lateralis muscles of middle-aged and older Nnt-/- mice. Notably, the soleus, which exhibited the highest NNT expression level, was the muscle most affected by aging, and NNT loss. Additionally, histology of the soleus fibers revealed increased numbers of centralized nuclei in older Nnt-/- mice, indicating abnormal morphology. In summary, our findings suggest that NNT expression deficiency causes locomotor impairments and muscle dysfunction during aging in mice.

Keywords:  Age-related muscle dysfunction; Locomotor impairment; Mitochondrial bioenergetics; NNT deficiency; Nicotinamide nucleotide transhydrogenase; Oxidative stress

DOI:  https://doi.org/10.1016/j.exger.2024.112465
J Orthop Translat. 2024 May;46 91-102

Effects of physical exercise on neuromuscular junction degeneration during ageing: A systematic review.

Qianjin Wang, Can Cui, Ning Zhang, Wujian Lin, Senlin Chai, Simon Kwoon-Ho Chow, Ronald Man Yeung Wong, Yong Hu, Sheung Wai Law, Wing-Hoi Cheung.

  The neuromuscular junction (NMJ) is a specialized chemical synapse that converts neural impulses into muscle action. Age-associated NMJ degeneration, which involves nerve terminal and postsynaptic decline, denervation, and loss of motor units, significantly contributes to muscle weakness and dysfunction. Although physical training has been shown to make substantial modifications in NMJ of both young and aged animals, the results are often influenced by methodological variables in existing studies. Moreover, there is still lack of strong consensus on the specific effects of exercise on improving the morphology and function of the ageing NMJ. Consequently, the purpose of this study was to conduct a systematic review to elucidate the effects of exercise training on NMJ compartments in the elderly. We conducted a systematic review using PubMed, Embase, and Web of Science databases, employing relevant keywords. Two independent reviewers selected studies that detailed NMJ changes during exercise in ageing, written in English, and available in full text. In total, 20 papers were included. We examined the altered adaptation of the NMJ to exercise, focusing on presynaptic and postsynaptic structures and myofibers in older animals or humans. Our findings indicated that aged NMJs exhibited different adaptive responses to physical exercise compared to younger counterparts. Endurance training, compared with resistance and voluntary exercise regimens, was found to have a more pronounced effect on NMJ structural remodeling, particularly in fast twitch muscle fibers. Physical exercise was observed to promote the formation and maintenance of acetylcholine receptor (AChR) clusters by increasing the recombinant docking protein 7 (Dok7) expression and stabilizing Agrin and lipoprotein receptor-related protein 4 (LRP4). These insights suggest that research on exercise-related therapies could potentially attenuate the progression of neuromuscular degeneration. Translational potential of this article: This systematic review provides a detailed overview of the effects of different types of physical exercise on improving NMJ in the elderly, providing scientific support for the timely intervention of muscle degeneration in the elderly by physical exercise, and providing help for the development of new therapeutic interventions in the future.

Keywords:  Ageing; Exercise; Neuromuscular junction; Physical training; Systematic review

DOI:  https://doi.org/10.1016/j.jot.2024.03.007
Biochem Biophys Res Commun. 2024 May 23. pii: S0006-291X(24)00699-5. [Epub ahead of print]723 150163

Physiological role for S-nitrosylation of RyR1 in skeletal muscle function and development.

Qi-An Sun, Zachary W Grimmett, Douglas T Hess, Lautaro G Perez, Zhaoxia Qian, Ruchi Chaube, Nicholas M Venetos, Bradley N Plummer, Kenneth R Laurita, Richard T Premont, Jonathan S Stamler.

  Excitation-contraction coupling in skeletal muscle myofibers depends upon Ca2+ release from the sarcoplasmic reticulum through the ryanodine receptor/Ca2+-release channel RyR1. The RyR1 contains ∼100 Cys thiols of which ∼30 comprise an allosteric network subject to posttranslational modification by S-nitrosylation, S-palmitoylation and S-oxidation. However, the role and function of these modifications is not understood. Although aberrant S-nitrosylation of multiple unidentified sites has been associated with dystrophic diseases, malignant hyperthermia and other myopathic syndromes, S-nitrosylation in physiological situations is reportedly specific to a single (1 of ∼100) Cys in RyR1, Cys3636 in a manner gated by pO2. Using mice expressing a form of RyR1 with a Cys3636→Ala point mutation to prevent S-nitrosylation at this site, we showed that Cys3636 was the principal target of endogenous S-nitrosylation during normal muscle function. The absence of Cys3636 S-nitrosylation suppressed stimulus-evoked Ca2+ release at physiological pO2 (at least in part by altering the regulation of RyR1 by Ca2+/calmodulin), eliminated pO2 coupling, and diminished skeletal myocyte contractility in vitro and measures of muscle strength in vivo. Furthermore, we found that abrogation of Cys3636 S-nitrosylation resulted in a developmental defect reflected in diminished myofiber diameter, altered fiber subtypes, and altered expression of genes implicated in muscle development and atrophy. Thus, our findings establish a physiological role for pO2-coupled S-nitrosylation of RyR1 in skeletal muscle contractility and development and provide foundation for future studies of RyR1 modifications in physiology and disease.

Keywords:  Excitation-contraction coupling; Muscle hypoxia; Nitric oxide; Ryanodine receptor; S-nitrosothiol; Sarcoplasmic reticulum

DOI:  https://doi.org/10.1016/j.bbrc.2024.150163
Curr Opin Support Palliat Care. 2024 May 27.

EDA2R-NIK signaling in cancer cachexia.

Samet Agca, Serkan Kir.

PURPOSE OF REVIEW: Cachexia is a debilitating condition causing weight loss and skeletal muscle wasting that negatively influences treatment and survival of cancer patients. The objective of this review is to describe recent discoveries on the role of a novel signaling pathway involving ectodysplasin A2 receptor (EDA2R) and nuclear factor κB (NFκB)-inducing kinase (NIK) in muscle atrophy.
RECENT FINDINGS: Studies identified tumor-induced upregulation of EDA2R expression in muscle tissues in pre-clinical cachexia models and patients with various cancers. Activation of EDA2R by its ligand promoted atrophy in cultured myotubes and muscle tissue, which depended on NIK activity. The non-canonical NFκB pathway via NIK also stimulated muscle atrophy. Mice lacking EDA2R or NIK were protected from muscle loss due to tumors. Tumor-induced cytokine oncostatin M (OSM) upregulated EDA2R expression in muscles whereas OSM receptor-deficient mice were resistant to muscle wasting.
SUMMARY: Recent discoveries revealed a mechanism involving EDA2R-NIK signaling and OSM that drives cancer-associated muscle loss, opening up new directions for designing anti-cachexia treatments. The therapeutic potential of targeting this mechanism to prevent muscle loss should be further investigated. Future research should also explore broader implications of the EDA2R-NIK pathway in other muscle wasting diseases and overall muscle health.

DOI: https://doi.org/10.1097/SPC.0000000000000705
FEBS Lett. 2024 May 27.

Unresolved questions in the regulation of skeletal muscle insulin action by reactive oxygen species.

Samantha Gallero, Kaspar W Persson, Carlos Henríquez-Olguín.

  Reactive oxygen species (ROS) are well-established signaling molecules implicated in a wide range of cellular processes, including both oxidative stress and intracellular redox signaling. In the context of insulin action within its target tissues, ROS have been reported to exert both positive and negative regulatory effects. However, the precise molecular mechanisms underlying this duality remain unclear. This Review examines the complex role of ROS in insulin action, with a particular focus on skeletal muscle. We aim to address three critical aspects: (a) the proposed intracellular pro-oxidative redox shift elicited by insulin, (b) the evidence supporting that redox-sensitive cysteine modifications impact insulin signaling and action, and (c) cellular mechanisms underlying how ROS can paradoxically act as both enhancers and inhibitors of insulin action. This Review underscores the urgent need for more systematic research to identify specific reactive species, redox targets, and the physiological significance of redox signaling in maintaining insulin action and metabolic health, with a particular emphasis on human skeletal muscle.

Keywords:  hydrogen peroxide; insulin action; insulin signaling; metabolism; reactive oxygen species; redox signaling; skeletal muscle

DOI:  https://doi.org/10.1002/1873-3468.14937
MedComm (2020). 2024 Jun;5(6): e558

Brassinin alleviates cancer cachexia by suppressing diverse inflammatory mechanisms in mice.

Min Hee Yang, Young Yun Jung, Jae-Young Um, Gautam Sethi, Kwang Seok Ahn.

  Cancer cachexia is a multifactorial condition that contributes to the death of about 20% of cancer patients. It has the potential to cause weight loss, reduction in muscle mass, and loss of fat tissue, significantly lowering the quality of life. Currently, there are no approved drugs for cancer cachexia. Here, we have explored the possible impact of brassinin (BSN) on cancer cachexia under in vitro and in vivo settings. After differentiation, C2C12 and 3T3-L1 cells were incubated with colorectal carcinoma cells conditioned media or BSN. For preclinical studies, mice were injected with HT-29 cells followed by intraperitoneal administration of BSN, and muscle and adipose tissues were evaluated by Western blotting and hematoxylin and eosin staining. BSN effectively suppressed muscle atrophy by down-regulating the levels of Muscle RING-finger protein-1 and Atrogin-1, while also increasing the expression of myosin heavy chain in cachexia-induced-C2C12 myotubes. The induction of adipogenesis by BSN prevented adipocyte atrophy in cachexia-induced 3T3-L1 adipocytes. We also noted that BSN disrupted the interaction between COX-2 and signaling transducer and activator of transcription 3 (STAT3) promoter, leading to down-regulation of STAT3 activation. Moreover, it was found that BSN inhibited weight loss in mice and demonstrated anti-cachexic effects. Overall, our observations indicate that BSN can attenuate cancer cachexia through diverse mechanisms.

Keywords:  Adipocyte atrophy; Brassinin; Cancer cachexia; Muscle atrophy; STAT3

DOI:  https://doi.org/10.1002/mco2.558
Front Endocrinol (Lausanne). 2024 ;15 1404047

Different roles of circulating and intramuscular GDF15 as markers of skeletal muscle health.

Antonio Chiariello, Giuseppe Conte, Luca Rossetti, Lorenzo Trofarello, Stefano Salvioli, Maria Conte.

   Introduction: Growth Differentiation Factor 15 (GDF15) is a mitokine expressed in response to various stresses whose circulating levels increase with age and are associated with numerous pathological conditions, including muscle wasting and sarcopenia. However, the use of circulating GDF15 (c-GDF15) as a biomarker of sarcopenia is still debated. Moreover, the role of GDF15 intracellular precursor, pro-GDF15, in human skeletal muscle (SM-GDF15) is not totally understood. In order to clarify these points, the association of both forms of GDF15 with parameters of muscle strength, body composition, metabolism and inflammation was investigated.
Methods: the levels of c-GDF15 and SM-GDF15 were evaluated in plasma and muscle biopsies, respectively, of healthy subjects (HS) and patients with lower limb mobility impairment (LLMI), either young (<40 years-old) or old (>70 years-old). Other parameters included in the analysis were Isometric Quadriceps Strength (IQS), BMI, lean and fat mass percentage, Vastus lateralis thickness, as well as circulating levels of Adiponectin, Leptin, Resistin, IGF-1, Insulin, IL6, IL15 and c-PLIN2. Principal Component Analysis (PCA), Canonical Discriminant Analysis (CDA) and Receiving Operating Characteristics (ROC) analysis were performed.
Results: c-GDF15 but not SM-GDF15 levels resulted associated with decreased IQS and IGF-1 levels in both HS and LLMI, while only in LLMI associated with increased levels of Resistin. Moreover, in LLMI both c-GDF15 and SM-GDF15 levels were associated with IL-6 levels, but interestingly SM-GDF15 is lower in LLMI with respect to HS. Furthermore, a discrimination of the four groups of subjects based on these parameters was possible with PCA and CDA. In particular HS, LLMI over 70 years or under 40 years of age were discriminated based on SM-GDF15, c-GDF15 and Insulin levels, respectively.
Conclusion: our data support the idea that c-GDF15 level could be used as a biomarker of decreased muscle mass and strength. Moreover, it is suggested that c-GDF15 has a different diagnostic significance with respect to SM-GDF15, which is likely linked to a healthy and active state.

Keywords:  GDF15; aging; biomarkers; inflammaging; muscle health

DOI:  https://doi.org/10.3389/fendo.2024.1404047
Eur J Appl Physiol. 2024 May 28.

Exposome on skeletal muscle system: a mini-review.

Cristina Purcaro, Lorenzo Marramiero, Carmen Santangelo, Danilo Bondi, Ester Sara Di Filippo.

  Exposomics is an ever-expanding field which captures the cumulative exposures to chemical, biological, physical, lifestyle, and social factors associated with biological responses. Since skeletal muscle is currently considered as the largest secretory organ and shows substantial plasticity over the life course, this reviews addresses the topic of exposome and skeletal muscle by reviewing the state-of-the-art evidence and the most intriguing perspectives. Muscle stem cells react to stressors via phosphorylated eukaryotic initiation factor 2α and tuberous sclerosis 1, and are sensible to hormetic factors via sirtuin 1. Microplastics can delay muscle regeneration via p38 mitogen-activated protein kinases and induce transdifferentiation to adipocytes via nuclear factor kappa B. Acrolein can inhibit myogenic differentiation and disrupt redox system. Heavy metals have been associated with reduced muscle strength in children. The deep study of pollutants and biological features can shed new light on neuromuscular pathophysiology. The analysis of a time-varying and dynamic exposome risk score from a panel of exposure and phenotypes of interest is promising. The systematization of hormetic factors and the role of the microbiota in modulating the effects of exposure on skeletal muscle responses are also promising. The comprehensive exposure assessment and its interactions with endogenous processes and the resulting biological effects deserve more efforts in the field of muscle health across the lifespan.

Keywords:  Hormesis; Lifestyle; Pollutants; Stem cells; Stress

DOI:  https://doi.org/10.1007/s00421-024-05515-1
Cureus. 2024 Apr;16(4): e59331

Dexamethasone and Insulin Modulate Alanine Aminotransferase (ALT) Activity and Alanine Oxidation in C2C12 Cells in a Dose-Dependent Manner.

Saed Woraikat, Defei Chen, Fuyu Yang, Chenglin Tang, Fan He, Kun Qian.

   BACKGROUND: The muscle cells myocytes are differentiated for the purpose of contraction function, which plays a major role in body metabolism and energy haemostasis, through different metabolic pathways, such as glucose and protein metabolic pathways. Alanine aminotransferase (ALT) plays a crucial role by reversibly catalysing transamination between alanine and a-ketoglutarate to form pyruvate and glutamate and by mediating the conversion of these four major intermediate metabolites. ALT plays important roles for energy homeostasis during fasting and prolonged exercise anaerobically, when muscle protein must first be broken down into its constituent amino acids.
METHODS: Mouse skeletal myoblast cell line C2C12 was cultured in Dulbecco's modified eagle medium (DMEM) growth medium, supplied with 2% horse serum supplemented with 1 uM insulin, 2 mM glutamine and penicillin and streptomycin antibiotics for seven days. The differentiation medium is refreshed every 24 hours. Then, C2C12 cells were treated with insulin and dexamethasone to examine their effects on myocytes' ALT activity.
RESULTS: In our study, we found an impact on ALT activity under different influences, including C2C12 differentiation, dexamethasone and insulin treatments, which shed light on the dynamic interplay between ALT activity, alanine metabolism, and cellular states, like differentiation and stress responses.
CONCLUSION: The study provides valuable insights into the dynamic regulation of ALT activity and alanine metabolism in C2C12 cells across differentiation and drug treatments. Further research is encouraged to explore the underlying mechanisms and their implications for muscle function, differentiation and potential therapeutic interventions in metabolic disorders.

Keywords:  alt; c2c12; dexamethasone; expression; insulin; myocytes

DOI:  https://doi.org/10.7759/cureus.59331
J Biosci. 2024 ;pii: 59. [Epub ahead of print]49

NMR-based comparative metabolomics of quiescent muscle cells.

Gunjan Purohit, Akila Ramesh, Anant B Patel, Jyotsna Dhawan.

Adult muscle tissue largely comprised of differentiated myofibers also harbors quiescent muscle-resident stem cells (MuSCs) that are responsible for its maintenance, repair and regeneration. Emerging evidence suggests that quiescent MuSCs exhibit a specific metabolic state, which is regulated during physiological and pathological alterations. However, a detailed understanding of the metabolic state of quiescent MuSCs and its alteration during activation and repair is lacking. Direct profiling of MuSCs in vivo is challenging because the cells are rare and dispersed, while isolation and enrichment leads to their activation and loss of quiescence. In this study, we employed 1H-nuclear magnetic resonance (NMR) spectroscopy to profile metabolites in an established culture model of quiescent MuSC-derived myoblasts and compared with activated, proliferative and differentiated muscle cells to determine the state-specific metabolome. We report that the proliferating and differentiated cells are highly enriched in metabolites involved in energy generation, the quiescent state is enriched in metabolites related to phospholipid catabolism (glycerophosphocholine and choline) and depleted for phosphocholine which is enriched in proliferating cells. We propose that the ratio of these metabolites may be useful as a biomarker of MuSC quiescence.
Signal Transduct Target Ther. 2024 May 29. 9(1): 138

Molecular insights of exercise therapy in disease prevention and treatment.

David Walzik, Tiffany Y Wences Chirino, Philipp Zimmer, Niklas Joisten.

Despite substantial evidence emphasizing the pleiotropic benefits of exercise for the prevention and treatment of various diseases, the underlying biological mechanisms have not been fully elucidated. Several exercise benefits have been attributed to signaling molecules that are released in response to exercise by different tissues such as skeletal muscle, cardiac muscle, adipose, and liver tissue. These signaling molecules, which are collectively termed exerkines, form a heterogenous group of bioactive substances, mediating inter-organ crosstalk as well as structural and functional tissue adaption. Numerous scientific endeavors have focused on identifying and characterizing new biological mediators with such properties. Additionally, some investigations have focused on the molecular targets of exerkines and the cellular signaling cascades that trigger adaption processes. A detailed understanding of the tissue-specific downstream effects of exerkines is crucial to harness the health-related benefits mediated by exercise and improve targeted exercise programs in health and disease. Herein, we review the current in vivo evidence on exerkine-induced signal transduction across multiple target tissues and highlight the preventive and therapeutic value of exerkine signaling in various diseases. By emphasizing different aspects of exerkine research, we provide a comprehensive overview of (i) the molecular underpinnings of exerkine secretion, (ii) the receptor-dependent and receptor-independent signaling cascades mediating tissue adaption, and (iii) the clinical implications of these mechanisms in disease prevention and treatment.

DOI: https://doi.org/10.1038/s41392-024-01841-0
J Biomed Res. 2024 May 25. 1-13

Macrophage scavenger receptor-A1 promotes skeletal muscle regeneration after hindlimb ischemia.

Siying Wang, Saiya Wang, Wenhan Cai, Jie Wang, Jianan Huang, Qing Yang, Hui Bai, Bin Jiang, Jingjing Ben, Hanwen Zhang, Xudong Zhu, Xiaoyu Li, Qi Chen.

  Macrophages mediated inflammatory response is crucial for the recovery of skeletal muscle following ischemia. Thus, it's necessary to exploit macrophages based therapeutic targets for ischemic disease. Here, we found mRNA level of SR-A1 was elevated in patients with critical limb ischemia by analysis of gene expression omnibus (GEO) database. Then we investigated the role and the underlined mechanisms of macrophage SR-A1 in a mouse HLI model. Compared with the SR-A1 fl/fl mice, the Lyz Cre/+/SR-A1 flox/flox (SR-A1 ΔMΦ) mice showed significantly lower laser doppler blood flow in the ischemic limb at day 7 after HLI. Consistently, histological analysis exhibited that ischemic limb of SR-A1 ΔMΦ mice displayed more sever and sustained necrotic morphology, inflammation and fibrosis, decreased vessel density and regeneration rate, compared with which of control SR-A1 fl/fl mice. Furthermore, restoration of wild-type myeloid cells to SR-A1 knock-out mice effectively relieved the doppler perfusion in the ischemic limb and restrained skeletal muscle damage 7 days post HLI. In line with in vivo findings, when co-cultivating macrophages with the mouse myoblast line C2C12, SR-A1 -/- bone marrow macrophage significantly inhibited myoblast differentiation in vitro. Mechanically, SR-A1 enhanced skeletal muscle regeneration response to HLI by inhibiting the oncostatin M (OSM) production via suppressed NF-κB signaling activation. These results indicates that SR-A1 is a promising candidate molecule to improve tissue repair and regeneration in peripheral ischemic arterial disease.

Keywords:  SR-A1; hindlimb ischemia; macrophage; oncostatin M

DOI:  https://doi.org/10.7555/JBR.38.20240117
Skelet Muscle. 2024 May 29. 14(1): 12

Studying intramuscular fat deposition and muscle regeneration: insights from a comparative analysis of mouse strains, injury models, and sex differences.

Alessandra M Norris, Kiara E Fierman, Jillian Campbell, Rhea Pitale, Muhammad Shahraj, Daniel Kopinke.

Intramuscular fat (IMAT) infiltration, pathological adipose tissue that accumulates between muscle fibers, is a shared hallmark in a diverse set of diseases including muscular dystrophies and diabetes, spinal cord and rotator cuff injuries, as well as sarcopenia. While the mouse has been an invaluable preclinical model to study skeletal muscle diseases, they are also resistant to IMAT formation. To better understand this pathological feature, an adequate pre-clinical model that recapitulates human disease is necessary. To address this gap, we conducted a comprehensive in-depth comparison between three widely used mouse strains: C57BL/6J, 129S1/SvlmJ and CD1. We evaluated the impact of strain, sex and injury type on IMAT formation, myofiber regeneration and fibrosis. We confirm and extend previous findings that a Glycerol (GLY) injury causes significantly more IMAT and fibrosis compared to Cardiotoxin (CTX). Additionally, females form more IMAT than males after a GLY injury, independent of strain. Of all strains, C57BL/6J mice, both females and males, are the most resistant to IMAT formation. In regard to injury-induced fibrosis, we found that the 129S strain formed the least amount of scar tissue. Surprisingly, C57BL/6J of both sexes demonstrated complete myofiber regeneration, while both CD1 and 129S1/SvlmJ strains still displayed smaller myofibers 21 days post injury. In addition, our data indicate that myofiber regeneration is negatively correlated with IMAT and fibrosis. Combined, our results demonstrate that careful consideration and exploration are needed to determine which injury type, mouse model/strain and sex to utilize as preclinical model especially for modeling IMAT formation.

DOI: https://doi.org/10.1186/s13395-024-00344-4