bims-moremu 2023-04-09 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2023‒04‒09
28 papers selected by
Anna Vainshtein
Craft Science Inc.

The transcription regulator ATF4 is a mediator of skeletal muscle aging.
Acute, next-generation AMPK activation initiates a disease-resistant gene expression program in dystrophic skeletal muscle.
Histone deacetylase functions and therapeutic implications for adult skeletal muscle metabolism.
Skeletal muscle aging and sarcopenia: Perspectives from mechanical studies of single permeabilized muscle fibers.
5'-CMP and 5'-UMP alleviate dexamethasone-induced muscular atrophy in C2C12 myotubes.
Tilorone increases glucose uptake in vivo and in skeletal muscle cells by enhancing Akt2/AS160 signaling and glucose transporter levels.
Editorial: Circadian rhythms and exercise in cardiometabolic health.
The dual and emerging role of physical exercise-induced TFEB activation in the protection against Alzheimer's disease.
Delayed skeletal muscle repair following inflammatory damage in simulated agent-based models of muscle regeneration.
The specific mitochondrial unfolded protein response in fast- and slow-twitch muscles of high-fat diet-induced insulin-resistant rats.
Skeletal muscle gene expression dysregulation in long-term spaceflights and aging is clock-dependent.
Single-cell RNA sequencing in skeletal muscle developmental biology.
Transplantation-based screen identifies inducers of muscle progenitor cell engraftment across vertebrate species.
Vemurafenib partially ameliorates muscle histopathology but does not improve muscle function in a mouse model of LAMA2-CMD.
Odd skipped-related 1 controls the pro-regenerative response of fibro-adipogenic progenitors.
Human skeletal muscle methylome after low carbohydrate energy balanced exercise.
IFN-γ blockade after genetic inhibition of PD-1 aggravates skeletal muscle damage and impairs skeletal muscle regeneration.
Klotho null mutation involvement in adenosine A2B receptor-related skeletal muscle degeneration.
Acute exercise increases the contact between lipid droplets and mitochondria independently of obesity and type 2 diabetes.
Senescent cells enhance newt limb regeneration by promoting muscle dedifferentiation.
Autophagy deficiency exacerbates iron overload induced reactive oxygen species production and apoptotic cell death in skeletal muscle cells.
Correction of Clcn1 alternative splicing reverses muscle fiber type transition in mice with myotonic dystrophy.
CHAC1 inactivation is effective to preserve muscle glutathione but is insufficient to protect against muscle wasting in cachexia.
Red blood cell extracellular vesicles deliver therapeutic siRNAs to skeletal muscles for treatment of cancer cachexia.
TOM complex-independent transport pathway of myoglobin into mitochondria in C2C12 myotubes.
NAD+ repletion with niacin counteracts cancer cachexia.
Skeletal muscle transcriptomics dissects the pathogenesis of Friedreich's Ataxia.
Aging: Epigenetic modifications.

Geroscience. 2023 Apr 04.

The transcription regulator ATF4 is a mediator of skeletal muscle aging.

Matthew J Miller, George R Marcotte, Nathan Basisty, Cameron Wehrfritz, Zachary C Ryan, Matthew D Strub, Andrew T McKeen, Jennifer I Stern, Karl A Nath, Blake B Rasmussen, Andrew R Judge, Birgit Schilling, Scott M Ebert, Christopher M Adams.

  Aging slowly erodes skeletal muscle strength and mass, eventually leading to profound functional deficits and muscle atrophy. The molecular mechanisms of skeletal muscle aging are not well understood. To better understand mechanisms of muscle aging, we investigated the potential role of ATF4, a transcription regulatory protein that can rapidly promote skeletal muscle atrophy in young animals deprived of adequate nutrition or activity. To test the hypothesis that ATF4 may be involved in skeletal muscle aging, we studied fed and active muscle-specific ATF4 knockout mice (ATF4 mKO mice) at 6 months of age, when wild-type mice have achieved peak muscle mass and function, and at 22 months of age, when wild-type mice have begun to manifest age-related muscle atrophy and weakness. We found that 6-month-old ATF4 mKO mice develop normally and are phenotypically indistinguishable from 6-month-old littermate control mice. However, as ATF4 mKO mice become older, they exhibit significant protection from age-related declines in strength, muscle quality, exercise capacity, and muscle mass. Furthermore, ATF4 mKO muscles are protected from some of the transcriptional changes characteristic of normal muscle aging (repression of certain anabolic mRNAs and induction of certain senescence-associated mRNAs), and ATF4 mKO muscles exhibit altered turnover of several proteins with important roles in skeletal muscle structure and metabolism. Collectively, these data suggest ATF4 as an essential mediator of skeletal muscle aging and provide new insight into a degenerative process that impairs the health and quality of life of many older adults.

Keywords:  ATF4; Aging; Protein turnover; Sarcopenia; Skeletal muscle; Skeletal muscle atrophy

DOI:  https://doi.org/10.1007/s11357-023-00772-y
FASEB J. 2023 05;37(5): e22863

Acute, next-generation AMPK activation initiates a disease-resistant gene expression program in dystrophic skeletal muscle.

Sean Y Ng, Andrew I Mikhail, Stephanie R Mattina, Alexander Manta, Ian J Diffey, Vladimir Ljubicic.

  Duchenne muscular dystrophy (DMD) is a life-limiting neuromuscular disorder characterized by muscle weakness and wasting. Previous proof-of-concept studies demonstrate that the dystrophic phenotype can be mitigated with the pharmacological stimulation of AMP-activated protein kinase (AMPK). However, first-generation AMPK activators have failed to translate from bench to bedside due to either their lack of potency or toxic, off-target effects. The identification of safe and efficacious molecules that stimulate AMPK in dystrophic muscle is of particular importance as it may broaden the therapeutic landscape for DMD patients regardless of their specific dystrophin mutation. Here, we demonstrate that a single dose of the next generation, orally-bioactive AMPK agonist MK-8722 (MK) to mdx mice evoked skeletal muscle AMPK and extensive downstream stimulation within 12 h post-treatment. Specifically, MK elicited a gene expression profile indicative of a more disease-resistant slow, oxidative phenotype including increased peroxisome proliferator-activated receptor ɣ coactivator-1⍺ activity and utrophin levels. In addition, we observed augmented autophagy signaling downstream of AMPK, as well as elevations in critical autophagic genes such as Map1lc3 and Sqstm1 subsequent to the myonuclear accumulation of the master regulator of the autophagy gene program, transcription factor EB. Lastly, we show that pharmacological AMPK stimulation normalizes the expression of myogenic regulatory factors and amends activated muscle stem cell content in mdx muscle. Our results indicate that AMPK activation via MK enhances disease-mitigating mechanisms in dystrophic muscle and prefaces further investigation on the chronic effects of novel small molecule AMPK agonists.

Keywords:  PGC-1α; autophagy; muscular dystrophy; myogenic regulatory factors; utrophin

DOI:  https://doi.org/10.1096/fj.202201846RR
Front Mol Biosci. 2023 ;10 1130183

Histone deacetylase functions and therapeutic implications for adult skeletal muscle metabolism.

Susanna Molinari, Carol Imbriano, Viviana Moresi, Alessandra Renzini, Silvia Belluti, Biliana Lozanoska-Ochser, Giuseppe Gigli, Alessia Cedola.

  Skeletal muscle is a highly adaptive organ that sustains continuous metabolic changes in response to different functional demands. Healthy skeletal muscle can adjust fuel utilization to the intensity of muscle activity, the availability of nutrients and the intrinsic characteristics of muscle fibers. This property is defined as metabolic flexibility. Importantly, impaired metabolic flexibility has been associated with, and likely contributes to the onset and progression of numerous pathologies, including sarcopenia and type 2 diabetes. Numerous studies involving genetic and pharmacological manipulations of histone deacetylases (HDACs) in vitro and in vivo have elucidated their multiple functions in regulating adult skeletal muscle metabolism and adaptation. Here, we briefly review HDAC classification and skeletal muscle metabolism in physiological conditions and upon metabolic stimuli. We then discuss HDAC functions in regulating skeletal muscle metabolism at baseline and following exercise. Finally, we give an overview of the literature regarding the activity of HDACs in skeletal muscle aging and their potential as therapeutic targets for the treatment of insulin resistance.

Keywords:  HDACs; fatty acid oxidation; glucose uptake; metabolic flexibility; neurogenic muscle atrophy; sarcopenia; sirtuins; type 2 diabetes

DOI:  https://doi.org/10.3389/fmolb.2023.1130183
J Biomech. 2023 Mar 27. pii: S0021-9290(23)00128-8. [Epub ahead of print]152 111559

Skeletal muscle aging and sarcopenia: Perspectives from mechanical studies of single permeabilized muscle fibers.

Jae-Young Lim, Walter R Frontera.

  The decline in muscle mass and strength with age is well documented and associated with weakness, decreased flexibility, vulnerability to diseases and/or injuries, and impaired functional restoration. The term sarcopenia has been used to refer to the loss of muscle mass, strength and impaired physical performance with advanced adult age and recently has become a major clinical entity in a super-aged society. To understand the pathophysiology and clinical manifestations of sarcopenia, it is essential to explore the age-related changes in the intrinsic properties of muscle fibers. Mechanical experiments with single muscle fibers have been conducted during the last 80 years and applied to human muscle research in the last 45 years as an in-vitro muscle function test. Fundamental active and passive mechanical properties of skeletal muscle can be evaluated using the isolated permeabilized (chemically skinned) single muscle fiber preparation. Changes in the intrinsic properties of older human single muscle fibers can be useful biomarkers of aging and sarcopenia. In this review, we summarize the historical development of single muscle fiber mechanical studies, the definition and diagnosis of muscle aging and sarcopenia, and age-related change of active and passive mechanical properties in single muscle fibers and discuss how these changes can be used to assess muscle aging and sarcopenia.

Keywords:  Muscle mechanics; Older adults; Skinned muscle fibers

DOI:  https://doi.org/10.1016/j.jbiomech.2023.111559
Biochem Biophys Rep. 2023 Jul;34 101460

5'-CMP and 5'-UMP alleviate dexamethasone-induced muscular atrophy in C2C12 myotubes.

Kosuke Nakagawara, Chieri Takeuchi, Kazuya Ishige.

  Atrogin-1 and muscle RING finger 1 (MuRF1) are ubiquitin ligases specifically expressed during skeletal muscle atrophy and mediate muscle protein degradation. In contrast, PGC-1α (peroxisome proliferator-activated receptor γ coactivator 1α), which is a master regulator of mitochondrial biosynthesis, protects skeletal muscle from atrophy. Pyrimidine nucleoside 5'-monophosphates, such as cytidine 5'-monophosphate (5'-CMP) and uridine 5'-monophosphate (5'-UMP), induce PGC-1α expression and promote myotube formation in mouse C2C12 cells. In this study, we determined the effect of 5'-CMP and 5'-UMP on muscular atrophy in C2C12 myotube cells. 5'-UMP decreased Atrogin-1 and MuRF1 mRNA levels that were upregulated by dexamethasone treatment. 5'-CMP and 5'-UMP ameliorated dexamethasone-mediated atrophy in C2C12 myotubes. Furthermore, the combination of 5'-CMP and 5'-UMP further alleviated dexamethasone-mediated atrophy. In addition, cytidine and uridine, the precursors of 5'-CMP and 5'-UMP, markedly ameliorated dexamethasone-mediated atrophy. Considering nucleotide metabolism and absorption, the active metabolites underlying the observed effects of 5'-CMP and 5'-UMP appear to be cytidine and uridine. Our results indicate that 5'-CMP alleviates muscle atrophy by activating PGC-1α and differentiation, and 5'-UMP alleviates muscle atrophy by suppressing the activation of the myolytic system, whereas the combined use of both enhances the muscle atrophy inhibitory effect. 5'-CMP and 5'-UMP may be an effective and safe treatment for muscular atrophy.

Keywords:  Cytidine 5′-monophosphate; E3 ubiquitin ligase; Muscle atrophy; Nutrition; PGC-1α; Uridine 5′-monophosphate

DOI:  https://doi.org/10.1016/j.bbrep.2023.101460
J Cell Physiol. 2023 Apr 03.

Tilorone increases glucose uptake in vivo and in skeletal muscle cells by enhancing Akt2/AS160 signaling and glucose transporter levels.

Zoltan M Kohler, Gyorgy Trencsenyi, Laszlo Juhasz, Agnes Zvara, Judit P Szabo, Laszlo Dux, Laszlo G Puskas, Laszlo Rovo, Aniko Keller-Pinter.

  Skeletal muscle plays a major role in whole-body glucose metabolism. Insulin resistance in skeletal muscle is characterized by decreased insulin-stimulated glucose uptake resulting from impaired intracellular trafficking and decreased glucose transporter 4 (GLUT4) expression. In this study, we illustrated that tilorone, a low-molecular-weight antiviral agent, improves glucose uptake in vitro and in vivo. Tilorone increased bone morphogenetic protein (BMP) signaling in C2C12 myoblasts, the transcription of multiple BMPs (BMP2, BMP4, BMP7, and BMP14), Smad4 expression, and the phosphorylation of BMP-mediated Smad1/5/8. The activation of Akt2/AS160 (TBC1D4) signaling, the critical regulator of GLUT4 translocation, was also increased, as well as the levels of GLUT4 and GLUT1, leading to enhanced uptake of the radioactively labeled glucose analog 18 F-fluoro-2-deoxyglucose (18 FDG). However, this excess glucose content did not result in increased ATP formation by mitochondrial respiration; both basal and ATP-linked respiration were diminished, thereby contributing to the induction of AMPK. In differentiated myotubes, AS160 phosphorylation and 18 FDG uptake also increased. Moreover, tilorone administration further increased insulin-stimulated phosphorylation of Akt2 and glucose uptake of myotubes indicating an insulin-sensitizing effect. Importantly, during in vivo experiments, the systemic administration of tilorone resulted in increased 18 FDG uptake of skeletal muscle, liver, and adipose tissue in C57BL/6 mice. Our results provide new perspectives for the treatment of type 2 diabetes, which has a limited number of treatments that regulate protein expression or translocation.

Keywords:  BMP; GLUT; insulin sensitivity; mitochondria; skeletal muscle; tilorone

DOI:  https://doi.org/10.1002/jcp.30998
Front Endocrinol (Lausanne). 2023 ;14 1180851

Editorial: Circadian rhythms and exercise in cardiometabolic health.

Milena Schönke, Karyn A Esser, Brendan M Gabriel.



Keywords:  circadian rhythms; exercise; metabolic health; physical activity; skeletal muscle

DOI:  https://doi.org/10.3389/fendo.2023.1180851
J Cell Physiol. 2023 Apr 03.

The dual and emerging role of physical exercise-induced TFEB activation in the protection against Alzheimer's disease.

Gustavo Paroschi Morais, Ivo Vieira de Sousa Neto, Bruno Brieda Marafon, Eduardo R Ropelle, Dennys E Cintra, José R Pauli, Adelino S R da Silva.

  The mechanisms of autophagy have been related to Alzheimer's disease (AD) pathogenesis by the endosomal-lysosomal system, having a critical function in forming amyloid-β (Aβ) plaques. Nevertheless, the exact mechanisms mediating disease pathogenesis remain unclear. The transcription factor EB (TFEB), a primary transcriptional autophagy regulator, improves gene expression, mediating lysosome function, autophagic flux, and autophagosome biogenesis. In this review, we present for the first time the hypothesis of how TFEB, autophagy, and mitochondrial function are interconnected in AD, providing a logical foundation for unraveling the critical role of chronic physical exercise in this process. Aerobic exercise training promotes Adiponectin Receptor 1 (AdipoR1)/AMP-activated protein kinase (AMPK)/TFEB axis activation in the brain of the AD animal model, which contributes to alleviated Aβ deposition and neuronal apoptosis while improving cognitive function. Moreover, TFEB upregulates Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and nuclear factor erythroid 2-related factor 2 (NRF-2), improving mitochondrial biogenesis and redox status. In addition, tissue contraction activates calcineurin in skeletal muscle, which induces TFEB nuclear translocation, raising the hypothesis that the same would occur in the brain. Thus, a deep and comprehensive exploration of the TFEB could provide new directions and strategies for preventing AD. We conclude that chronic exercise can be an effective TFEB activator, inducing autophagy and mitochondrial biogenesis, representing a potential nonpharmacological strategy contributing to brain health.

Keywords:  Alzheimer; TFEB; autophagy; brain; exercise

DOI:  https://doi.org/10.1002/jcp.31005
PLoS Comput Biol. 2023 Apr 06. 19(4): e1011042

Delayed skeletal muscle repair following inflammatory damage in simulated agent-based models of muscle regeneration.

Stephanie Khuu, Justin W Fernandez, Geoffrey G Handsfield.

Healthy skeletal muscle undergoes repair in response to mechanically localised strains during activities such as exercise. The ability of cells to transduce the external stimuli into a cascade of cell signalling responses is important to the process of muscle repair and regeneration. In chronic myopathies such as Duchenne muscular dystrophy and inflammatory myopathies, muscle is often subject to chronic necrosis and inflammation that perturbs tissue homeostasis and leads to non-localised, widespread damage across the tissue. Here we present an agent-based model that simulates muscle repair in response to both localised eccentric contractions similar to what would be experienced during exercise, and non-localised widespread inflammatory damage that is present in chronic disease. Computational modelling of muscle repair allows for in silico exploration of phenomena related to muscle disease. In our model, widespread inflammation led to delayed clearance of tissue damage, and delayed repair for recovery of initial fibril counts at all damage levels. Macrophage recruitment was delayed and significantly higher in widespread compared to localised damage. At higher damage percentages of 10%, widespread damage led to impaired muscle regeneration and changes in muscle geometry that represented alterations commonly observed in chronic myopathies, such as fibrosis. This computational work offers insight into the progression and aetiology of inflammatory muscle diseases, and suggests a focus on the muscle regeneration cascade in understanding the progression of muscle damage in inflammatory myopathies.

DOI: https://doi.org/10.1371/journal.pcbi.1011042
Front Endocrinol (Lausanne). 2023 ;14 1127524

The specific mitochondrial unfolded protein response in fast- and slow-twitch muscles of high-fat diet-induced insulin-resistant rats.

Can Li, Nan Li, Ziyi Zhang, Yu Song, Jialin Li, Zhe Wang, Hai Bo, Yong Zhang.

  Introduction: Skeletal muscle insulin resistance (IR) plays an important role in the pathogenesis of type 2 diabetes mellitus. Skeletal muscle is a heterogeneous tissue composed of different muscle fiber types that contribute distinctly to IR development. Glucose transport shows more protection in slow-twitch muscles than in fast-twitch muscles during IR development, while the mechanisms involved remain unclear. Therefore, we investigated the role of the mitochondrial unfolded protein response (UPRmt) in the distinct resistance of two types of muscle in IR.Methods: Male Wistar rats were divided into high-fat diet (HFD) feeding and control groups. We measured glucose transport, mitochondrial respiration, UPRmt and histone methylation modification of UPRmt-related proteins to examine the UPRmt in the slow fiber-enriched soleus (Sol) and fast fiber-enriched tibialis anterior (TA) under HFD conditions.
Results: Our results indicate that 18 weeks of HFD can cause systemic IR, while the disturbance of Glut4-dependent glucose transport only occurred in fast-twitch muscle. The expression levels of UPRmt markers, including ATF5, HSP60 and ClpP, and the UPRmt-related mitokine MOTS-c were significantly higher in slow-twitch muscle than in fast-twitch muscle under HFD conditions. Mitochondrial respiratory function is maintained only in slow-twitch muscle. Additionally, in the Sol, histone methylation at the ATF5 promoter region was significantly higher than that in the TA after HFD feeding.
Conclusion: The expression of proteins involved in glucose transport in slow-twitch muscle remains almost unaltered after HFD intervention, whereas a significant decline of these proteins was observed in fast-twitch muscle. Specific activation of the UPRmt in slow-twitch muscle, accompanied by higher mitochondrial respiratory function and MOTS-c expression, may contribute to the higher resistance to HFD in slow-twitch muscle. Notably, the different histone modifications of UPRmt regulators may underlie the specific activation of the UPRmt in different muscle types. However, future work applying genetic or pharmacological approaches should further uncover the relationship between the UPRmt and insulin resistance.

Keywords:  MOTS-c; UPRmt; epigenetic modification; insulin resistance; skeletal muscle fiber type

DOI:  https://doi.org/10.3389/fendo.2023.1127524
NPJ Microgravity. 2023 Apr 03. 9(1): 30

Skeletal muscle gene expression dysregulation in long-term spaceflights and aging is clock-dependent.

Deeksha Malhan, Müge Yalçin, Britt Schoenrock, Dieter Blottner, Angela Relógio.

The circadian clock regulates cellular and molecular processes in mammals across all tissues including skeletal muscle, one of the largest organs in the human body. Dysregulated circadian rhythms are characteristic of aging and crewed spaceflight, associated with, for example, musculoskeletal atrophy. Molecular insights into spaceflight-related alterations of circadian regulation in skeletal muscle are still missing. Here, we investigated potential functional consequences of clock disruptions on skeletal muscle using published omics datasets obtained from spaceflights and other clock-altering, external (fasting and exercise), or internal (aging) conditions on Earth. Our analysis identified alterations of the clock network and skeletal muscle-associated pathways, as a result of spaceflight duration in mice, which resembles aging-related gene expression changes observed in humans on Earth (e.g., ATF4 downregulation, associated with muscle atrophy). Furthermore, according to our results, external factors such as exercise or fasting lead to molecular changes in the core-clock network, which may compensate for the circadian disruption observed during spaceflights. Thus, maintaining circadian functioning is crucial to ameliorate unphysiological alterations and musculoskeletal atrophy reported among astronauts.

DOI: https://doi.org/10.1038/s41526-023-00273-4
Biomed Pharmacother. 2023 Mar 30. pii: S0753-3322(23)00419-5. [Epub ahead of print]162 114631

Single-cell RNA sequencing in skeletal muscle developmental biology.

Cuicui Cai, Yuan Yue, Binglin Yue.

  Skeletal muscle is the most extensive tissue in mammals, and they perform several functions; it is derived from paraxial mesodermal somites and undergoes hyperplasia and hypertrophy to form multinucleated, contractile, and functional muscle fibers. Skeletal muscle is a complex heterogeneous tissue composed of various cell types that establish communication strategies to exchange biological information; therefore, characterizing the cellular heterogeneity and transcriptional signatures of skeletal muscle is central to understanding its ontogeny's details. Studies of skeletal myogenesis have focused primarily on myogenic cells' proliferation, differentiation, migration, and fusion and ignored the intricate network of cells with specific biological functions. The rapid development of single-cell sequencing technology has recently enabled the exploration of skeletal muscle cell types and molecular events during development. This review summarizes the progress in single-cell RNA sequencing and its applications in skeletal myogenesis, which will provide insights into skeletal muscle pathophysiology.

Keywords:  Cellular heterogeneity; Cell–cell communication; Pseudotime patterns; ScRNA-seq; Skeletal muscle

DOI:  https://doi.org/10.1016/j.biopha.2023.114631
Cell Rep. 2023 Apr 04. pii: S2211-1247(23)00376-5. [Epub ahead of print]42(4): 112365

Transplantation-based screen identifies inducers of muscle progenitor cell engraftment across vertebrate species.

Sahar Tavakoli, Vivian Garcia, Eric Gähwiler, Isaac Adatto, Apoorva Rangan, Kathleen A Messemer, Sara Ashrafi Kakhki, Song Yang, Victoria S Chan, Margot E Manning, Haleh Fotowat, Yi Zhou, Amy J Wagers, Leonard I Zon.

  Stem cell transplantation presents a potentially curative strategy for genetic disorders of skeletal muscle, but this approach is limited by the deleterious effects of cell expansion in vitro and consequent poor engraftment efficiency. In an effort to overcome this limitation, we sought to identify molecular signals that enhance the myogenic activity of cultured muscle progenitors. Here, we report the development and application of a cross-species small-molecule screening platform employing zebrafish and mice, which enables rapid, direct evaluation of the effects of chemical compounds on the engraftment of transplanted muscle precursor cells. Using this system, we screened a library of bioactive lipids to discriminate those that could increase myogenic engraftment in vivo in zebrafish and mice. This effort identified two lipids, lysophosphatidic acid and niflumic acid, both linked to the activation of intracellular calcium-ion flux, which showed conserved, dose-dependent, and synergistic effects in promoting muscle engraftment across these vertebrate species.

Keywords:  CP: Developmental biology; cell therapy; engraftment; lysophosphatidic acid; muscular dystrophy; niflumic acid; satellite cell

DOI:  https://doi.org/10.1016/j.celrep.2023.112365
Dis Model Mech. 2023 Apr 06. pii: dmm.049916. [Epub ahead of print]

Vemurafenib partially ameliorates muscle histopathology but does not improve muscle function in a mouse model of LAMA2-CMD.

Ariany Oliveira-Santos, Marisela Dagda, Jennifer Wittmann, Robert Smalley, Dean J Burkin.

  Laminin-α2-related Congenital Muscular Dystrophy (LAMA2-CMD) is a neuromuscular disease affecting around 1-9/1,000,000 children. LAMA2-CMD is caused by mutations in the LAMA2 gene resulting in the loss of laminin-211/221 heterotrimers in skeletal muscle. LAMA2-CMD patients exhibit severe hypotonia and progressive muscle weakness. Currently, there is no effective treatment for LAMA2-CMD and patients die prematurely. The loss of laminin-α2 results in muscle degeneration, defective muscle repair, and dysregulation of multiple signaling pathways. Signaling pathways that regulate muscle metabolism, survival, and fibrosis have been shown to be dysregulated in LAMA2-CMD. Since vemurafenib is an FDA-approved serine/threonine kinase inhibitor, we investigated whether vemurafenib could restore some of the serine/threonine kinase-related signaling pathways and prevent disease progression in the dyW-/- mouse model of LAMA2-CMD. Our results show vemurafenib reduced muscle fibrosis, increased myofiber size, and reduced the percentage of fibers with centrally located nuclei in dyW-/- mice hindlimbs. These studies show treatment with vemurafenib restored the TGF-β/SMAD3 and mTORC1/p70S6K signaling pathways in skeletal muscle. Together our results indicate vemurafenib partially improves histopathology but does not improve muscle function in a mouse model of LAMA2-CMD.

Keywords:  Congenital Muscular Dystrophy; LAMA2-CMD; Laminin-α2; MDC1A; TGF-β; Vemurafenib

DOI:  https://doi.org/10.1242/dmm.049916
NPJ Regen Med. 2023 Apr 05. 8(1): 19

Odd skipped-related 1 controls the pro-regenerative response of fibro-adipogenic progenitors.

Georgios Kotsaris, Taimoor H Qazi, Christian H Bucher, Hafsa Zahid, Sophie Pöhle-Kronawitter, Vladimir Ugorets, William Jarassier, Stefan Börno, Bernd Timmermann, Claudia Giesecke-Thiel, Aris N Economides, Fabien Le Grand, Pedro Vallecillo-García, Petra Knaus, Sven Geissler, Sigmar Stricker.

Skeletal muscle regeneration requires the coordinated interplay of diverse tissue-resident- and infiltrating cells. Fibro-adipogenic progenitors (FAPs) are an interstitial cell population that provides a beneficial microenvironment for muscle stem cells (MuSCs) during muscle regeneration. Here we show that the transcription factor Osr1 is essential for FAPs to communicate with MuSCs and infiltrating macrophages, thus coordinating muscle regeneration. Conditional inactivation of Osr1 impaired muscle regeneration with reduced myofiber growth and formation of excessive fibrotic tissue with reduced stiffness. Osr1-deficient FAPs acquired a fibrogenic identity with altered matrix secretion and cytokine expression resulting in impaired MuSC viability, expansion and differentiation. Immune cell profiling suggested a novel role for Osr1-FAPs in macrophage polarization. In vitro analysis suggested that increased TGFβ signaling and altered matrix deposition by Osr1-deficient FAPs actively suppressed regenerative myogenesis. In conclusion, we show that Osr1 is central to FAP function orchestrating key regenerative events such as inflammation, matrix secretion and myogenesis.

DOI: https://doi.org/10.1038/s41536-023-00291-6
Am J Physiol Endocrinol Metab. 2023 Apr 05.

Human skeletal muscle methylome after low carbohydrate energy balanced exercise.

Piotr P Gorski, Daniel C Turner, Juma Iraki, James P Morton, Adam P Sharples, José L Areta.

  We aimed to investigate the human skeletal muscle (SkM) DNA methylome after exercise in low carbohydrate (CHO) energy balance (with high fat) compared with exercise in low-CHO energy deficit (with low fat) conditions. The objective to identify novel epigenetically regulated genes and pathways associated with 'train-low sleep-low' paradigms. The sleep-low conditions included 9 males that cycled to deplete muscle glycogen while reaching a set energy expenditure. Post-exercise, low-CHO meals (protein-matched) completely replaced (using high-fat) or only partially replaced (low-fat) the energy expended. The following morning resting baseline biopsies were taken and the participants then undertook 75 minutes of cycling exercise, with skeletal muscle biopsies collected 30 minutes and 3.5 hours post exercise. Discovery of genome-wide DNA methylation was undertaken using Illumina EPIC arrays and targeted gene expression analysis was conducted by RT-qPCR. At baseline participants under energy balance (high fat) demonstrated a predominantly hypermethylated (60%) profile across the genome compared to energy deficit-low fat conditions. However, post exercise performed in energy balance (with high fat) elicited a more prominent hypomethylation signature 30 minutes post-exercise in gene regulatory regions important for transcription (CpG islands within promoter regions) compared with exercise in energy deficit (with low fat) conditions. Such hypomethylation was enriched within pathways related to: IL6-JAK-STAT signalling, metabolic processes, p53 / cell cycle and oxidative / fatty acid metabolism. Hypomethylation within the promoter regions of genes: HDAC2, MECR, IGF2 and c13orf16 were associated with significant increases in gene expression in the post-exercise period in energy balance compared with energy deficit. Furthermore, histone deacetylase, HDAC11 was oppositely regulated at the gene expression level compared with HDAC2, where HDAC11 was hypomethylated yet increased in energy deficit compared with energy balance conditions. Overall, we identify some novel epigenetically regulated genes associated with train-low sleep-low paradigms.

Keywords:  HDAC; exercise; low CHO; methylome

DOI:  https://doi.org/10.1152/ajpendo.00029.2023
Cell Mol Biol Lett. 2023 Apr 04. 28(1): 27

IFN-γ blockade after genetic inhibition of PD-1 aggravates skeletal muscle damage and impairs skeletal muscle regeneration.

Shuzhao Zhuang, Aaron Russell, Yifan Guo, Yingying Xu, Weihua Xiao.

  BACKGROUND: Innate immune responses play essential roles in skeletal muscle recovery after injury. Programmed cell death protein 1 (PD-1) contributes to skeletal muscle regeneration by promoting macrophage proinflammatory to anti-inflammatory phenotype transition. Interferon (IFN)-γ induces proinflammatory macrophages that appear to hinder myogenesis in vitro. Therefore, we tested the hypothesis that blocking IFN-γ in PD-1 knockout mice may dampen inflammation and promote skeletal muscle regeneration via regulating the macrophage phenotype and neutrophils.METHODS: Anti-IFN-γ antibody was administered in PD-1 knockout mice, and cardiotoxin (CTX) injection was performed to induce acute skeletal muscle injury. Hematoxylin and eosin (HE) staining was used to view morphological changes of injured and regenerated skeletal muscle. Masson's trichrome staining was used to assess the degree of fibrosis. Gene expressions of proinflammatory and anti-inflammatory factors, fibrosis-related factors, and myogenic regulator factors were determined by real-time polymerase chain reaction (PCR). Changes in macrophage phenotype were examined by western blot and real-time PCR. Immunofluorescence was used to detect the accumulation of proinflammatory macrophages, anti-inflammatory macrophages, and neutrophils.
RESULTS: IFN-γ blockade in PD-1 knockout mice did not alleviate skeletal muscle damage or improve regeneration following acute cardiotoxin-induced injury. Instead, it exacerbated skeletal muscle inflammation and fibrosis, and impaired regeneration via inhibiting macrophage accumulation, blocking macrophage proinflammatory to anti-inflammatory transition, and enhancing infiltration of neutrophils.
CONCLUSION: IFN-γ is crucial for efficient skeletal muscle regeneration in the absence of PD-1.

Keywords:  IFN-γ; Macrophage; Neutrophil; PD-1; Skeletal muscle

DOI:  https://doi.org/10.1186/s11658-023-00439-8
Am J Pathol. 2023 Apr 05. pii: S0002-9440(23)00120-7. [Epub ahead of print]

Klotho null mutation involvement in adenosine A2B receptor-related skeletal muscle degeneration.

Hung-Liang Pai, Pei-Yu Wu, De-Ming Chen, Zhi-Jia Chen, Yi-Sun Yang, Han-Hsin Chang, David Pei-Cheng Lin.

  Klotho is known for its age-suppressing function and has been implicated in sarcopenia pathology. It has recently been proposed that the adenosine A2B receptor plays a crucial role in skeletal muscle energy expenditure. However, the association between Klotho and A2B remains elusive. In this study, Klotho knockout mice aged 10 weeks and wild-type mice aged 10 and 64 weeks were used for comparison in indicators of sarcopenia (n=6 for each group). Polymerase chain reaction was performed to confirm the mice genotypes. Skeletal muscle sections were analyzed using hematoxylin and eosin staining as well as immunohistochemistry staining. The results indicate that the skeletal muscle cross-sectional area was significantly reduced in Klotho knockout mice and wild-type mice aged 64 weeks when compared to wild-type mice aged 10 weeks, with a decreased percentage of type IIa and IIb myofibers. Likely impaired regenerative capacity, as reflected by the reduction of Pax7- and MyoD- positive cells, was also observed in Klotho knockout mice and aged wild-type mice. 8-hydroxy-2-deoxyguanosine expression was enhanced with Klotho knockout and aging, indicating higher oxidative stress. Adenosine A2B signaling was impaired with a lower expression of the A2B receptor and the cAMP-response element binding protein in Klotho knockout and aged mice. The present study provides the novel finding that sarcopenia involves adenosine signaling under the influence of Klotho knockout.

Keywords:  Klotho; adenosine A2B receptor; aging; sarcopenia

DOI:  https://doi.org/10.1016/j.ajpath.2023.03.007
J Physiol. 2023 Apr 03.

Acute exercise increases the contact between lipid droplets and mitochondria independently of obesity and type 2 diabetes.

Martin Eisemann de Almeida, Niels Ørtenblad, Maria Houborg Petersen, Ann-Sofie Nybøle Schjerning, Emil Kleis Wentorf, Kurt Jensen, Kurt Højlund, Joachim Nielsen.

  Intramuscular lipid droplets (LDs) and mitochondria are essential organelles in cellular communication and metabolism, supporting local energy demands during muscle contractions. While insulin resistance impacts cellular functions and systems within the skeletal muscle, it remains unclear whether the interaction of LDs and mitochondria is affected by exercise and the role of obesity and type 2 diabetes. By employing transmission electron microscopy (TEM), we aimed to investigate the effects of 1-hour ergometry cycling on LD morphology, subcellular distribution, and mitochondrial contact in skeletal muscle fibres of patients with type 2 diabetes and glucose-tolerant lean and obese controls, matched for equal exercise intensities. Exercise did not change LD volumetric density, numerical density, profile size, or subcellular distribution. However, evaluated as the magnitude of inter-organelle contact, exercise increased the contact between LDs and mitochondria with no differences between the three groups. This effect was most profound in the subsarcolemmal space of type 1 muscle fibres, and here the absolute contact length increased on average from ∼275 to ∼420 nm. Furthermore, the absolute contact length before exercise (ranging from ∼140 to ∼430 nm) was positively associated with the fat oxidation rate during exercise. In conclusion, we showed that acute exercise did not mediate changes in the LD volume fractions, numbers, or size but increased the contact between LDs and mitochondria, irrespective of obesity or type 2 diabetes. These data suggest that the increased LD-mitochondrial contact with exercise is not disturbed in obesity or type 2 diabetes. KEY POINTS: Type 2 diabetes is associated with altered interactivity between lipid droplets (LDs) and mitochondria in the skeletal muscle. Physical contact between the surface of LDs and the surrounding mitochondrial network is considered favorable for fat oxidation. We show that one hour of acute exercise increases the length of contact between LDs and mitochondria, irrespective of obesity or type 2 diabetes. This contact length between LDs and mitochondria is not associated with a net decrease in the LD volumetric density after the acute exercise. However, it correlates with the fat oxidation rate during exercise. Our data establish that exercise mediates contact between LDs and the mitochondrial network and that this effect is not impaired in individuals with type 2 diabetes or obesity. Abstract figure legend One hour of acute exercise increases the absolute and relative measured contact between lipid droplets and mitochondria, irrespective of obesity or type 2 diabetes. Increases in lipid droplet-mitochondrial contact were not associated with changes in lipid droplet content (volume fractions) nor volumetric composition (number or size). The figure was designed using BioRender and resources from Flaticon.com. This article is protected by copyright. All rights reserved.

Keywords:  LD-mitochondria contact; acute exercise; lipid droplets; skeletal muscle; transmission electron microscopy; type 2 diabetes

DOI:  https://doi.org/10.1113/JP284386
Aging Cell. 2023 Apr 06. e13826

Senescent cells enhance newt limb regeneration by promoting muscle dedifferentiation.

Hannah E Walters, Konstantin E Troyanovskiy, Alwin M Graf, Maximina H Yun.

  Salamanders are able to regenerate their entire limbs throughout lifespan, through a process that involves significant modulation of cellular plasticity. Limb regeneration is accompanied by the endogenous induction of cellular senescence, a state of irreversible cell cycle arrest associated with profound non-cell-autonomous consequences. While traditionally associated with detrimental physiological effects, here, we show that senescent cells can enhance newt limb regeneration. Through a lineage tracing approach, we demonstrate that exogenously derived senescent cells promote dedifferentiation of mature muscle tissue to generate regenerative progenitors. In a paradigm of newt myotube dedifferentiation, we uncover that senescent cells promote myotube cell cycle re-entry and reversal of muscle identity via secreted factors. Transcriptomic profiling and loss of function approaches identify the FGF-ERK signalling axis as a critical mediator of senescence-induced muscle dedifferentiation. While chronic senescence constrains muscle regeneration in physiological mammalian contexts, we thus highlight a beneficial role for cellular senescence as an important modulator of dedifferentiation, a key mechanism for regeneration of complex structures.

Keywords:  ERK; FGF; WNT; cellular senescence; dedifferentiation; regeneration; reprogramming; salamander

DOI:  https://doi.org/10.1111/acel.13826
Cell Death Dis. 2023 Apr 07. 14(4): 252

Autophagy deficiency exacerbates iron overload induced reactive oxygen species production and apoptotic cell death in skeletal muscle cells.

Hye Kyoung Sung, Mayoorey Murugathasan, Ali A Abdul-Sater, Gary Sweeney.

Iron overload is associated with various pathological changes which contribute to metabolic syndrome, many of which have been proposed to occur via damaging tissue through an excessive amount of reactive oxygen species (ROS) production. In this study, we established a model of iron overload in L6 skeletal muscle cells and observed that iron enhanced cytochrome c release from depolarized mitochondria, assayed by immunofluorescent colocalization of cytochrome c with Tom20 and the use of JC-1, respectively. This subsequently elevated apoptosis, determined via use of a caspase-3/7 activatable fluorescent probe and western blotting for cleaved caspase-3. Using CellROX deep red and mBBr, we observed that iron increased generation of reactive oxygen species (ROS), and that pretreatment with the superoxide dismutase mimetic MnTBAP reduced ROS production and attenuated iron-induced intrinsic apoptosis and cell death. Furthermore, using MitoSox Red we observed that iron enhanced mROS and the mitochondria-targeted anti-oxidant SKQ1 reduced iron-induced ROS generation and cell death. Western blotting for LC3-II and P62 levels as well as immunofluorescent detection of autophagy flux with LC3B and P62 co-localization indicated that iron acutely (2-8 h) activated and later (12-24 h) attenuated autophagic flux. We used autophagy-deficient cell models generated by overexpressing a dominant-negative Atg5 mutant or CRISPR-mediated ATG7 knock out to test the functional significance of autophagy and observed that autophagy-deficiency exacerbated iron-induced ROS production and apoptosis. In conclusion, our study showed that high iron levels promoted ROS production, blunted the self-protective autophagy response and led to cell death in L6 skeletal muscle cells.

DOI: https://doi.org/10.1038/s41419-022-05484-3
Nat Commun. 2023 Apr 07. 14(1): 1956

Correction of Clcn1 alternative splicing reverses muscle fiber type transition in mice with myotonic dystrophy.

Ningyan Hu, Eunjoo Kim, Layal Antoury, Thurman M Wheeler.

In myotonic dystrophy type 1 (DM1), deregulated alternative splicing of the muscle chloride channel Clcn1 causes myotonia, a delayed relaxation of muscles due to repetitive action potentials. The degree of weakness in adult DM1 is associated with increased frequency of oxidative muscle fibers. However, the mechanism for glycolytic-to-oxidative fiber type transition in DM1 and its relationship to myotonia are uncertain. Here we cross two mouse models of DM1 to create a double homozygous model that features progressive functional impairment, severe myotonia, and near absence of type 2B glycolytic fibers. Intramuscular injection of an antisense oligonucleotide for targeted skipping of Clcn1 exon 7a corrects Clcn1 alternative splicing, increases glycolytic 2B levels to ≥ 40% frequency, reduces muscle injury, and improves fiber hypertrophy relative to treatment with a control oligo. Our results demonstrate that fiber type transitions in DM1 result from myotonia and are reversible, and support the development of Clcn1-targeting therapies for DM1.

DOI: https://doi.org/10.1038/s41467-023-37619-1
PLoS One. 2023 ;18(4): e0283806

CHAC1 inactivation is effective to preserve muscle glutathione but is insufficient to protect against muscle wasting in cachexia.

Junjie Li, Mingjian Lu, Youngwook Ahn, Kevin Cao, Cynthia A Pinkus, John C Stansfield, Zhidan Wu, Bei B Zhang.

Muscle wasting is one of the main characteristics of cachexia associated with cancer and other chronic diseases and is often exacerbated by antineoplastic agents. Increased oxidative stress is associated with muscle wasting, along with depletion of glutathione, the most abundant endogenous antioxidant. Therefore, boosting endogenous glutathione has been proposed as a therapeutic strategy to prevent muscle wasting. Here, we tested this hypothesis by inactivating CHAC1, an intracellular glutathione degradation enzyme. We found CHAC1 expression is increased under multiple muscle wasting conditions in animal models, including fasting, cancer cachexia, and chemotherapy. The elevation of muscle Chac1 expression is associated with reduced glutathione level. CHAC1 inhibition via CRSPR/Cas9 mediated knock-in of an enzyme inactivating mutation demonstrates a novel strategy to preserve muscle glutathione levels under wasting conditions but fails to prevent muscle wasting in mice. These results suggest that preserving intracellular glutathione level alone may not be sufficient to prevent cancer or chemotherapy induced muscle wasting.

DOI: https://doi.org/10.1371/journal.pone.0283806
Mol Ther. 2023 Apr 03. pii: S1525-0016(23)00196-X. [Epub ahead of print]

Red blood cell extracellular vesicles deliver therapeutic siRNAs to skeletal muscles for treatment of cancer cachexia.

Boya Peng, Yuqi Yang, Zhiyuan Wu, Rachel Tan, Thach Tuan Pham, Eric Yew Meng Yeo, Marco Pirisinu, Migara Kavishka Jayasinghe, Tin Chanh Pham, Kun Liang, Ng Shyh-Chang, Minh Tn Le.

Cancer cachexia is a multifactorial syndrome characterized by a significant loss of skeletal muscle, that negatively affects the quality of life. Inhibition of myostatin (Mstn), a negative regulator of skeletal muscle growth and differentiation, has been proven to preserve muscle mass in muscle atrophy diseases, including cachexia. However, myostatin inhibitors have repeatedly failed clinical trials because of modest therapeutic effects and side effects due to the poor efficiency and toxicity of existing delivery methods. Here, we describe a novel method for delivering Mstn siRNA to skeletal muscles using red blood cell extracellular vesicles (RBCEVs) in a cancer cachectic mouse model. Our data show that RBCEVs are taken up by myofibers via intramuscular administration. Repeated intramuscular administrations with RBCEVs allowed the delivery of siRNAs, thereby inhibiting Mstn, increasing muscle growth and preventing cachexia in cancer-bearing mice. We observed the same therapeutic effects when delivering siRNAs against malonyl-CoA decarboxylase, an enzyme driving dysfunctional fatty acid metabolism in skeletal muscles during cancer cachexia. We demonstrate that intramuscular siRNA delivery by RBCEVs is safe and non-inflammatory. Hence, this method is useful to reduce the therapeutic dose of siRNAs, to avoid toxicity and off-target effects caused by systemic administration of naked siRNAs at high doses.

DOI: https://doi.org/10.1016/j.ymthe.2023.03.036
Physiol Rep. 2023 Apr;11(7): e15632

TOM complex-independent transport pathway of myoglobin into mitochondria in C2C12 myotubes.

Rikuhide Koma, Tsubasa Shibaguchi, Yuhei Araiso, Tatsuya Yamada, Yudai Nonaka, Thomas Jue, Kazumi Masuda.

  Recently, we found that myoglobin (Mb) localizes in both the cytosol and mitochondrial intermembrane space in rodent skeletal muscle. Most proteins of the intermembrane space pass through the outer mitochondrial membrane via the translocase of the outer membrane (TOM) complex. However, whether the TOM complex imports Mb remains unknown. The purpose of this study was to investigate the involvement of the TOM complex in Mb import into the mitochondria. A proteinase K protection assay of mitochondria from C2C12 myotubes confirmed that Mb integrated into the mitochondria. An immunoprecipitation assay verified the interaction of Mb and TOM complex receptors (Tom20, Tom70) in isolated mitochondria. The assay showed a clear interaction of Mb with Tom20 and Tom70. A knockdown experiment using siRNA for TOM complex receptors (Tom20, Tom70) and TOM complex channel (Tom40) did not alter the amount of Mb expression in the mitochondrial fraction. These results suggested that Mb does not necessarily require the TOM complex for mitochondrial import of Mb. Although the physiological role of Mb interactions with TOM complex receptors remains unclear, further studies are needed to clarify how Mb enters the mitochondria independently of the TOM complex.

Keywords:  Tom20; Tom40; Tom70; skeletal muscle

DOI:  https://doi.org/10.14814/phy2.15632
Nat Commun. 2023 Apr 03. 14(1): 1849

NAD+ repletion with niacin counteracts cancer cachexia.

Marc Beltrà, Noora Pöllänen, Claudia Fornelli, Kialiina Tonttila, Myriam Y Hsu, Sandra Zampieri, Lucia Moletta, Samantha Corrà, Paolo E Porporato, Riikka Kivelä, Carlo Viscomi, Marco Sandri, Juha J Hulmi, Roberta Sartori, Eija Pirinen, Fabio Penna.

Cachexia is a debilitating wasting syndrome and highly prevalent comorbidity in cancer patients. It manifests especially with energy and mitochondrial metabolism aberrations that promote tissue wasting. We recently identified nicotinamide adenine dinucleotide (NAD+) loss to associate with muscle mitochondrial dysfunction in cancer hosts. In this study we confirm that depletion of NAD+ and downregulation of Nrk2, an NAD+ biosynthetic enzyme, are common features of severe cachexia in different mouse models. Testing NAD+ repletion therapy in cachectic mice reveals that NAD+ precursor, vitamin B3 niacin, efficiently corrects tissue NAD+ levels, improves mitochondrial metabolism and ameliorates cancer- and chemotherapy-induced cachexia. In a clinical setting, we show that muscle NRK2 is downregulated in cancer patients. The low expression of NRK2 correlates with metabolic abnormalities underscoring the significance of NAD+ in the pathophysiology of human cancer cachexia. Overall, our results propose NAD+ metabolism as a therapy target for cachectic cancer patients.

DOI: https://doi.org/10.1038/s41467-023-37595-6
Hum Mol Genet. 2023 Apr 07. pii: ddad051. [Epub ahead of print]

Skeletal muscle transcriptomics dissects the pathogenesis of Friedreich's Ataxia.

Elisabetta Indelicato, Alexander Kirchmair, Matthias Amprosi, Stephan Steixner, Wolfgang Nachbauer, Andreas Eigentler, Nico Wahl, Galina Apostolova, Anne Krogsdam, Rainer Schneider, Julia Wanschitz, Zlatko Trajanoski, Sylvia Boesch.

OBJECTIVE: In Friedreich ́s Ataxia (FRDA), the most affected tissues are not accessible to sampling and available transcriptomic findings originate from blood-derived cells and animal models. Herein, we aimed at dissecting for the first time the pathophysiology of FRDA by means of RNA-sequencing in an affected tissue sampled in vivo.METHODS: Skeletal muscle biopsies were collected from seven FRDA patients before and after treatment with recombinant human Erythropoietin (rhuEPO) within a clinical trial. Total RNA extraction, 3'-mRNA library preparation and sequencing were performed according to standard procedures. We tested for differential gene expression with DESeq2 and performed gene set enrichment analysis with respect to control subjects.
RESULTS: FRDA transcriptomes showed 1873 genes differentially expressed from controls. Two main signatures emerged: 1) a global downregulation of the mitochondrial transcriptome as well as of ribosome/translational machinery and 2) an upregulation of genes related to transcription and chromatin regulation, especially of repressor terms. Downregulation of the mitochondrial transcriptome was more profound than previously shown in other cellular systems. Furthermore, we observed in FRDA patients a marked upregulation of leptin, the master regulator of energy homeostasis. RhuEPO treatment further enhanced leptin expression.
INTERPRETATION: Our findings reflect a double hit in the pathophysiology of FRDA: a transcriptional/translational issue, and a profound mitochondrial failure downstream. Leptin upregulation in the skeletal muscle in FRDA may represent a compensatory mechanism of mitochondrial dysfunction, which is amenable to pharmacological boosting. Skeletal muscle transcriptomics is a valuable biomarker to monitor therapeutic interventions in FRDA.

DOI: https://doi.org/10.1093/hmg/ddad051
Prog Mol Biol Transl Sci. 2023 ;pii: S1877-1173(23)00036-4. [Epub ahead of print]197 171-209

Aging: Epigenetic modifications.

Sarita Mishra, Mahima Raval, Akanksha Singh Kachhawaha, Budhi Sagar Tiwari, Anand Krishna Tiwari.

  Aging is one of the most complex and irreversible health conditions characterized by continuous decline in physical/mental activities that eventually poses an increased risk of several diseases and ultimately death. These conditions cannot be ignored by anyone but there are evidences that suggest that exercise, healthy diet and good routines may delay the Aging process significantly. Several studies have demonstrated that Epigenetics plays a key role in Aging and Aging-associated diseases through methylation of DNA, histone modification and non-coding RNA (ncRNA). Comprehension and relevant alterations in these epigenetic modifications can lead to new therapeutic avenues of age-delaying contrivances. These processes affect gene transcription, DNA replication and DNA repair, comprehending epigenetics as a key factor in understanding Aging and developing new avenues for delaying Aging, clinical advancements in ameliorating aging-related diseases and rejuvenating health. In the present article, we have described and advocated the epigenetic role in Aging and associated diseases.

Keywords:  Age-related diseases; Aging; DNA methylation; Epigenetics; Histone modification; Neurodegenerative diseases; Non-coding RNA

DOI:  https://doi.org/10.1016/bs.pmbts.2023.02.002