bims-moremu 2023-08-27 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2023‒08‒27
thirty papers selected by
Anna Vainshtein, Craft Science Inc.

Abnormal myosin post-translational modifications and ATP turnover time associated with human congenital myopathy-related RYR1 mutations.
Muscle p62 stimulates the expression of antioxidant proteins alleviating cancer cachexia.
Lack of Musashi-2 induces type IIa fiber-dominated muscle atrophy.
Extracellular Vesicles for Muscle Atrophy Treatment.
Thrown for a Loop: Fibro-Adipogenic Progenitors in Skeletal Muscle Fibrosis.
Exploring the Role of Oxidative Stress in Skeletal Muscle Atrophy: Mechanisms and Implications.
Organ Crosstalk Contributes to Muscle Wasting in Chronic Kidney Disease.
Sex differences in skeletal muscle size, function, and myosin heavy chain isoform expression during post-injury regeneration in mice.
Energy (and Reactive Oxygen Species Generation) Saving Distribution of Mitochondria for the Activation of ATP Production in Skeletal Muscle.
Decrease in Mouse Skeletal Muscle During Aging is Due to Altered Mitochondrial Networks and the MICOS Complex.
Stiffness anisotropy coordinates supracellular contractility driving long-range myotube-ECM alignment.
Unsaturated Long-Chain Fatty Acids Activate Resident Macrophages and Stem Cells in a Human Skeletal Muscle Tissue Model.
Crosstalk between Bone and Muscles during Physical Activity.
The Developmental Implications of Muscle-Targeted Magnetic Mitohormesis: A Human Health and Longevity Perspective.
Single-cell transcriptomic analysis of the identity and function of fibro/adipogenic progenitors in healthy and dystrophic muscle.
High-intensity aerobic, but not resistance or combined, exercise training improves both cardiometabolic health and skeletal muscle mitochondrial dynamics.
Skeletal muscle cell protein dysregulation highlights the pathogenesis mechanism of myopathy-associated p97/VCP R155H mutations.
Structural Adaptation of the Excitation-Contraction Coupling Apparatus in Calsequestrin1-Null Mice during Postnatal Development.
Tripartite Motif-Containing Protein 32 (TRIM32): What Does It Do for Skeletal Muscle?
The effect of serum from calorie-restricted mouse on mTOR signaling in C2C12 myotube.
TGF-β1 stimulation and VDR-dependent activation modulate calcitriol action on skeletal muscle fibroblasts and Smad signalling-associated fibrogenesis.
From the discovery of myokines to exercise as medicine.
Exercise Ameliorates Skeletal Muscle Insulin Resistance by modulating GRK4-mediated D1R expression.
Melatonin Improves Skeletal Muscle Structure and Oxidative Phenotype by Regulating Mitochondrial Dynamics and Autophagy in Zücker Diabetic Fatty Rat.
The Adiponectin Receptor Agonist, ALY688: A Promising Therapeutic for Fibrosis in the Dystrophic Muscle.
Caenorhabditis elegans models for striated muscle disorders caused by missense variants of human LMNA.
NMJ-related diseases beyond the congenital myasthenic syndromes.
Cytokines and exosomal miRNAs in skeletal muscle-adipose crosstalk.
ANT-dependent MPTP underlies necrotic myofiber death in muscular dystrophy.
The role of immunosuppressive myofibroblasts in the aging process and age-related diseases.

Acta Physiol (Oxf). 2023 Aug 21. e14035

Abnormal myosin post-translational modifications and ATP turnover time associated with human congenital myopathy-related RYR1 mutations.

Alexander Sonne, Anna Katarina Antonovic, Elise Melhedegaard, Fariha Akter, Jesper L Andersen, Heinz Jungbluth, Nanna Witting, John Vissing, Edmar Zanoteli, Arianna Fornili, Julien Ochala.

  AIM: Conditions related to mutations in the gene encoding the skeletal muscle ryanodine receptor 1 (RYR1) are genetic muscle disorders and include congenital myopathies with permanent weakness, as well as episodic phenotypes such as rhabdomyolysis/myalgia. Although RYR1 dysfunction is the primary mechanism in RYR1-related disorders, other downstream pathogenic events are less well understood and may include a secondary remodeling of major contractile proteins. Hence, in the present study, we aimed to investigate whether congenital myopathy-related RYR1 mutations alter the regulation of the most abundant contractile protein, myosin.METHODS: We used skeletal muscle tissues from five patients with RYR1-related congenital myopathy and compared those with five controls and five patients with RYR1-related rhabdomyolysis/myalgia. We then defined post-translational modifications on myosin heavy chains (MyHCs) using LC/MS. In parallel, we determined myosin relaxed states using Mant-ATP chase experiments and performed molecular dynamics (MD) simulations.
RESULTS: LC/MS revealed two additional phosphorylations (Thr1309-P and Ser1362-P) and one acetylation (Lys1410-Ac) on the β/slow MyHC of patients with congenital myopathy. This method also identified six acetylations that were lacking on MyHC type IIa of these patients (Lys35-Ac, Lys663-Ac, Lys763-Ac, Lys1171-Ac, Lys1360-Ac, and Lys1733-Ac). MD simulations suggest that modifying myosin Ser1362 impacts the protein structure and dynamics. Finally, Mant-ATP chase experiments showed a faster ATP turnover time of myosin heads in the disordered-relaxed conformation.
CONCLUSIONS: Altogether, our results suggest that RYR1 mutations have secondary negative consequences on myosin structure and function, likely contributing to the congenital myopathic phenotype.

Keywords:  ATP; acetylation; congenital myopathy; myosin heavy chain; phosphorylation; relaxed state; skeletal muscle

DOI:  https://doi.org/10.1111/apha.14035
FASEB J. 2023 Sep;37(9): e23156

Muscle p62 stimulates the expression of antioxidant proteins alleviating cancer cachexia.

Mami Yamada, Eiji Warabi, Hisashi Oishi, Vitor A Lira, Mitsuharu Okutsu.

  Oxidative stress plays an important role in skeletal muscle atrophy during cancer cachexia, and more glycolytic muscles are preferentially affected. Sequestosome1/SQSTM1 (i.e., p62), particularly when phosphorylated at Ser 349 (Ser 351 in mice), competitively binds to the Kelch-like ECH-associated protein 1 (Keap1) activating Nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 then stimulates the transcription of antioxidant/electrophile-responsive elements in target genes. However, a potential role for p62 in the protection of muscle wasting in cachexia remains to be determined. Here, using the well-established cachexia-inducing model of Lewis Lung Carcinoma (LLC) in mice we demonstrate higher expression of antioxidant proteins (i.e., NQO1, HO-1, GSTM1, CuZnSOD, MnSOD, and EcSOD) in the more oxidative and cachexia resistant soleus muscle than in the more glycolytic and cachexia prone extensor digitorum longus muscle. This was accompanied by higher p62 (total and phosphorylated) and nuclear Nrf2 levels in the soleus, which were paralleled by higher expression of proteins known to either phosphorylate or promote p62 phosphorylation (i.e., NBR1, CK1, PKCδ, and TAK1). Muscle-specific p62 gain-of-function (i.e., in p62 mTg mice) activated Nrf2 nuclear translocation and increased the expression of multiple antioxidant proteins (i.e., CuZnSOD, MnSOD, EcSOD, NQO1, and GSTM1) in glycolytic muscles. Interestingly, skeletal muscle Nrf2 haplodeficiency blunted the increases of most of these proteins (i.e., CuZnSOD, EcSOD, and NQO1) suggesting that muscle p62 stimulates antioxidant protein expression also via additional, yet to be determined mechanisms. Of note, p62 gain-of-function mitigated glycolytic muscle wasting in LLC-affected mice. Collectively, our findings identify skeletal muscle p62 as a potential therapeutic target for cancer cachexia.

Keywords:  Nrf2; SQSTM1/p62; antioxidants; muscle atrophy; oxidative stress; skeletal muscle

DOI:  https://doi.org/10.1096/fj.202300349R
FASEB J. 2023 Sep;37(9): e23154

Lack of Musashi-2 induces type IIa fiber-dominated muscle atrophy.

Yasuro Furuichi, Ayana Furutani, Kotaro Tamura, Yasuko Manabe, Nobuharu L Fujii.

  Skeletal muscle is a highly plastic tissue, adapting its structure and metabolism in response to diverse conditions such as contractile activity, nutrients, and diseases. Finding a novel master regulator of muscle mass and quality will provide new therapeutic targets for the prevention and treatment of muscle weakness. Musashi is an RNA-binding protein that dynamically regulates protein expression; it was originally discovered as a cell fate determination factor in neural cells. Here, we report that Musashi-2 (Msi2) is dominantly expressed in slow-type muscle fibers, fibers characterized by high metabolism and endurance. Msi2 knockout (KO) mice exhibited a decrease in both soleus myofiber size and number compared to control mice. Biochemical and histological analyses revealed that type IIa fibers, which are of the fast type but have high metabolic capacity, were decreased in Msi2 KO mice. The contraction force of isolated soleus muscle was lower in KO mice, and the expression of the metabolic proteins, cytochrome c oxidase and myoglobin, was also decreased in KO muscle. Our data demonstrate the critical role of Msi2 in the maintenance of normal fiber-type composition and metabolism.

Keywords:  RNA-binding protein; glucose tolerance; glucose transport; muscle atrophy; muscle fiber type

DOI:  https://doi.org/10.1096/fj.202300563R
Adv Exp Med Biol. 2023 ;1418 119-126

Extracellular Vesicles for Muscle Atrophy Treatment.

Xuan Su, Yan Shen, Il-Man Kim, Neal L Weintraub, Mark Hamrick, Yaoliang Tang.

  Skeletal muscle atrophy is a progressive chronic disease associated with various conditions, such as aging, cancer, and muscular dystrophy. Interleukin-6 (IL-6) is highly correlated with or plays a crucial role in inducing skeletal muscle atrophy. Extracellular vehicles (EVs), including exosomes, mediate cell-cell communication, and alterations in the genetic material contained in EVs during muscle atrophy may impair muscle cell signaling. Transplantation of muscle progenitor cell-derived EVs (MPC-EVs) is a promising approach for treating muscle diseases such as Duchenne muscular dystrophy (DMD). Moreover, stem cell-derived EVs with modification of microRNAs (e.g., miR-26 and miR-29) have been reported to attenuate muscle atrophy. Unbiased RNA-Seq analysis suggests that MPC-EVs may exert an inhibitory effect on IL-6 pathway. Here, we review the latest advances concerning the mechanisms of stem cell/progenitor cell-derived EVs in alleviating muscle atrophy, including anti-inflammatory and anti-fibrotic effects. We also discuss the clinical application of EVs in the treatment of muscle atrophy.

Keywords:  Bioengineering; Extracellular vesicles; IL-6; Muscle atrophy; Myogenic progenitor cells

DOI:  https://doi.org/10.1007/978-981-99-1443-2_8
Am J Physiol Cell Physiol. 2023 Aug 21.

Thrown for a Loop: Fibro-Adipogenic Progenitors in Skeletal Muscle Fibrosis.

Taryn Loomis, Lucas R Smith.

  Fibro-adipogenic progenitors (FAPs) are key regulators of skeletal muscle regeneration and homeostasis. However, dysregulation of these cells leads to fibro-fatty infiltration across various muscle diseases. FAPs are the key source of extracellular matrix (ECM) deposition in muscle, and disruption to this process leads to a pathological accumulation of ECM, known as fibrosis. The replacement of contractile tissue with fibrotic ECM functionally impairs the muscle and increasing muscle stiffness. FAPs and fibrotic muscle form a progressively degenerative feedback loop where, as a muscle becomes fibrotic, it induces a fibrotic FAP phenotype leading to further development of fibrosis. In this review we summarize FAPs' role in fibrosis in terms of their activation, heterogeneity, contributions to fibrotic degeneration, and role across musculoskeletal diseases. We also discuss current research on potential therapeutic avenues to attenuate fibrosis by targeting FAPs.

Keywords:  Fibro-adipogenic progenitors (FAPs); extracellular matrix (ECM); fibrosis; skeletal muscle; stem cells

DOI:  https://doi.org/10.1152/ajpcell.00245.2023
Cureus. 2023 Jul;15(7): e42178

Exploring the Role of Oxidative Stress in Skeletal Muscle Atrophy: Mechanisms and Implications.

Suyash Agrawal, Swarupa Chakole, Nidhi Shetty, Roshan Prasad, Tejaswee Lohakare, Mayur Wanjari.

  Skeletal muscle atrophy is a complex physiological process characterized by progressive muscle mass and strength loss. It is associated with various health conditions, including aging, disease, and certain diseases. Emerging research has indicated that oxidative stress plays a significant role in developing and progressing skeletal muscle atrophy. This review article explores the mechanisms by which oxidative stress influences skeletal muscle atrophy and its implications for potential therapeutic interventions. The review begins by providing an overview of skeletal muscle atrophy and the current understanding of its underlying mechanisms, highlighting the intricate balance between protein degradation and synthesis pathways. Subsequently, the concept of oxidative stress is introduced, discussing its sources and the intricate redox signaling pathways present in skeletal muscle cells. This review's main focus is exploring the multifaceted role of oxidative stress in skeletal muscle atrophy. The detrimental effects of excessive reactive oxygen species (ROS) production on cellular components, including proteins, lipids, and deoxyribonucleic acid (DNA), are discussed. In addition, the impact of oxidative stress on key signaling pathways involved in muscle wasting, such as the ubiquitin-proteasome system and autophagy, is examined. Furthermore, the review highlights the implications of oxidative stress in modulating muscle regeneration and the importance of redox balance in maintaining muscle health. Potential therapeutic strategies targeting oxidative stress, such as antioxidant supplementation, exercise interventions, and pharmacological approaches, are also discussed. In conclusion, this review comprehensively explains the intricate relationship between oxidative stress and skeletal muscle atrophy. By elucidating the underlying mechanisms and discussing potential therapeutic interventions, this review aims to contribute to the development of novel strategies for mitigating muscle wasting and improving overall muscle health.

Keywords:  antioxidant supplementation; muscle regeneration; oxidative stress; protein degradation; reactive oxygen species (ros); redox signaling; skeletal muscle atrophy; therapeutic interventions

DOI:  https://doi.org/10.7759/cureus.42178
Semin Nephrol. 2023 Aug 21. pii: S0270-9295(23)00119-5. [Epub ahead of print]43(2): 151409

Organ Crosstalk Contributes to Muscle Wasting in Chronic Kidney Disease.

Xiaonan H Wang, S Russ Price.

  Muscle wasting (ie, atrophy) is a serious consequence of chronic kidney disease (CKD) that reduces muscle strength and function. It reduces the quality of life for CKD patients and increases the risks of comorbidities and mortality. Current treatment strategies to prevent or reverse skeletal muscle loss are limited owing to the broad and systemic nature of the initiating signals and the multifaceted catabolic mechanisms that accelerate muscle protein degradation and impair protein synthesis and repair pathways. Recent evidence has shown how organs such as muscle, adipose, and kidney communicate with each other through interorgan exchange of proteins and RNAs during CKD. This crosstalk changes cell functions in the recipient organs and represents an added dimension in the complex processes that are responsible for muscle atrophy in CKD. This complexity creates challenges for the development of effective therapies to ameliorate muscle wasting and weakness in patients with CKD.

Keywords:  Chronic kidney disease; crosstalk; muscle atrophy; protein-energy wasting; skeletal muscle

DOI:  https://doi.org/10.1016/j.semnephrol.2023.151409
Physiol Rep. 2023 Aug;11(16): e15791

Sex differences in skeletal muscle size, function, and myosin heavy chain isoform expression during post-injury regeneration in mice.

Jae-Sung You, Pallob Barai, Jie Chen.

  Skeletal muscle regeneration is an essential process to restore muscle function after injury and is influenced by various factors. Despite the known importance of sex hormones in muscle regeneration, whether and what sex difference exists in this process is still unclear. In this study, we provide evidence for a clear sex difference in muscle regeneration in mice. At 7 and 14 days after barium chloride-induced muscle injury, female mice showed a faster recovery of muscle fiber size than males. Consistently, muscle force in female mice was restored faster than in males after injury, and this functional difference was maintained at 14 months of age when regenerative capacity declined. Myosin heavy chain isoform profiling and fatigability test revealed dynamic remodeling of myosin heavy chain isoform expression including a type IIB to IIA/X MHC transition and reduced fatigability in regenerated muscles compared to uninjured muscles. A significant sex difference was detected in myosin heavy chain IIX content, although this did not lead to different fatigability. Together, our results suggest that sex is an important determinant of the recovery of regenerating skeletal muscle and is partially involved in the remodeling of myosin heavy chain isoforms during muscle regeneration.

Keywords:  cross-sectional area; fatigability; force

DOI:  https://doi.org/10.14814/phy2.15791
Antioxidants (Basel). 2023 Aug 17. pii: 1624. [Epub ahead of print]12(8):

Energy (and Reactive Oxygen Species Generation) Saving Distribution of Mitochondria for the Activation of ATP Production in Skeletal Muscle.

Alejandra Espinosa, Mariana Casas, Enrique Jaimovich.

  Exercise produces oxidants from a variety of intracellular sources, including NADPH oxidases (NOX) and mitochondria. Exercise-derived reactive oxygen species (ROS) are beneficial, and the amount and location of these ROS is important to avoid muscle damage associated with oxidative stress. We discuss here some of the evidence that involves ROS production associated with skeletal muscle contraction and the potential oxidative stress associated with muscle contraction. We also discuss the potential role of H2O2 produced after NOX activation in the regulation of glucose transport in skeletal muscle. Finally, we propose a model based on evidence for the role of different populations of mitochondria in skeletal muscle in the regulation of ATP production upon exercise. The subsarcolemmal population of mitochondria has the enzymatic and metabolic components to establish a high mitochondrial membrane potential when fissioned at rest but lacks the capacity to produce ATP. Calcium entry into the mitochondria will further increase the metabolic input. Upon exercise, subsarcolemmal mitochondria will fuse to intermyofibrillar mitochondria and will transfer the mitochondria membrane potential to them. These mitochondria are rich in ATP synthase and will subsequentially produce the ATP needed for muscle contraction in long-term exercise. These events will optimize energy use and minimize mitochondria ROS production.

Keywords:  ATP production; MCU; mitochondria dynamics; mitochondrial network

DOI:  https://doi.org/10.3390/antiox12081624
Microsc Microanal. 2023 Jul 22. 29(Supplement_1): 1199-1200

Decrease in Mouse Skeletal Muscle During Aging is Due to Altered Mitochondrial Networks and the MICOS Complex.

Zer Vue, Edgar Garza-Lopez, Kit Neikirk, Larry Vang, Antentor Hinton.

DOI: https://doi.org/10.1093/micmic/ozad067.617
bioRxiv. 2023 Aug 11. pii: 2023.08.08.552197. [Epub ahead of print]

Stiffness anisotropy coordinates supracellular contractility driving long-range myotube-ECM alignment.

Nathaniel P Skillin, Bruce E Kirkpatrick, Katie M Herbert, Benjamin R Nelson, Grace K Hach, Kemal Arda Günay, Ryan M Khan, Frank W DelRio, Timothy J White, Kristi S Anseth.

In skeletal muscle tissue, injury-related changes in stiffness activate muscle stem cells through mechanosensitive signaling pathways. Functional muscle tissue regeneration also requires the effective coordination of myoblast proliferation, migration, polarization, differentiation, and fusion across multiple length scales. Here, we demonstrate that substrate stiffness anisotropy coordinates contractility-driven collective cellular dynamics resulting in C2C12 myotube alignment over millimeter-scale distances. When cultured on mechanically anisotropic liquid crystalline polymer networks (LCNs) lacking topographic features that could confer contact guidance, C2C12 myoblasts collectively polarize in the stiffest direction of the substrate. Cellular coordination is amplified through reciprocal cell-ECM dynamics that emerge during fusion, driving global myotube-ECM ordering. Conversely, myotube alignment was restricted to small local domains with no directional preference on mechanically isotropic LCNs of same chemical formulation. These findings reveal a role for stiffness anisotropy in coordinating emergent collective cellular dynamics, with implications for understanding skeletal muscle tissue development and regeneration.

DOI: https://doi.org/10.1101/2023.08.08.552197
Biology (Basel). 2023 Aug 09. pii: 1111. [Epub ahead of print]12(8):

Unsaturated Long-Chain Fatty Acids Activate Resident Macrophages and Stem Cells in a Human Skeletal Muscle Tissue Model.

Xiaoying Chen, Dandan Hao, Nils Becker, Aline Müller, Miguel Pishnamaz, Leo Cornelius Bollheimer, Frank Hildebrand, Mahtab Nourbakhsh.

  Phenotypically heterogeneous populations of tissue-resident macrophages and stem cells play important roles in the regeneration of the skeletal muscle tissue. Previous studies using animal and cell culture models implied a beneficial effect of fatty acid (FA) species on tissue regeneration. Here, we applied a human experimental model using excised muscle tissues from reconstructive surgeries to study the effects of FAs on resident macrophages and stem cells in the natural environment of human skeletal muscle tissue. Muscle tissue samples from 20 donors were included in this study. The expression of 34 cytokines/chemokines was determined, using multiplex protein analysis. The phenotypes of macrophages and stem cells were determined immunohistochemically. The numbers of CD80+ macrophages correlated with the expression levels of IL-1α, IL-1RA, IL-8, IL-17A, and MCP-1, while the PAX7+ and MyoD+ stem cell counts were positively correlated with the expression level of CXCL12α, a recognized chemoattractant for muscle stem cells. Treatment of additional tissue sections with FAs revealed that CD80+ or MARCO+ macrophages- and PAX7+ or MyoD+ stem cells were simultaneously increased by unsaturated long-chain FAs. Taken together, this is the first experimental demonstration of a coordinated activation of macrophages and stem cells in human skeletal muscle tissue.

Keywords:  aging; chemokines; cytokines; fatty acids; human; macrophages; myoblasts; sarcopenia; satellite cells; skeletal muscle; stem cells; tissue model

DOI:  https://doi.org/10.3390/biology12081111
Cells. 2023 Aug 18. pii: 2088. [Epub ahead of print]12(16):

Crosstalk between Bone and Muscles during Physical Activity.

Luca Dalle Carbonare, Arianna Minoia, Sharazed Zouari, Francesca Cristiana Piritore, Anna Vareschi, Maria Grazia Romanelli, Maria Teresa Valenti.

  Bone-muscle crosstalk is enabled thanks to the integration of different molecular signals, and it is essential for maintaining the homeostasis of skeletal and muscle tissue. Both the skeletal system and the muscular system perform endocrine activity by producing osteokines and myokines, respectively. These cytokines play a pivotal role in facilitating bone-muscle crosstalk. Moreover, recent studies have highlighted the role of non-coding RNAs in promoting crosstalk between bone and muscle in physiological or pathological conditions. Therefore, positive stimuli or pathologies that target one of the two systems can affect the other system as well, emphasizing the reciprocal influence of bone and muscle. Lifestyle and in particular physical activity influence both the bone and the muscular apparatus by acting on the single system but also by enhancing its crosstalk. Several studies have in fact demonstrated the modulation of circulating molecular factors during physical activity. These molecules are often produced by bone or muscle and are capable of activating signaling pathways involved in bone-muscle crosstalk but also of modulating the response of other cell types. Therefore, in this review we will discuss the effects of physical activity on bone and muscle cells, with particular reference to the biomolecular mechanisms that regulate their cellular interactions.

Keywords:  bone; extracellular vesicles; muscle; physical activity; progenitor cells

DOI:  https://doi.org/10.3390/cells12162088
Bioengineering (Basel). 2023 Aug 12. pii: 956. [Epub ahead of print]10(8):

The Developmental Implications of Muscle-Targeted Magnetic Mitohormesis: A Human Health and Longevity Perspective.

Alfredo Franco-Obregón, Yee Kit Tai, Kwan Yu Wu, Jan Nikolas Iversen, Craig Jun Kit Wong.

  Muscle function reflects muscular mitochondrial status, which, in turn, is an adaptive response to physical activity, representing improvements in energy production for de novo biosynthesis or metabolic efficiency. Differences in muscle performance are manifestations of the expression of distinct contractile-protein isoforms and of mitochondrial-energy substrate utilization. Powerful contractures require immediate energy production from carbohydrates outside the mitochondria that exhaust rapidly. Sustained muscle contractions require aerobic energy production from fatty acids by the mitochondria that is slower and produces less force. These two patterns of muscle force generation are broadly classified as glycolytic or oxidative, respectively, and require disparate levels of increased contractile or mitochondrial protein production, respectively, to be effectively executed. Glycolytic muscle, hence, tends towards fibre hypertrophy, whereas oxidative fibres are more disposed towards increased mitochondrial content and efficiency, rather than hypertrophy. Although developmentally predetermined muscle classes exist, a degree of functional plasticity persists across all muscles post-birth that can be modulated by exercise and generally results in an increase in the oxidative character of muscle. Oxidative muscle is most strongly correlated with organismal metabolic balance and longevity because of the propensity of oxidative muscle for fatty-acid oxidation and associated anti-inflammatory ramifications which occur at the expense of glycolytic-muscle development and hypertrophy. This muscle-class size disparity is often at odds with common expectations that muscle mass should scale positively with improved health and longevity. Brief magnetic-field activation of the muscle mitochondrial pool has been shown to recapitulate key aspects of the oxidative-muscle phenotype with similar metabolic hallmarks. This review discusses the common genetic cascades invoked by endurance exercise and magnetic-field therapy and the potential physiological differences with regards to human health and longevity. Future human studies examining the physiological consequences of magnetic-field therapy are warranted.

Keywords:  PEMF; exercise; healthspan; magnetic fields; muscle secretome

DOI:  https://doi.org/10.3390/bioengineering10080956
iScience. 2023 Aug 18. 26(8): 107479

Single-cell transcriptomic analysis of the identity and function of fibro/adipogenic progenitors in healthy and dystrophic muscle.

Prech Uapinyoying, Marshall Hogarth, Surajit Battacharya, Davi A G Mázala, Karuna Panchapakesan, Carsten G Bönnemann, Jyoti K Jaiswal.

  Fibro/adipogenic progenitors (FAPs) are skeletal muscle stromal cells that support regeneration of injured myofibers and their maintenance in healthy muscles. FAPs are related to mesenchymal stem cells (MSCs/MeSCs) found in other adult tissues, but there is poor understanding of the extent of similarity between these cells. Using single-cell RNA sequencing (scRNA-seq) datasets from multiple mouse tissues, we have performed comparative transcriptomic analysis. This identified remarkable transcriptional similarity between FAPs and MeSCs, confirmed the suitability of PDGFRα as a reporter for FAPs, and identified extracellular proteolysis as a new FAP function. Using PDGFRα as a cell surface marker, we isolated FAPs from healthy and dysferlinopathic mouse muscles and performed scRNA-seq analysis. This revealed decreased FAP-mediated Wnt signaling as a potential driver of FAP dysfunction in dysferlinopathic muscles. Analysis of FAPs in dysferlin- and dystrophin-deficient muscles identified a relationship between the nature of muscle pathology and alteration in FAP gene expression.

Keywords:  Omics; Stem cells research; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2023.107479
J Appl Physiol (1985). 2023 Aug 24.

High-intensity aerobic, but not resistance or combined, exercise training improves both cardiometabolic health and skeletal muscle mitochondrial dynamics.

Gregory N Ruegsegger, Mark W Pataky, Suvyaktha Simha, Matthew M Robinson, Katherine A Klaus, K Sreekumaran Nair.

  This study investigated how different exercise training modalities influence skeletal muscle mitochondrial dynamics. Healthy (average B.M.I.: 25.8 kg/m2), sedentary younger and older participants underwent 12 weeks of supervised high-intensity aerobic interval training (HIIT) (n = 13), resistance training (RT) (n = 14), or combined training (CT) (n = 11). Mitochondrial structure was assessed using transmission electron microscopy (TEM). Regulators of mitochondrial fission and fusion, cardiorespiratory fitness (VO2peak), insulin sensitivity via a hyperinsulinemic-euglycemic clamp, and muscle mitochondrial respiration were assessed. TEM showed increased mitochondrial volume, number, and perimeter following HIIT (p < 0.01), increased mitochondrial number following CT (p < 0.05), and no change in mitochondrial abundance after RT. Increased mitochondrial volume associated with increased mitochondrial respiration and insulin sensitivity following HIIT (p < 0.05). Increased mitochondrial perimeter associated with increased mitochondrial respiration, insulin sensitivity, and VO2peak following HIIT (p < 0.05). No such relationships were observed following CT or RT. OPA1, a regulator of fusion, was increased following HIIT (p < 0.05), while FIS1, a regulator of fission, was decreased following HIIT and CT (p < 0.05). HIIT also increased the ratio of OPA1/FIS1 (p < 0.01), indicative of the balance between fission and fusion, which positively correlated with improvements in respiration, insulin sensitivity, and VO2peak (p <0.05). In conclusion, HIIT induces a larger, more fused mitochondrial tubular network. Changes indicative of increased fusion following HIIT associate with improvements in mitochondrial respiration, insulin sensitivity, and VO2peak supporting the idea that enhanced mitochondrial fusion accompanies notable health benefits of HIIT.

Keywords:  HIIT; aerobic exercise; fission; fusion; mitochondria

DOI:  https://doi.org/10.1152/japplphysiol.00405.2023
Front Neurol. 2023 ;14 1211635

Skeletal muscle cell protein dysregulation highlights the pathogenesis mechanism of myopathy-associated p97/VCP R155H mutations.

Anna Luzzi, Feng Wang, Shan Li, Michelina Iacovino, Tsui-Fen Chou.

  p97/VCP, a hexametric member of the AAA-ATPase superfamily, has been associated with a wide range of cellular protein pathways, such as proteasomal degradation, the unfolding of polyubiquitinated proteins, and autophagosome maturation. Autosomal dominant p97/VCP mutations cause a rare hereditary multisystem disorder called IBMPFD/ALS (Inclusion Body Myopathy with Paget's Disease and Frontotemporal Dementia/Amyotrophic Lateral Sclerosis), characterized by progressive weakness and subsequent atrophy of skeletal muscles, and impacting bones and brains, such as Parkinson's disease, Lewy body disease, Huntington's disease, and amyotrophic lateral ALS. Among all disease-causing mutations, Arginine 155 to Histidine (R155H/+) was reported to be the most common one, affecting over 50% of IBMPFD patients, resulting in disabling muscle weakness, which might eventually be life-threatening due to cardiac and respiratory muscle involvement. Induced pluripotent stem cells (iPSCs) offer an unlimited resource of cells to study pathology's underlying molecular mechanism, perform drug screening, and investigate regeneration. Using R155H/+ patients' fibroblasts, we generated IPS cells and corrected the mutation (Histidine to Arginine, H155R) to generate isogenic control cells before differentiating them into myotubes. The further proteomic analysis allowed us to identify differentially expressed proteins associated with the R155H mutation. Our results showed that R155H/+ cells were associated with dysregulated expression of several proteins involved in skeletal muscle function, cytoskeleton organization, cell signaling, intracellular organelles organization and function, cell junction, and cell adhesion. Our findings provide molecular evidence of dysfunctional protein expression in R155H/+ myotubes and offer new therapeutic targets for treating IBMPFD/ALS.

Keywords:  IBMPFD/ALS; R155H mutation; VCP/p97; iPSCs; myopathy; skeletal muscle

DOI:  https://doi.org/10.3389/fneur.2023.1211635
Biology (Basel). 2023 Jul 29. pii: 1064. [Epub ahead of print]12(8):

Structural Adaptation of the Excitation-Contraction Coupling Apparatus in Calsequestrin1-Null Mice during Postnatal Development.

Stefania Murzilli, Matteo Serano, Laura Pietrangelo, Feliciano Protasi, Cecilia Paolini.

  The precise arrangement and peculiar interaction of transverse tubule (T-tubule) and sarcoplasmic reticulum (SR) membranes efficiently guarantee adequate contractile properties of skeletal muscle fibers. Fast muscle fibers from mice lacking calsequestrin 1 (CASQ1) are characterized by the profound ultrastructural remodeling of T-tubule/SR junctions. This study investigates the role of CASQ1, an essential component of calcium release units (CRUs), in the postnatal development of muscle fibers. By using CASQ1-knockout mice, we examined the maturation of CRUs and the involvement of different junctional proteins in the juxtaposition of the membrane system. Our morphological investigation of both wild-type (WT) and CASQ1-null extensor digitorum longus (EDL) fibers, from 1 week to 4 months of age, yielded noteworthy findings. Firstly, we observed that the absence of CASQ1 hindered the full maturation of CRUs, despite the correct localization of key junctional components (ryanodine receptor, dihydropyridine receptor, and triadin) to the junctional SR in adult animals. Furthermore, analysis of protein expression profiles related to T-tubule biogenesis and organization (junctophilin 1, amphiphysin 2, caveolin 3, and mitsugumin 29) demonstrated delayed progression in their expression during postnatal development in the absence of CASQ1, suggesting the impaired maturation of CRUs. The absence of CASQ1 directly impacts the proper assembly of CRUs during development and influences the expression and coordination of other proteins involved in T-tubule biogenesis and organization.

Keywords:  EC coupling; calsequestrin; development; skeletal muscle

DOI:  https://doi.org/10.3390/biology12081064
Cells. 2023 Aug 19. pii: 2104. [Epub ahead of print]12(16):

Tripartite Motif-Containing Protein 32 (TRIM32): What Does It Do for Skeletal Muscle?

Seung Yeon Jeong, Jun Hee Choi, Jooho Kim, Jin Seok Woo, Eun Hui Lee.

  Tripartite motif-containing protein 32 (TRIM32) is a member of the tripartite motif family and is highly conserved from flies to humans. Via its E3 ubiquitin ligase activity, TRIM32 mediates and regulates many physiological and pathophysiological processes, such as growth, differentiation, muscle regeneration, immunity, and carcinogenesis. TRIM32 plays multifunctional roles in the maintenance of skeletal muscle. Genetic variations in the TRIM32 gene are associated with skeletal muscular dystrophies in humans, including limb-girdle muscular dystrophy type 2H (LGMD2H). LGMD2H-causing genetic variations of TRIM32 occur most frequently in the C-terminal NHL (ncl-1, HT2A, and lin-41) repeats of TRIM32. LGMD2H is characterized by skeletal muscle dystrophy, myopathy, and atrophy. Surprisingly, most patients with LGMD2H show minimal or no dysfunction in other tissues or organs, despite the broad expression of TRIM32 in various tissues. This suggests more prominent roles for TRIM32 in skeletal muscle than in other tissues or organs. This review is focused on understanding the physiological roles of TRIM32 in skeletal muscle, the pathophysiological mechanisms mediated by TRIM32 genetic variants in LGMD2H patients, and the correlations between TRIM32 and Duchenne muscular dystrophy (DMD).

Keywords:  DMD; LGMD2H; NHL repeats; TRIM32; muscular dystrophy

DOI:  https://doi.org/10.3390/cells12162104
J Endocrinol. 2023 Aug 01. pii: JOE-23-0111. [Epub ahead of print]

The effect of serum from calorie-restricted mouse on mTOR signaling in C2C12 myotube.

Takanaga Shirai, Tomohiro Iwata, Kazuki Uemichi, Riku Tanimura, Ryoto Iwai, Tohru Takemasa.

Calorie restriction (CR) is a widely recognized dietary approach with beneficial impacts on the entire body, including enhancements in oxidative-metabolism and lifespan extension, while maintaining nutritional balance and calorie intake. However, CR leads to reductions in skeletal muscle and fat mass due to decreased food intake. Consequently, CR significantly modifies the metabolic profile of the entire body and its tissues. The observed benefits in skeletal muscle during CR may be attributed to CR-induced signaling mediators or significant changes in blood profiles associated with CR that regulate homeostasis maintenance. This study aimed to examine the mTOR signaling and mitochondrial function of skeletal muscle from mice that undergone 8 weeks of CR and cells cultured in their serum to determine whether changes in blood secreted factors during CR affect skeletal muscle cells. C57BL6/J male mice were used. For 8 weeks, these were subjected to ad libitum (AL) or 40% CR. C2C12 myotubes were subsequently treated with media containing 10% mouse serum from AL or CR for 24 h. The results indicated that 8 weeks of CR decreased muscle mass and protein synthesis response compared with the AL group. Interestingly, myotubes conditioned with CR serum exhibited an elevation in the protein synthesis response compared with those treated with AL serum. Furthermore, mitochondrial function was enhanced in both CR mice and cells treated with CR serum. These findings suggest that while CR decrease the protein synthesis response, secretory factors present in the blood during CR can activate protein synthesis and promote mitochondrial function.

DOI: https://doi.org/10.1530/JOE-23-0111
Sci Rep. 2023 Aug 23. 13(1): 13811

TGF-β1 stimulation and VDR-dependent activation modulate calcitriol action on skeletal muscle fibroblasts and Smad signalling-associated fibrogenesis.

Ratchakrit Srikuea, Muthita Hirunsai.

Fibroblasts play a pivotal role in fibrogenesis after skeletal muscle injury. Excess fibrous formation can disrupt contractile functions and delay functional recovery. Although vitamin D receptor (VDR) is expressed explicitly in regenerating muscle compared with uninjured muscle, how calcitriol [1α,25(OH)2D3] directly regulates skeletal muscle primary fibroblast proliferation, the transition to myofibroblasts, and Smad signalling-associated fibrogenesis is currently unknown. Herein, the effects of calcitriol on cultured skeletal muscle primary fibroblasts of male C57BL/6 mice (aged 1 month old) were investigated. The percentage of BrdU+ nuclei in primary fibroblasts was significantly decreased after calcitriol treatment; however, the antiproliferative effect of calcitriol was diminished after TGF-β1 stimulation to induce fibroblast to myofibroblast transition. This suppressive effect was associated with significantly decreased VDR expression in TGF-β1-treated cells. In addition, Vdr siRNA transfection abolished the effects of calcitriol on the suppression of α-SMA expression and Smad2/3 signalling in myofibroblasts, supporting that its antifibrogenic effect requires VDR activation. Compared with calcitriol, the antifibrotic agent suramin could inhibit fibroblast/myofibroblast proliferation and suppress the expression of TCF-4, which regulates fibrogenic determination. Collectively, these findings suggest that profibrotic stimulation and VDR-dependent activation could modulate the effects of calcitriol on skeletal muscle fibroblast proliferation and fibrogenesis processes. Therefore, TGF-β1 and VDR expression levels are crucial determinants for the antifibrogenic effect of calcitriol on skeletal muscle after injury.

DOI: https://doi.org/10.1038/s41598-023-40978-w
Dan Med J. 2023 Aug 03. pii: A12220766. [Epub ahead of print]70(9):

From the discovery of myokines to exercise as medicine.

Bente Klarlund Pedersen.

Skeletal muscle is an endocrine organ that produces and secretes hundreds of myokines, allowing for crosstalk between the muscle and other organs. The discovery of myokines has contributed to laying the groundwork for exercise as medicine. Exercise activates multiple signalling pathways of importance for health. However, for the individual and society to benefit from such exercise effects, a true translational perspective on exercise as medicine is needed, ranging from molecular and physiological events to political decisions with direct implications for clinical practice and public health.
Clin Sci (Lond). 2023 Aug 25. pii: CS20230664. [Epub ahead of print]

Exercise Ameliorates Skeletal Muscle Insulin Resistance by modulating GRK4-mediated D1R expression.

Yu Tao, Wenbin Luo, Yue Chen, Caiyu Chen, Shengnan Chen, Xiaoping Li, Ken Chen, Chunyu Zeng.

  Exercise has been recommended as a nonpharmaceutical therapy to treat insulin resistance (IR). Previous studies showed dopamine D1-like receptor agonists, e.g., fenoldopam, could improve peripheral insulin sensitivity and antipsychotics which are dopamine receptor antagonists increased the susceptibility to type 2 diabetes (T2DM). Meanwhile, exercise has been proved to stimulate dopamine receptors. However, whether the dopamine D1 receptor (D1R) is involved in exercise-mediated amelioration of IR remains unclear. We found that the D1-like receptor antagonist, SCH23390, reduced the effect of exercise on lowering blood glucose and insulin in insulin-resistant mice, and inhibited the contraction-induced glucose uptake in C2C12 myotubes. Similarly, the opposite was true for the D1-like receptor agonist, fenoldopam. Furthermore, the expression of D1R was decreased in skeletal muscles from streptozotocin (STZ)- and high-fat intake-induced T2DM mice, accompanied by increased D1R phosphorylation, which was reversed by exercise. A screening study showed that G protein-coupled receptor kinase 4 (GRK4) may be the candidate kinase for the regulation of D1R function, because, in addition to the increased GRK4 expression in skeletal muscles of T2DM mice, GRK4 transgenic T2DM mice exhibited lower insulin sensitivity, accompanied by higher D1R phosphorylation than control mice, whereas the AAV9-shGRK4 mice were much more sensitive to insulin than AAV9-null mice. Mechanistically, the upregulation of GRK4 expression caused by increased reactive oxygen species (ROS) in IR was ascribed to the enhanced expression of c-Myc, a transcriptional factor of GRK4. Taken together, this study shows that exercise, via regulation of ROS/c-Myc/GRK4 pathway, ameliorates D1R dysfunction and improves insulin sensitivity.

Keywords:  G protein-coupled receptor kinase 4; dopamine D1 receptor; exercise; insulin resistance; skeletal muscle

DOI:  https://doi.org/10.1042/CS20230664
Antioxidants (Basel). 2023 Jul 27. pii: 1499. [Epub ahead of print]12(8):

Melatonin Improves Skeletal Muscle Structure and Oxidative Phenotype by Regulating Mitochondrial Dynamics and Autophagy in Zücker Diabetic Fatty Rat.

Diego Salagre, Enrique Raya Álvarez, Cruz Miguel Cendan, Samira Aouichat, Ahmad Agil.

  Obesity-induced skeletal muscle (SKM) inflexibility is closely linked to mitochondrial dysfunction. The present study aimed to evaluate the effects of melatonin on the red vastus lateralis (RVL) muscle in obese rat models at the molecular and morphological levels. Five-week-old male Zücker diabetic fatty (ZDF) rats and their age-matched lean littermates (ZL) were orally treated either with melatonin (10 mg/kg body weight (BW)/24 h) (M-ZDF and M-ZL) or non-treated (control) (C-ZDF and C-ZL) for 12 weeks. Western blot analysis showed that mitochondrial fission, fusion, and autophagy were altered in the C-ZDF group, accompanied by reduced SIRT1 levels. Furthermore, C-ZDF rats exhibited depleted ATP production and nitro-oxidative stress, as indicated by increased nitrites levels and reduced SOD activity. Western blotting of MyH isoforms demonstrated a significant decrease in both slow and fast oxidative fiber-specific markers expression in the C-ZDF group, concomitant with an increase in the fast glycolytic fiber markers. At the tissue level, marked fiber atrophy, less oxidative fibers, and excessive lipid deposition were noted in the C-ZDF group. Interestingly, melatonin treatment partially restored mitochondrial fission/fusion imbalance in the RVL muscle by enhancing the expression of fission (Fis1 and DRP1) markers and decreasing that of fusion (OPA1 and Mfn2) markers. It was also found to restore autophagy, as indicated by increased p62 protein level and LC3BII/I ratio. In addition, melatonin treatment increased SIRT1 protein level, mitochondrial ATP production, and SOD activity and decreased nitrites production. These effects were associated with enhanced oxidative phenotype, as evidenced by amplified oxidative fiber-specific markers expression, histochemical reaction for NADH enzyme, and muscular lipid content. In this study, we showed that melatonin might have potential therapeutic implications for obesity-induced SKM metabolic inflexibility among patients with obesity and T2DM.

Keywords:  ZDF rat; autophagy; diabesity; melatonin; mitochondrial fission-fusion; muscle fiber composition; oxidative stress; red vastus lateralis; skeletal muscle

DOI:  https://doi.org/10.3390/antiox12081499
Cells. 2023 Aug 19. pii: 2101. [Epub ahead of print]12(16):

The Adiponectin Receptor Agonist, ALY688: A Promising Therapeutic for Fibrosis in the Dystrophic Muscle.

Nicolas Dubuisson, Romain Versele, Maria A Davis-López de Carrizosa, Camille M Selvais, Laurence Noel, Chloé Planchon, Peter Y K Van den Bergh, Sonia M Brichard, Michel Abou-Samra.

  Duchenne muscular dystrophy (DMD) is one of the most devastating myopathies, where severe inflammation exacerbates disease progression. Previously, we demonstrated that adiponectin (ApN), a hormone with powerful pleiotropic effects, can efficiently improve the dystrophic phenotype. However, its practical therapeutic application is limited. In this study, we investigated ALY688, a small peptide ApN receptor agonist, as a potential novel treatment for DMD. Four-week-old mdx mice were subcutaneously treated for two months with ALY688 and then compared to untreated mdx and wild-type mice. In vivo and ex vivo tests were performed to assess muscle function and pathophysiology. Additionally, in vitro tests were conducted on human DMD myotubes. Our results showed that ALY688 significantly improved the physical performance of mice and exerted potent anti-inflammatory, anti-oxidative and anti-fibrotic actions on the dystrophic muscle. Additionally, ALY688 hampered myonecrosis, partly mediated by necroptosis, and enhanced the myogenic program. Some of these effects were also recapitulated in human DMD myotubes. ALY688's protective and beneficial properties were mainly mediated by the AMPK-PGC-1α axis, which led to suppression of NF-κβ and TGF-β. Our results demonstrate that an ApN mimic may be a promising and effective therapeutic prospect for a better management of DMD.

Keywords:  ALY688; AMPK; adiponectin; duchenne muscular dystrophy; fibrosis; inflammation; myonecrosis; necroptosis; regeneration; skeletal muscle

DOI:  https://doi.org/10.3390/cells12162101
PLoS Genet. 2023 Aug 25. 19(8): e1010895

Caenorhabditis elegans models for striated muscle disorders caused by missense variants of human LMNA.

Ellen F Gregory, Shilpi Kalra, Trisha Brock, Gisèle Bonne, G W Gant Luxton, Christopher Hopkins, Daniel A Starr.

Striated muscle laminopathies caused by missense mutations in the nuclear lamin gene LMNA are characterized by cardiac dysfunction and often skeletal muscle defects. Attempts to predict which LMNA variants are pathogenic and to understand their physiological effects lags behind variant discovery. We created Caenorhabditis elegans models for striated muscle laminopathies by introducing pathogenic human LMNA variants and variants of unknown significance at conserved residues within the lmn-1 gene. Severe missense variants reduced fertility and/or motility in C. elegans. Nuclear morphology defects were evident in the hypodermal nuclei of many lamin variant strains, indicating a loss of nuclear envelope integrity. Phenotypic severity varied within the two classes of missense mutations involved in striated muscle disease, but overall, variants associated with both skeletal and cardiac muscle defects in humans lead to more severe phenotypes in our model than variants predicted to disrupt cardiac function alone. We also identified a separation of function allele, lmn-1(R204W), that exhibited normal viability and swimming behavior but had a severe nuclear migration defect. Thus, we established C. elegans avatars for striated muscle laminopathies and identified LMNA variants that offer insight into lamin mechanisms during normal development.

DOI: https://doi.org/10.1371/journal.pgen.1010895
Front Cell Dev Biol. 2023 ;11 1216726

NMJ-related diseases beyond the congenital myasthenic syndromes.

Alejandra Navarro-Martínez, Cristina Vicente-García, Jaime J Carvajal.

  Neuromuscular junctions (NMJs) are a special type of chemical synapse that transmits electrical stimuli from motor neurons (MNs) to their innervating skeletal muscle to induce a motor response. They are an ideal model for the study of synapses, given their manageable size and easy accessibility. Alterations in their morphology or function lead to neuromuscular disorders, such as the congenital myasthenic syndromes, which are caused by mutations in proteins located in the NMJ. In this review, we highlight novel potential candidate genes that may cause or modify NMJs-related pathologies in humans by exploring the phenotypes of hundreds of mouse models available in the literature. We also underscore the fact that NMJs may differ between species, muscles or even sexes. Hence the importance of choosing a good model organism for the study of NMJ-related diseases: only taking into account the specific features of the mammalian NMJ, experimental results would be efficiently translated to the clinic.

Keywords:  comparative analysis; human disease; mouse models; neuromuscular junction; synaptic transmission

DOI:  https://doi.org/10.3389/fcell.2023.1216726
Trends Endocrinol Metab. 2023 Aug 18. pii: S1043-2760(23)00149-2. [Epub ahead of print]

Cytokines and exosomal miRNAs in skeletal muscle-adipose crosstalk.

Liu Guo, Menchus Quan, Weijun Pang, Yulong Yin, Fengna Li.

  Skeletal muscle and adipose tissues (ATs) are secretory organs that release secretory factors including cytokines and exosomes. These factors mediate muscle-adipose crosstalk to regulate systemic metabolism via paracrine and endocrine pathways. Myokines and adipokines are cytokines secreted by skeletal muscle and ATs, respectively. Exosomes loaded with nucleic acids, proteins, lipid droplets, and organelles can fuse with the cytoplasm of target cells to perform regulatory functions. A major regulatory component of exosomes is miRNA. In addition, numerous novel myokines and adipokines have been identified through technological innovations. These discoveries have identified new biomarkers and sparked new insights into the molecular regulation of skeletal muscle growth and adipose deposition. The knowledge may contribute to potential diagnostic and therapeutic targets in metabolic disease.

Keywords:  adipokines; exosomal miRNAs; metabolic disease; muscle–adipose crosstalk; myokines

DOI:  https://doi.org/10.1016/j.tem.2023.07.006
Sci Adv. 2023 Aug 25. 9(34): eadi2767

ANT-dependent MPTP underlies necrotic myofiber death in muscular dystrophy.

Michael J Bround, Julian R Havens, Allen J York, Michelle A Sargent, Jason Karch, Jeffery D Molkentin.

Mitochondrial permeability transition pore (MPTP) formation contributes to ischemia-reperfusion injury in the heart and several degenerative diseases, including muscular dystrophy (MD). MD is a family of genetic disorders characterized by progressive muscle necrosis and premature death. It has been proposed that the MPTP has two molecular components, the adenine nucleotide translocase (ANT) family of proteins and an unknown component that requires the chaperone cyclophilin D (CypD) to activate. This model was examined in vivo by deleting the gene encoding ANT1 (Slc25a4) or CypD (Ppif) in a δ-sarcoglycan (Sgcd) gene-deleted mouse model of MD, revealing that dystrophic mice lacking Slc25a4 were partially protected from cell death and MD pathology. Dystrophic mice lacking both Slc25a4 and Ppif together were almost completely protected from necrotic cell death and MD disease. This study provides direct evidence that ANT1 and CypD are required MPTP components governing in vivo cell death, suggesting a previously unrecognized therapeutic approach in MD and other necrotic diseases.

DOI: https://doi.org/10.1126/sciadv.adi2767
J Mol Med (Berl). 2023 Aug 22.

The role of immunosuppressive myofibroblasts in the aging process and age-related diseases.

Antero Salminen.

  Tissue-resident fibroblasts are mesenchymal cells which control the structural integrity of the extracellular matrix (ECM). Fibroblasts possess a remarkable plasticity to allow them to adapt to the changes in the microenvironment and thus maintain tissue homeostasis. Several stresses, also those associated with the aging process, convert quiescent fibroblasts into myofibroblasts which not only display fibrogenic properties but also act as immune regulators cooperating both with tissue-resident immune cells and those immune cells recruited into affected tissues. TGF-β cytokine and reactive oxygen species (ROS) are major inducers of myofibroblast differentiation in pathological conditions either from quiescent fibroblasts or via transdifferentiation from certain other cell types, e.g., macrophages, adipocytes, pericytes, and endothelial cells. Intriguingly, TGF-β and ROS are also important signaling mediators between immunosuppressive cells, such as MDSCs, Tregs, and M2 macrophages. It seems that in pathological states, myofibroblasts are able to interact with the immunosuppressive network. There is clear evidence that a low-grade chronic inflammatory state in aging tissues is counteracted by activation of compensatory immunosuppression. Interestingly, common enhancers of the aging process, such as oxidative stress, loss of DNA integrity, and inflammatory insults, are inducers of myofibroblasts, whereas anti-aging treatments with metformin and rapamycin suppress the differentiation of myofibroblasts and thus prevent age-related tissue fibrosis. I will examine the reciprocal interactions between myofibroblasts and immunosuppressive cells within aging tissues. It seems that the differentiation of myofibroblasts with age-related harmful stresses enhances the activity of the immunosuppressive network which promotes tissue fibrosis and degeneration in elderly individuals.

Keywords:  Aging; CAF; Fibroaging; Fibrosis; Immunosenescence; Immunosuppression; Longevity

DOI:  https://doi.org/10.1007/s00109-023-02360-1