bims-moremu 2023-08-13 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2023–08–13
29 papers selected by
Anna Vainshtein, Craft Science Inc.

Inflammation o'clock: interactions of circadian rhythms with inflammation-induced skeletal muscle atrophy.
The Role of Supporting Cell Populations in Satellite Cell Mediated Muscle Repair.
Skeletal muscle structure, physiology, and function.
Amniotic Membrane-Derived Stromal Cells Release Extracellular Vesicles That Favor Regeneration of Dystrophic Skeletal Muscles.
A combination of metformin and galantamine exhibits synergistic benefits in the treatment of sarcopenia.
Inhibition of skeletal muscle Lands cycle ameliorates weakness induced by physical inactivity.
Rab44 deficiency accelerates recovery from muscle damage by regulating mTORC1 signaling and transport of fusogenic regulators.
Rab44 negatively regulates myoblast differentiation by controlling fusogenic protein transport and mTORC1 signaling.
Transgene-free direct conversion of murine fibroblasts into functional muscle stem cells.
Decoding the Gene Regulatory Network of Muscle Stem Cells in Mouse Duchenne Muscular Dystrophy: Revelations from Single-Nuclei RNA Sequencing Analysis.
BMP9 functions as a negative regulator in the myogenic differentiation of primary mouse myoblasts.
Cellular and Genomic Features of Muscle Differentiation from Isogenic Fibroblasts and Myoblasts.
Thyroid Hormone Regulates the Lipid Content of Muscle Fibers, Thus Affecting Physical Exercise Performance.
Synergistically Acting on Myostatin and Agrin Pathways Increases Neuromuscular Junction Stability and Endurance in Old Mice.
AAV1.NT-3 gene therapy in the SOD1KO mouse model of accelerated sarcopenia.
DNM2 levels normalization improves muscle phenotypes of a novel mouse model for moderate centronuclear myopathy.
Sarcopenia: Loss of mighty armor against frailty and aging.
MiR-222-3p suppresses C2C12 myoblast proliferation and differentiation via the inhibition of IRS-1/PI3K/Akt pathway.
Differential Effects of Endurance Exercise on Musculoskeletal and Hematopoietic Modulation in Old Mice.
Reciprocal Regulation of Peroxisome Biogenesis and Myogenic Factors Is Critical for Myogenesis.
Adipocyte Rnf20 ablation increases the fast-twitch fibers of skeletal muscle via lysophosphatidylcholine 16:0.
Phosphorylation of AMPKα at Ser485/491 Is Dependent on Muscle Contraction and Not Muscle-Specific IGF-I Overexpression.
Clock genes regulate skeletal muscle energy metabolism through NAMPT/NAD+/SIRT1 following heavy-load exercise.
Functional role of skeletal muscle-derived interleukin-6 and its effects on lipid metabolism.
Estrogen-Related Receptor Gamma Gene Therapy Promotes Therapeutic Angiogenesis and Muscle Recovery in Preclinical Model of PAD.
Skeletal muscle endurance declines with impaired mitochondrial respiration and inadequate supply of acetyl-CoA during muscle fatigue in 5/6 nephrectomized rats.
Automated in-depth fiber and nuclei typing in cross-sectional muscle images can pave the way to a better understanding of skeletal muscle diseases.
Stanniocalcin-2 inhibits skeletal muscle growth and is upregulated in functional overload-induced hypertrophy.
The secretome atlas of two mouse models of progeria.

J Physiol. 2023 Aug 10.

Inflammation o'clock: interactions of circadian rhythms with inflammation-induced skeletal muscle atrophy.

Francielly Morena da Silva, Karyn A Esser, Kevin A Murach, Nicholas P Greene.

  Circadian rhythms are ∼24 h cycles evident in behaviour, physiology and metabolism. The molecular mechanism directing circadian rhythms is the circadian clock, which is composed of an interactive network of transcription-translation feedback loops. The core clock genes include Bmal1, Clock, Rev-erbα/β, Per and Cry. In addition to keeping time, the core clock regulates a daily programme of gene expression that is important for overall cell homeostasis. The circadian clock mechanism is present in all cells, including skeletal muscle fibres, and disruption of the muscle clock is associated with changes in muscle phenotype and function. Skeletal muscle atrophy is largely associated with a lower quality of life, frailty and reduced lifespan. Physiological and genetic modification of the core clock mechanism yields immune dysfunction, alters inflammatory factor expression and secretion and is associated with skeletal muscle atrophy in multiple conditions, such as ageing and cancer cachexia. Here, we summarize the possible interplay between the circadian clock modulation of immune cells, systemic inflammatory status and skeletal muscle atrophy in chronic inflammatory conditions. Although there is a clear disruption of circadian clocks in various models of atrophy, the mechanism behind such alterations remains unknown. Understanding the modulatory potential of muscle and immune circadian clocks in inflammation and skeletal muscle health is essential for the development of therapeutic strategies to protect skeletal muscle mass and function of patients with chronic inflammation.

Keywords:  ageing; cancer cachexia; immune system; muscle clock; skeletal muscle; type 2 diabetes mellitus

DOI:  https://doi.org/10.1113/JP284808
Cells. 2023 Jul 30. pii: 1968. [Epub ahead of print]12(15):

The Role of Supporting Cell Populations in Satellite Cell Mediated Muscle Repair.

Amanda L Johnson, Michael Kamal, Gianni Parise.

  Skeletal muscle has a high capacity to repair and remodel in response to damage, largely through the action of resident muscle stem cells, termed satellite cells. Satellite cells are required for the proper repair of skeletal muscle through a process known as myogenesis. Recent investigations have observed relationships between satellite cells and other cell types and structures within the muscle microenvironment. These findings suggest that the crosstalk between inflammatory cells, fibrogenic cells, bone-marrow-derived cells, satellite cells, and the vasculature is essential for the restoration of muscle homeostasis. This review will discuss the influence of the cells and structures within the muscle microenvironment on satellite cell function and muscle repair.

Keywords:  fibrotic cells; inflammation; microenvironment; myogenesis; regeneration; satellite cell; skeletal muscle; supporting cells; vasculature

DOI:  https://doi.org/10.3390/cells12151968
Handb Clin Neurol. 2023 ;pii: B978-0-323-98818-6.00013-3. [Epub ahead of print]195 3-16

Skeletal muscle structure, physiology, and function.

Susan V Brooks, Steve D Guzman, Lloyd P Ruiz.

  Contractions of skeletal muscles provide the stability and power for all body movements. Consequently, any impairment in skeletal muscle function results in some degree of instability or immobility. Factors that influence skeletal muscle structure and function are therefore of great interest scientifically and clinically. Injury, neuromuscular disease, and old age are among the factors that commonly contribute to impairments in skeletal muscle function. The goal of this chapter is to summarize the fundamentals of skeletal muscle structure and function to provide foundational knowledge for this Handbook volume. We examine the molecular interactions that provide the basis for the generation of force and movement, discuss mechanisms of the regulation of contraction at the level of myofibers, and introduce concepts of the activation and control of muscle function in vivo. Where appropriate, the chapter updates the emerging science that will increase understanding of muscle function.

Keywords:  Contraction; Cross-bridge cycle; Motor unit; Myosin; Neuromuscular junction; Review

DOI:  https://doi.org/10.1016/B978-0-323-98818-6.00013-3
Int J Mol Sci. 2023 Aug 05. pii: 12457. [Epub ahead of print]24(15):

Amniotic Membrane-Derived Stromal Cells Release Extracellular Vesicles That Favor Regeneration of Dystrophic Skeletal Muscles.

Martina Sandonà, Federica Esposito, Anna Cargnoni, Antonietta Silini, Pietro Romele, Ornella Parolini, Valentina Saccone.

  Duchenne muscular dystrophy (DMD) is a muscle disease caused by mutations in the dystrophin gene characterized by myofiber fragility and progressive muscle degeneration. The genetic defect results in a reduced number of self-renewing muscle stem cells (MuSCs) and an impairment of their activation and differentiation, which lead to the exhaustion of skeletal muscle regeneration potential and muscle replacement by fibrotic and fatty tissue. In this study, we focused on an unexplored strategy to improve MuSC function and to preserve their niche based on the regenerative properties of mesenchymal stromal cells from the amniotic membrane (hAMSCs), that are multipotent cells recognized to have a role in tissue repair in different disease models. We demonstrate that the hAMSC secretome (CM hAMSC) and extracellular vesicles (EVs) isolated thereof directly stimulate the in vitro proliferation and differentiation of human myoblasts and mouse MuSC from dystrophic muscles. Furthermore, we demonstrate that hAMSC secreted factors modulate the muscle stem cell niche in dystrophic-mdx-mice. Interestingly, local injection of EV hAMSC in mdx muscles correlated with an increase in the number of activated Pax7+/Ki67+ MuSCs and in new fiber formation. EV hAMSCs also significantly reduced muscle collagen deposition, thus counteracting fibrosis and MuSCs exhaustion, two hallmarks of DMD. Herein for the first time we demonstrate that CM hAMSC and EVs derived thereof promote muscle regeneration by supporting proliferation and differentiation of resident muscle stem cells. These results pave the way for the development of a novel treatment to counteract DMD progression by reducing fibrosis and enhancing myogenesis in dystrophic muscles.

Keywords:  Duchenne muscular dystrophy; amnion; extracellular vesicles; mesenchymal stem/stromal cells; skeletal muscle regeneration

DOI:  https://doi.org/10.3390/ijms241512457
JCI Insight. 2023 08 08. pii: e168787. [Epub ahead of print]8(15):

A combination of metformin and galantamine exhibits synergistic benefits in the treatment of sarcopenia.

Caterina Tezze, Francesco Ivan Amendolagine, Leonardo Nogara, Martina Baraldo, Stefano Ciciliot, Diletta Arcidiacono, Alice Zaramella, Giulio Masiero, Giulia Ferrarese, Stefano Realdon, Bert Blaauw, Giel Detienne, Ann Tj Beliën, Marco Sandri, Evi M Mercken.

  Age-associated sarcopenia, characterized by a progressive loss in muscle mass and strength, is the largest cause of frailty and disability in the elderly worldwide. Current treatments involve nonpharmacological guidelines that few subjects can abide by, highlighting the need for effective drugs. Preclinical models were employed to test the benefits of RJx-01, a combination drug composed of metformin and galantamine, on sarcopenia. In worms, RJx-01 treatment improved lifespan, locomotion, pharyngeal pumping, and muscle fiber organization. The synergistic effects of RJx-01 were recapitulated in a transgenic mouse model that displays an exacerbated aging phenotype (Opa1-/-). In these mice, RJx-01 ameliorated physical performance, muscle mass and force, neuromuscular junction stability, and systemic inflammation. RJx-01 also improved physical performance and muscle strength in 22-month-old WT mice and also improved skeletal muscle ultrastructure, mitochondrial morphology, autophagy, lysosomal function, and satellite cell content. Denervation and myofiber damage were decreased in RJx-01-treated animals compared with controls. RJx-01 improved muscle quality rather than quantity, indicating that the improvement in quality underlies the beneficial effects of the combination drug. The studies herein indicate synergistic beneficial effects of RJx-01 in the treatment of sarcopenia and support the pursuit of RJx-01 in a human clinical trial as a therapeutic intervention for sarcopenia.

Keywords:  Aging; Drug therapy; Muscle Biology; Skeletal muscle

DOI:  https://doi.org/10.1172/jci.insight.168787
bioRxiv. 2023 Jul 28. pii: 2023.07.25.550576. [Epub ahead of print]

Inhibition of skeletal muscle Lands cycle ameliorates weakness induced by physical inactivity.

Justin L Shahtout, Hiroaki Eshima, Patrick J Ferrara, J Alan Maschek, James E Cox, Micah J Drummond, Katsuhiko Funai.

Background: Lipid hydroperoxides (LOOH) have been implicated in skeletal muscle atrophy with age and disuse. Lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme of Lands cycle, conjugates a polyunsaturated fatty acyl chain to a lysophospholipid (PUFA-PL) molecule, providing substrates for LOOH propagation. Previous studies suggest that inhibition of Lands cycle is an effective strategy to suppress LOOH. Mice with skeletal muscle-specific tamoxifen-inducible knockout of LPCAT3 (LPCAT3-MKO) were utilized to determine if muscle-specific attenuation of LOOH may alleviate muscle atrophy and weakness with disuse.
Methods: LPCAT3-MKO and control mice underwent 7 days of sham or hindlimb unloading (HU model) to study muscle mass and force-generating capacity. LOOH was assessed by quantifying 4-hydroxynonenal (4-HNE)-conjugated peptides. Quantitative PCR and lipid mass spectrometry were used to validate LPCAT3 deletion.
Results: 7 days of HU was sufficient to induce muscle atrophy and weakness concomitant to an increase in 4-HNE. Deletion of LPCAT3 reversed HU-induced increase in muscle 4HNE. No difference was found in body mass, body composition, or caloric intake between genotypes. The soleus (SOL) and plantaris (PLANT) muscles of the LPCAT3-MKO mice were partially protected from atrophy compared to controls, concomitant to attenuated decrease in cross-sectional areas in type I and IIa fibers. Strikingly, SOL and extensor digitorum longus (EDL) were robustly protected from HU-induced reduction in force-generating capacity in the LPCAT3-MKO mice compared to controls.
Conclusion: Our findings demonstrate that attenuation of muscle LOOH is sufficient to restore skeletal muscle function, in particular a protection from reduction in muscle specific force. Thus, muscle LOOH contributes to atrophy and weakness induced by HU in mice.

DOI: https://doi.org/10.1101/2023.07.25.550576
J Cell Physiol. 2023 Aug 10.

Rab44 deficiency accelerates recovery from muscle damage by regulating mTORC1 signaling and transport of fusogenic regulators.

Shun Oyakawa, Yu Yamaguchi, Tomoko Kadowaki, Eiko Sakai, Mayuko Noguromi, Ayuko Tanimoto, Yusuke Ono, Hiroshi Murata, Takayuki Tsukuba.

  The skeletal muscle is a tissue that shows remarkable plasticity to adapt to various stimuli. The development and regeneration of skeletal muscles are regulated by numerous molecules. Among these, we focused on Rab44, a large Rab GTPase, that has been recently identified in immune cells and osteoclasts. Recently, bioinformatics data has revealed that Rab44 is upregulated during the myogenic differentiation of myoblasts into myotubes in C2C12 cells. Thus, Rab44 may be involved in myogenesis. Here, we have investigated the effects of Rab44 deficiency on the development and regeneration of skeletal muscle in Rab44 knockout (KO) mice. Although KO mice exhibited body and muscle weights similar to those of wild-type (WT) mice, the histochemical analysis showed that the myofiber cross-sectional area (CSA) of KO mice was significantly smaller than that of WT mice. Importantly, the results of muscle regeneration experiments using cardiotoxin revealed that the CSA of KO mice was significantly larger than that of WT mice, suggesting that Rab44 deficiency promotes muscle regeneration. Consistent with the in vivo results, in vitro experiments indicated that satellite cells derived from KO mice displayed enhanced proliferation and differentiation. Mechanistically, KO satellite cells exhibited an increased mechanistic target of rapamycin complex 1 (mTORC1) signaling compared to WT cells. Additionally, enhanced cell surface transport of myomaker and myomixer, which are essential membrane proteins for myoblast fusion, was observed in KO satellite cells compared to WT cells. Therefore, Rab44 deficiency enhances muscle regeneration by modulating the mTORC1 signaling pathway and transport of fusogenic regulators.

Keywords:  Rab GTPase; Rab44; myofiber cross-sectional area; satellite cells; skeletal muscle

DOI:  https://doi.org/10.1002/jcp.31082
J Cell Biochem. 2023 Aug 11.

Rab44 negatively regulates myoblast differentiation by controlling fusogenic protein transport and mTORC1 signaling.

Ayuko Tanimoto, Yu Yamaguchi, Tomoko Kadowaki, Eiko Sakai, Shun Oyakawa, Yusuke Ono, Noriaki Yoshida, Takayuki Tsukuba.

  Skeletal muscle is composed of multinucleated myotubes formed by the fusion of mononucleated myoblasts. Skeletal muscle differentiation, termed as myogenesis, have been investigated using the mouse skeletal myoblast cell line C2C12. It has been reported that several "small" Rab proteins, major membrane-trafficking regulators, possibly regulate membrane protein transport in C2C12 cells; however, the role of Rab proteins in myogenesis remains unexplored. Rab44, a member of "large" Rab GTPases, has recently been identified as a negative regulator of osteoclast differentiation. In this study, using C2C12 cells, we found that Rab44 expression was upregulated during myoblast differentiation into myotubes. Knockdown of Rab44 enhanced myoblast differentiation and myotube formation. Consistent with these results, Rab44 knockdown in myoblasts increased expression levels of several myogenic marker genes. Rab44 knockdown increased the surface accumulation of myomaker and myomixer, two fusogenic proteins required for multinucleation, implying enhanced cell fusion. Conversely, Rab44 overexpression inhibited myoblast differentiation and tube formation, accompanied by decreased expression of some myogenic markers. Furthermore, Rab44 was found to be predominantly localized in lysosomes, and Rab44 overexpression altered the number and size of lysosomes. Considering the underlying molecular mechanism, Rab44 overexpression impaired the signaling pathway of the mechanistic target of rapamycin complex1 (mTORC1) in C2C12 cells. Namely, phosphorylation levels of mTORC1 and downstream mTORC1 substrates, such as S6 and P70-S6K, were notably lower in Rab44 overexpressing cells than those in control cells. These results indicate that Rab44 negatively regulates myoblast differentiation into myotubes by controlling fusogenic protein transport and mTORC1 signaling.

Keywords:  C2C12 cells; Rab GTPase; Rab44; myoblast differentiation; myogenesis

DOI:  https://doi.org/10.1002/jcb.30457
NPJ Regen Med. 2023 Aug 08. 8(1): 43

Transgene-free direct conversion of murine fibroblasts into functional muscle stem cells.

Xhem Qabrati, Inseon Kim, Adhideb Ghosh, Nicola Bundschuh, Falko Noé, Andrew S Palmer, Ori Bar-Nur.

Transcription factor-based cellular reprogramming provides an attractive approach to produce desired cell types for regenerative medicine purposes. Such cellular conversions are widely dependent on viral vectors to efficiently deliver and express defined factors in target cells. However, use of viral vectors is associated with unfavorable genomic integrations that can trigger deleterious molecular consequences, rendering this method a potential impediment to clinical applications. Here, we report on a highly efficient transgene-free approach to directly convert mouse fibroblasts into induced myogenic progenitor cells (iMPCs) by overexpression of synthetic MyoD-mRNA in concert with an enhanced small molecule cocktail. First, we performed a candidate compound screen and identified two molecules that enhance fibroblast reprogramming into iMPCs by suppression of the JNK and JAK/STAT pathways. Simultaneously, we developed an optimal transfection protocol to transiently overexpress synthetic MyoD-mRNA in fibroblasts. Combining these two techniques enabled robust and rapid reprogramming of fibroblasts into Pax7 positive iMPCs in as little as 10 days. Nascent transgene-free iMPCs proliferated extensively in vitro, expressed a suite of myogenic stem cell markers, and could differentiate into highly multinucleated and contractile myotubes. Furthermore, using global and single-cell transcriptome assays, we delineated gene expression changes associated with JNK and JAK/STAT pathway inhibition during reprogramming, and identified in iMPCs a Pax7+ stem cell subpopulation resembling satellite cells. Last, transgene-free iMPCs robustly engrafted skeletal muscles of a Duchenne muscular dystrophy mouse model, restoring dystrophin expression in hundreds of myofibers. In summary, this study reports on an improved and clinically safer approach to convert fibroblasts into myogenic stem cells that can efficiently contribute to muscle regeneration in vivo.

DOI: https://doi.org/10.1038/s41536-023-00317-z
Int J Mol Sci. 2023 Aug 05. pii: 12463. [Epub ahead of print]24(15):

Decoding the Gene Regulatory Network of Muscle Stem Cells in Mouse Duchenne Muscular Dystrophy: Revelations from Single-Nuclei RNA Sequencing Analysis.

Yan Shen, Il-Man Kim, Yaoliang Tang.

  The gene dystrophin is responsible for Duchenne muscular dystrophy (DMD), a grave X-linked recessive ailment that results in respiratory and cardiac failure. As the expression of dystrophin in muscle stem cells (MuSCs) is a topic of debate, there exists a limited understanding of its influence on the gene network of MuSCs. This study was conducted with the objective of investigating the effects of dystrophin on the regulatory network of genes in MuSCs. To comprehend the function of dystrophin in MuSCs from DMD, this investigation employed single-nuclei RNA sequencing (snRNA-seq) to appraise the transcriptomic profile of MuSCs obtained from the skeletal muscles of dystrophin mutant mice (DMDmut) and wild-type control mice. The study revealed that the dystrophin mutation caused the disruption of several long non-coding RNAs (lncRNAs), leading to the inhibition of MEG3 and NEAT1 and the upregulation of GM48099, GM19951, and GM15564. The Gene Ontology (GO) enrichment analysis of biological processes (BP) indicated that the dystrophin mutation activated the cell adhesion pathway in MuSCs, inhibited the circulatory system process, and affected the regulation of binding. The study also revealed that the metabolic pathway activity of MuSCs was altered. The metabolic activities of oxidative phosphorylation (OXPHOS) and glycolysis were elevated in MuSCs from DMDmut. In summary, this research offers novel insights into the disrupted gene regulatory program in MuSCs due to dystrophin mutation at the single-cell level.

Keywords:  Duchenne muscular dystrophy; cell metabolism; dystrophin; single-nuclear RNA sequencing (snRNA-seq); skeletal muscle-derived muscle stem cells

DOI:  https://doi.org/10.3390/ijms241512463
Biosci Biotechnol Biochem. 2023 Aug 08. pii: zbad104. [Epub ahead of print]

BMP9 functions as a negative regulator in the myogenic differentiation of primary mouse myoblasts.

Xiya Lu, Liang Li, Nanhui Wu, Wenjuan Chen, Sheng Hong, Mingyuan Xu, Yangfeng Ding, Yunlu Gao.

  BMP9, a member of the TGF-β superfamily, reveals the great translational promise for it has been shown to have the strong effect of osteogenic activity in vitro and in vivo. However, the implantation of certain BMPs (bone morphogenetic proteins) into muscular tissues induces ectopic bone formation. BMPs induce osteoblastic differentiation in skeletal muscle, suggesting that myogenic stem cells, such as myoblasts, are the potential progenitors of osteoblasts during heterotopic bone differentiation. Here we investigate the role of BMP9 during primary mouse myoblasts differentiation. We found BMP9 enhanced cell proliferation and reduced myogenic differentiation of primary mouse myoblasts. In addition, adenovirus-mediated overexpression of BMP9 delayed muscle regeneration after BaCl2-induced injury. ALK1 knockdown reversed the inhibition of myoblast differentiation induced by BMP9. Our data indicate that BMP9 inhibits myogenic differentiation in primary mouse myoblasts and delays skeletal muscle regeneration after injury.

Keywords:  BMP9; myoblast; myogenic differentiation; skeletal muscle regeneration

DOI:  https://doi.org/10.1093/bbb/zbad104
Cells. 2023 Aug 03. pii: 1995. [Epub ahead of print]12(15):

Cellular and Genomic Features of Muscle Differentiation from Isogenic Fibroblasts and Myoblasts.

Louise Benarroch, Julia Madsen-Østerbye, Mohamed Abdelhalim, Kamel Mamchaoui, Jessica Ohana, Anne Bigot, Vincent Mouly, Gisèle Bonne, Anne T Bertrand, Philippe Collas.

  The ability to recapitulate muscle differentiation in vitro enables the exploration of mechanisms underlying myogenesis and muscle diseases. However, obtaining myoblasts from patients with neuromuscular diseases or from healthy subjects poses ethical and procedural challenges that limit such investigations. An alternative consists in converting skin fibroblasts into myogenic cells by forcing the expression of the myogenic regulator MYOD. Here, we directly compared cellular phenotype, transcriptome, and nuclear lamina-associated domains (LADs) in myo-converted human fibroblasts and myotubes differentiated from myoblasts. We used isogenic cells from a 16-year-old donor, ruling out, for the first time to our knowledge, genetic factors as a source of variations between the two myogenic models. We show that myo-conversion of fibroblasts upregulates genes controlling myogenic pathways leading to multinucleated cells expressing muscle cell markers. However, myotubes are more advanced in myogenesis than myo-converted fibroblasts at the phenotypic and transcriptomic levels. While most LADs are shared between the two cell types, each also displays unique domains of lamin A/C interactions. Furthermore, myotube-specific LADs are more gene-rich and less heterochromatic than shared LADs or LADs unique to myo-converted fibroblasts, and they uniquely sequester developmental genes. Thus, myo-converted fibroblasts and myotubes retain cell type-specific features of radial and functional genome organization. Our results favor a view of myo-converted fibroblasts as a practical model to investigate the phenotypic and genomic properties of muscle cell differentiation in normal and pathological contexts, but also highlight current limitations in using fibroblasts as a source of myogenic cells.

Keywords:  chromatin; fibroblast; lamina-associated domain; myogenesis; myogenic conversion; myotube; transcriptome

DOI:  https://doi.org/10.3390/cells12151995
Int J Mol Sci. 2023 Jul 28. pii: 12074. [Epub ahead of print]24(15):

Thyroid Hormone Regulates the Lipid Content of Muscle Fibers, Thus Affecting Physical Exercise Performance.

Caterina Miro, Annarita Nappi, Serena Sagliocchi, Emery Di Cicco, Melania Murolo, Sepehr Torabinejad, Lucia Acampora, Arianna Pastore, Paolo Luciano, Evelina La Civita, Daniela Terracciano, Mariano Stornaiuolo, Monica Dentice, Annunziata Gaetana Cicatiello.

  Skeletal muscle (SkM) lipid composition plays an essential role in physiological muscle maintenance and exercise performance. Thyroid hormones (THs) regulate muscle formation and fuel energy utilization by modulating carbohydrates and lipid and protein metabolism. The best-known effects of THs in SkM include the promotion of mitochondrial biogenesis, the fiber-type switch from oxidative to glycolytic fibers, and enhanced angiogenesis. To assess the role of THs on the lipidic composition of SkM fibers, we performed lipidomic analyses of SkM cells and tissues, glucose tolerance experiments, and exercise performance tests. Our data demonstrated that TH treatment induces remodeling of the lipid profile and changes the proportion of fatty acids in SkM. In brief, THs significantly reduced the ratio of stearic/oleic acid in the muscle similar to what is induced by physical activity. The increased proportion of unsaturated fatty acids was linked to an improvement in insulin sensitivity and endurance exercise. These findings point to THs as critical endocrine factors affecting exercise performance and indicate that homeostatic maintenance of TH signals, by improving cell permeability and receptor stability at the cell membrane, is crucial for muscle physiology.

Keywords:  exercise; fatty acids; lipids; skeletal muscle; thyroid hormone

DOI:  https://doi.org/10.3390/ijms241512074
Aging Dis. 2023 Aug 02.

Synergistically Acting on Myostatin and Agrin Pathways Increases Neuromuscular Junction Stability and Endurance in Old Mice.

Roberta Schellino, Marina Boido, Jan W Vrijbloed, Ruggero G Fariello, Alessandro Vercelli.

Sarcopenia is the primary cause of impaired motor performance in the elderly. The current prevailing approach to counteract such condition is increasing the muscle mass through inhibition of the myostatin system: however, this strategy only moderately improves muscular strength, not being able to sustain the innervation of the hypertrophic muscle per se, leading to a progressive worsening of motor performances. Thus, we proposed the administration of ActR-Fc-nLG3, a protein that combines the soluble activin receptor, a strong myostatin inhibitor, with the C-terminal agrin nLG3 domain. This compound has the potential of reinforcing neuro-muscular stability to the hypertrophic muscle. We previously demonstrated an enhancement of motor endurance and ACh receptor aggregation in young mice after ActR-Fc-nLG3 administration. Now we extended these observations by demonstrating that also in aged (2 years-old) mice, long-term administration of ActR-Fc-nLG3 increases in a sustained way both motor endurance and muscle strength, compared with ActRFc, a myostatin inhibitor, alone. Histological data demonstrate that the administration of this biological improves neuromuscular stability and fiber innervation maintenance, preventing muscle fiber atrophy and inducing only moderate hypertrophy. Moreover, at the postsynaptic site we observe an increased folding in the soleplate, a likely anatomical substrate for improved neurotransmission efficiency in the NMJ, that may lead to enhanced motor endurance. We suggest that ActR-Fc-nLG3 may become a valid option for treating sarcopenia and possibly other disorders of striatal muscles.

DOI: https://doi.org/10.14336/AD.2023.0713-1
J Cachexia Sarcopenia Muscle. 2023 Aug 08.

AAV1.NT-3 gene therapy in the SOD1KO mouse model of accelerated sarcopenia.

Lingying Tong, Burcak Ozes, Kyle Moss, Morgan Myers, Alicia Ridgley, Zarife Sahenk.

   BACKGROUND: Sarcopenia, an age-related loss of muscle mass, is a critical factor that affects the health of the older adults. The SOD1KO mouse is deficient of Cu/Zn superoxide dismutase, used as an accelerated aging model. We previously showed that NT-3 improves muscle fibre size by activating the mTOR pathway, suggesting a potential for attenuating age-related muscle loss. This study assessed the therapeutic efficacy of AAV1.NT-3 in this accelerated aging model.
METHODS: Twelve 6 months old SOD1KO mice were injected intramuscularly with a 1 × 1011 vg dose of AAV1.tMCK.NT-3, and 13 age-matched SOD1KO mice were used as controls. The treatment effect was evaluated using treadmill, rotarod and gait analyses as well as histological studies assessing changes in muscle fibre, and fibre type switch, in tibialis anterior, gastrocnemius, and triceps muscles, and myelin thickness by calculating G ratio in sciatic and tibial nerves. Molecular studies involved qPCR experiments to analyse the expression levels of mitochondrial and glycolysis markers and western blot experiments to assess the activity of mTORC1 pathway.
RESULTS: Treatment resulted in a 36% (154.9 vs. 114.1; P < 0.0001) and 76% increase (154.3 vs. 87.6; P < 0.0001) in meters ran, with treadmill test at 3 and 6 months post gene delivery. In addition, the treated cohort stayed on rotarod 30% (52.7 s vs. 40.4 s; P = 0.0095) and 54% (50.4 s vs. 32.7 s; P = 0.0007) longer, compared with untreated counterparts at 3 and 6 months post injection. Gait analysis, performed at endpoint, showed that stride width was normalized to wild type levels (29.3 mm) by an 11% decrease, compared with untreated cohort (28.6 mm vs. 32.1 mm; P = 0.0014). Compared with wild-type, SOD1KO mice showed 9.4% and 11.4% fibre size decrease in tibialis anterior and gastrocnemius muscles, respectively, which were normalized to wild type levels with treatment. Fibre diameter increase was observed prominently in FTG fibre type. G ratio analysis revealed hypomyelination in the tibial (0.721) and sciatic (0.676) nerves of SOD1KO model, which was reversed in the NT-3 cohort (0.646 and 0.634, respectively). Fibre size increase correlated with the increase in the p-S6 and p-4E-BP1 levels, and in the glycolysis markers in tibialis anterior. Alterations observed in the mitochondrial markers were not rescued with treatment. Overall, response to NT-3 was subdued in gastrocnemius muscle.
CONCLUSIONS: This study shows that AAV1.NT-3 gene therapy protected SOD1KO mouse from accelerated aging effects functionally and histologically. We further confirmed that NT-3 has potential to activate the mTOR and glycolytic pathways in muscle.

Keywords:  Aging; Gene therapy; NT-3; SOD1KO; Sarcopenia; mTORC

DOI:  https://doi.org/10.1002/jcsm.13303
Mol Ther Nucleic Acids. 2023 Sep 12. 33 321-334

DNM2 levels normalization improves muscle phenotypes of a novel mouse model for moderate centronuclear myopathy.

Juliana de Carvalho Neves, Foteini Moschovaki-Filippidou, Johann Böhm, Jocelyn Laporte.

  Dynamin 2 (DNM2) is a ubiquitously expressed GTPase regulating membrane trafficking and cytoskeleton dynamics. Heterozygous dominant mutations in DNM2 cause centronuclear myopathy (CNM), associated with muscle weakness and atrophy and histopathological hallmarks as fiber hypotrophy and organelles mis-position. Different severities range from the severe neonatal onset form to the moderate form with childhood onset and to the mild adult onset form. No therapy is approved for CNM. Here we aimed to validate and rescue a mouse model for the moderate form of DNM2-CNM harboring the common DNM2 R369W missense mutation. Dnm2R369W/+ mice presented with increased DNM2 protein level in muscle and moderate CNM-like phenotypes with force deficit, muscle and fiber hypotrophy, impaired mTOR signaling, and progressive mitochondria and nuclei mis-position with age. Molecular analyses revealed a fiber type switch toward oxidative metabolism correlating with decreased force and alteration of mitophagy markers paralleling mitochondria structural defects. Normalization of DNM2 levels through intramuscular injection of AAV-shDnm2 targeting Dnm2 mRNA significantly improved histopathology and muscle and myofiber hypotrophy. These results showed that the Dnm2R369W/+ mouse is a faithful model for the moderate form of DNM2-CNM and revealed that DNM2 normalization after a short 4-week treatment is sufficient to improve the CNM phenotypes.

Keywords:  MT: Oligonucleotides: Therapies and Applications; RNA interference; adeno-associated virus; centronuclear myopathy; congenital myopathy; dynamin; gene therapy; mitophagy; mouse model; myotubular myopathy

DOI:  https://doi.org/10.1016/j.omtn.2023.07.003
J Diabetes Investig. 2023 Aug 08.

Sarcopenia: Loss of mighty armor against frailty and aging.

Takayoshi Sasako, Kohjiro Ueki.

The goal of diabetes management is to achieve longevity and quality of life equivalent to those of people without diabetes, and for that, it is now deemed important to pay close attention not only to diabetic vascular complications but also to diabetic comorbidities, as is recommended by the Japan Diabetes Society. In this editorial, we focus on sarcopenia as an important diabetic comorbidity which is an aging-related phenomenon in skeletal muscle. Taking our recent report on a sarcopenia mouse model and other accumulated evidence into account, we propose the existence of a skeletal muscle-centered inter-tissue network that regulates frailty and systemic aging. Sarcopenia is deemed to be a state in which skeletal muscle serving as a protective mighty armor against frailty and systemic aging is lost, and it is vitally important to establish how to recover it and keep it in good shape, so that the goal of diabetes management can be achieved.

DOI: https://doi.org/10.1111/jdi.14067
J Cell Biochem. 2023 Aug 10.

MiR-222-3p suppresses C2C12 myoblast proliferation and differentiation via the inhibition of IRS-1/PI3K/Akt pathway.

Xiaofang Wei, Juan Wang, Yaqin Sun, Tong Zhao, Xiaomao Luo, Jiayin Lu, Wei Hou, Xiuju Yu, Linli Xue, Yi Yan, Haidong Wang.

  Numerous studies have revealed the profound impact of microRNAs on regulating skeletal muscle development and regeneration. However, the biological function and regulation mechanism of miR-222-3p in skeletal muscle remains largely unknown. In this study, miR-222-3p was found to be abundantly expressed in the impaired skeletal muscles, indicating that it might have function in the development and regeneration process of the skeletal muscle. MiR-222-3p overexpression impeded C2C12 myoblast proliferation and myogenic differentiation, whereas inhibition of miR-222-3p got the opposite results. The dual-luciferase reporter assay showed that insulin receptor substrate-1 (IRS-1) was the target gene of miR-222-3p. We next found that knockdown of IRS-1 could obviously suppress C2C12 myoblast proliferation and differentiation. Additionally, miR-222-3p-induced repression of myoblast proliferation and differentiation was verified to be associated with a decrease in phosphoinositide 3-kinase (PI3K)-Akt signaling. Overall, we demonstrated that miR-222-3p inhibited C2C12 cells myogenesis via IRS-1/PI3K/Akt pathway. Therefore, miR-222-3p may be used as a therapeutic target for alleviating muscle loss caused by inherited and nonhereditary diseases.

Keywords:  C2C12 cells; IRS-1/PI3K/Akt pathway; differentiation; miR-222-3p; myogenesis; proliferation

DOI:  https://doi.org/10.1002/jcb.30453
Aging Dis. 2023 Jul 17.

Differential Effects of Endurance Exercise on Musculoskeletal and Hematopoietic Modulation in Old Mice.

Zilin Wang, Hyun-Jaung Sim, Wenduo Liu, Jae Cheol Kim, Jeong-Chae Lee, Sung-Ho Kook, Sang Hyun Kim.

One of the most important strategies for successful aging is exercise. However, the effect of exercise can differ among individuals, even with exercise of the same type and intensity. Therefore, this study aims to confirm whether endurance training (ETR) has the same health-promoting effects on the musculoskeletal and hematopoietic systems regardless of age. Ten weeks of ETR improved endurance exercise capacity, with increased skeletal muscle mitochondrial enzymes in both young and old mice. In addition, age-related deterioration of muscle fiber size and bone microstructure was improved. The expression levels of myostatin, muscle RING-finger protein-1, and muscle atrophy F-box in skeletal muscle and peroxisome proliferator-activated receptor-γ in the femur increased with age but decreased after ETR. ETR differentially modulated hematopoietic stem cells (HSCs) depending on age; ETR induced HSC quiescence in young mice but caused HSC senescence in old mice. ETR has differential effects on modulation of the musculoskeletal and hematopoietic systems in old mice. In other words, endurance exercise is a double-edged sword for successful aging, and great effort is required to establish exercise strategies for healthy aging.

DOI: https://doi.org/10.14336/AD.2023.0713
Int J Mol Sci. 2023 Jul 31. pii: 12262. [Epub ahead of print]24(15):

Reciprocal Regulation of Peroxisome Biogenesis and Myogenic Factors Is Critical for Myogenesis.

Chuan-Che Wu, Wei-Cheng Chen, Wen-Po Hsiao, Kai-Fan Huang, Yi-Shiuan Liao, Huang-Bin Lin, Yi-Ju Wu, Chien-Han Kao, Shen-Liang Chen.

  Mitochondria (MITO) and peroxisomes (PEXO) are the major organelles involved in the oxidative metabolism of cells, but detailed examination of their dynamics and functional adaptations during skeletal muscle (SKM) development (myogenesis) is still lacking. In this study, we found that during myogenesis, MITO DNA, ROS level, and redox ratio increased in myotubes, but the membrane potential (Δψm) and ATP content reduced, implying that the MITO efficiency might reduce during myogenesis. The PEXO number and density both increased during myogenesis, which probably resulted from the accumulation and increased biogenesis of PEXO. The expression of PEXO biogenesis factors was induced during myogenesis in vitro and in utero, and their promoters were also activated by MyoD. Knockdown of the biogenesis factors Pex3 repressed not only the PEXO density and functions but also the levels of MITO genes and functions, suggesting a close coupling between PEXO biogenesis and MITO functions. Surprisingly, Pex3 knockdown by the CRISPRi system repressed myogenic differentiation, indicating critical involvement of PEXO biogenesis in myogenesis. Taken together, these observations suggest that the dynamics and functions of both MITO and PEXO are coupled with each other and with the metabolic changes that occur during myogenesis, and these metabolic couplings are critical to myogenesis.

Keywords:  Pex3; catalase; mitochondria; muscle; myogenesis; peroxisome

DOI:  https://doi.org/10.3390/ijms241512262
Cell Mol Life Sci. 2023 Aug 09. 80(9): 243

Adipocyte Rnf20 ablation increases the fast-twitch fibers of skeletal muscle via lysophosphatidylcholine 16:0.

Ying Zhao, Chuanhe Chen, Jianfei Pan, Sin Man Lam, Guanghou Shui, Shulin Yang, Tianwen Wu, Ning Yang, Cong Tao, Jianguo Zhao, Yanfang Wang.

  Both adipose tissue and skeletal muscle are highly dynamic tissues and interact at the metabolic and hormonal levels in response to internal and external stress, and they coordinate in maintaining whole-body metabolic homeostasis. In our previous study, we revealed that adipocyte-specific Rnf20 knockout mice (ASKO mice) exhibited lower fat mass but higher lean mass, providing a good model for investigating the adipose-muscle crosstalk and exploring the effect of the adipocyte Rnf20 gene on the physiology and metabolism of skeletal muscle. Here, we confirmed that ASKO mice exhibited the significantly increased body weight and gastrocnemius muscle weight. Fiber-type switching in the soleus muscle of ASKO mice was observed, as evidenced by the increased number of fast-twitch fibers and decreased number of slow-twitch fibers. Serum metabolites with significant alteration in abundance were identified by metabolomic analysis and the elevated lysophosphatidylcholine 16:0 [LysoPC (16:0)] was observed in ASKO mice. In addition, lipidome analysis of gonadal white adipose tissue revealed a significant increase in LysoPCs and LysoPC (16:0) in ASKO mice. Furthermore, knockdown of Rnf20 gene in 3T3-L1 cells significantly increased the secretion of LysoPC, suggesting that LysoPC might be a critical metabolite in the adipose-muscle crosstalk of ASKO mice. Furthermore, in vitro study demonstrated that LysoPC (16:0) could induce the expression of fast-twitch muscle fibers related genes in differentiated C2C12 cells, indicating its potential role in adipose-muscle crosstalk. Taken together, these findings not only expand our understanding of the biological functions of Rnf20 gene in systemic lipid metabolism, but also provide insight into adipose tissue dysfunction-induced physiological alterations in skeletal muscle.

Keywords:  Adipose-muscle crosstalk; Fiber-type switching; LysoPC (16:0); RNF20

DOI:  https://doi.org/10.1007/s00018-023-04896-4
Int J Mol Sci. 2023 Jul 26. pii: 11950. [Epub ahead of print]24(15):

Phosphorylation of AMPKα at Ser485/491 Is Dependent on Muscle Contraction and Not Muscle-Specific IGF-I Overexpression.

Chih-Hsuan Chou, Elisabeth R Barton.

  Glucose is an important fuel for highly active skeletal muscles. Increased adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratios during repetitive contractions trigger AMP-activated protein kinase (AMPK), indicated by phosphorylation of AMPKαThr172, which promotes glucose uptake to support heightened energy needs, but it also suppresses anabolic processes. Inhibition of AMPK can occur by protein kinase B (AKT)-mediated phosphorylation of AMPKαSer485/491, releasing its brake on growth. The influence of insulin-like growth factor I (IGF-I) on glucose uptake and its interplay with AMPK activation is not well understood. Thus, the goal of this study was to determine if increased muscle IGF-I altered AMPKα phosphorylation and activity during muscle contraction. Adult male mice harboring the rat Igf1a cDNA regulated by the fast myosin light chain promoter (mIgf1+/+) and wildtype littermates (WT) were used in the study. mIgf1+/+ mice had enhanced glucose tolerance and insulin-stimulated glucose uptake, but similar exercise capacity. Fatiguing stimulations of extensor digitorum longus (EDL) muscles resulted in upregulated AMPKα phosphorylation at both Thr172 and Ser485/491 in WT and mIgf1+/+ muscles. No differences in the phosphorylation response of the downstream AMPK target TBC1D1 were observed, but phosphorylation of raptor was significantly higher only in WT muscles. Further, total raptor content was elevated in mIgf1+/+ muscles. The results show that high muscle IGF-I can enhance glucose uptake under resting conditions; however, in contracting muscle, it is not sufficient to inhibit AMPK activity.

Keywords:  AMPK; IGF-I; muscle contraction; skeletal muscle

DOI:  https://doi.org/10.3390/ijms241511950
Am J Physiol Regul Integr Comp Physiol. 2023 Aug 07.

Clock genes regulate skeletal muscle energy metabolism through NAMPT/NAD+/SIRT1 following heavy-load exercise.

Yu Xia, Binyu Yao, Zeting Fu, Lunyu Li, Songlin Jin, Bo Qu, Ying Huang, Haili Ding.

  The biological clock is an invisible "clock" in the organism, which can regulate behavior, physiology, and biochemical reactions. However, the relationship between clock genes and energy metabolism in post-exercise skeletal muscle is not well known. The purpose of this study was to determine the mechanisms through which peripheral clock genes regulate energy metabolism in skeletal muscle. We analyzed the rhythm of mRNA content of the clock genes Bmal1 and Clock in skeletal muscle following heavy-load exercise and measured related indicators of mitochondrial structure and function. We obtained the following experimental results: Heavy load exercise induced loss of circadian rhythm of Bmal1 between ZT0 and ZT24, and the circadian rhythm of Clock was not restored between ZT0 and ZT72. Analysis of mitochondrial morphology in group E showed abnormal swelling and ridge structure damage at ZT0, which recovered somewhat at ZT24 and ZT48, and the damage had essentially disappeared by ZT72. The expression of NAMPT/NAD+/SIRT1 signaling axis proteins in group E was abnormal at ZT0, the content of NAMPT and the activity of SIRT1 significantly increased, and the content of NAD+ significantly decreased. The expression of Bmal1 and PGC-1α in group E significantly increased, while the ATP and ADP content, as well as the activities of COXII and COXIV, were significantly changed. The co-localization of BMAL1 and SIRT1 in group E was significantly upregulated at ZT0. These results suggest that the skeletal muscle clock gene Bmal1 may regulate the energy metabolism level of skeletal muscle after exercise through the NAMPT/NAD+/SIRT1 signaling pathway.

Keywords:  Clock genes; Energy metabolism; Heavy-load exercise

DOI:  https://doi.org/10.1152/ajpregu.00261.2022
Front Physiol. 2023 ;14 1110926

Functional role of skeletal muscle-derived interleukin-6 and its effects on lipid metabolism.

Weimin Lin, Hongbin Song, Jieqiong Shen, Jing Wang, Yue Yang, Yinhua Yang, Jiacheng Cao, Li'e Xue, Fanglu Zhao, Tianfang Xiao, Ruiyi Lin.

  The detrimental impact of obesity on human health is increasingly evident with the rise in obesity-related diseases. Skeletal muscle, the crucial organ responsible for energy balance metabolism, plays a significant role as a secretory organ by releasing various myokines. Among these myokines, interleukin 6 (IL-6) is closely associated with skeletal muscle contraction. IL-6 triggers the process of lipolysis by mobilizing energy-storing adipose tissue, thereby providing energy for physical exercise. This phenomenon also elucidates the health benefits of regular exercise. However, skeletal muscle and adipose tissue maintain a constant interaction, both directly and indirectly. Direct interaction occurs through the accumulation of excess fat within skeletal muscle, known as ectopic fat deposition. Indirect interaction takes place when adipose tissue is mobilized to supply the energy for skeletal muscle during exercise. Consequently, maintaining a functional balance between skeletal muscle and adipose tissue becomes paramount in regulating energy metabolism and promoting overall health. IL-6, as a representative cytokine, participates in various inflammatory responses, including non-classical inflammatory responses such as adipogenesis. Skeletal muscle influences adipogenesis through paracrine mechanisms, primarily by secreting IL-6. In this research paper, we aim to review the role of skeletal muscle-derived IL-6 in lipid metabolism and other physiological activities, such as insulin resistance and glucose tolerance. By doing so, we provide valuable insights into the regulatory function of skeletal muscle-derived myokines in lipid metabolism.

Keywords:  IL-6; adipose tisse; lipids metabolism; myokine; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2023.1110926
J Am Heart Assoc. 2023 Aug 07. e028880

Estrogen-Related Receptor Gamma Gene Therapy Promotes Therapeutic Angiogenesis and Muscle Recovery in Preclinical Model of PAD.

Danesh H Sopariwala, Andrea S Rios, Addison Saley, Ashok Kumar, Vihang A Narkar.

  Background Peripheral arterial disease and critical limb ischemia are cardiovascular complications associated with vascular insufficiency, oxidative metabolic dysfunction, and myopathy in the limbs. Estrogen-related receptor gamma (ERRγ) has emerged as a dual regulator of paracrine angiogenesis and oxidative metabolism through transgenic mouse studies. Here our objective was to investigate whether postischemic intramuscular targeting of ERRγ via gene therapy promotes ischemic recovery in a preclinical model of peripheral arterial disease/critical limb ischemia. Methods and Results Adeno-associated virus 9 (AAV9) Esrrg gene delivery vector was developed and first tested via intramuscular injection in murine skeletal muscle. AAV9-Esrrg robustly increased ERRγ protein expression, induced angiogenic and oxidative genes, and boosted capillary density and succinate dehydrogenase oxidative metabolic activity in skeletal muscles of C57Bl/6J mice. Next, hindlimb ischemia was induced via unilateral femoral vessel ligation in mice, followed by intramuscular AAV9-Esrrg (or AAV9-green fluorescent protein) gene delivery 24 hours after injury. ERRγ overexpression increased ischemic neoangiogenesis and markers of endothelial activation, and significantly improved ischemic revascularization measured using laser Doppler flowmetry. Moreover, ERRγ overexpression restored succinate dehydrogenase oxidative metabolic capacity in ischemic muscle, which correlated with increased mitochondrial respiratory complex protein expression. Most importantly, myofiber size to number quantification revealed that AAV9-Esrrg restores myofibrillar size and mitigates ischemia-induced myopathy. Conclusions These results demonstrate that intramuscular AAV9-Esrrg delivery rescues ischemic pathology after hindlimb ischemia, underscoring that Esrrg gene therapy or pharmacological activation could be a promising strategy for the management of peripheral arterial disease/critical limb ischemia.

Keywords:  angiogenesis; estrogen‐related receptor gamma; gene therapy; limb ischemia; muscle recovery

DOI:  https://doi.org/10.1161/JAHA.122.028880
J Appl Physiol (1985). 2023 Aug 10.

Skeletal muscle endurance declines with impaired mitochondrial respiration and inadequate supply of acetyl-CoA during muscle fatigue in 5/6 nephrectomized rats.

Hiroyori Fusagawa, Tatsuya Sato, Takashi Yamada, Yuki Ashida, Iori Kimura, Azuma Naito, Nao Tokuda, Nao Yamauchi, Nobutoshi Ichise, Yoshinori Terashima, Izaya Ogon, Atsushi Teramoto, Toshihiko Yamashita, Noritsugu Tohse.

  Chronic kidney disease (CKD)-related cachexia increases the risks of reduced physical activity and mortality. However, the physiological phenotype of skeletal muscle fatigue and changes in intramuscular metabolites during muscle fatigue in CKD-related cachexia remain unclear. In the present study, we performed detailed muscle physiological evaluation, analysis of mitochondrial function, and comprehensive analysis of metabolic changes before and after muscle fatigue in a 5/6 nephrectomized rat model of CKD. Wistar rats were randomized to a sham-operation (Sham) group that served as a control group or a 5/6 nephrectomy (Nx) group. Eight weeks after the operation, in situ torque and force measurements in plantar flexor muscles in Nx rats using electrical stimulation revealed a significant decrease in muscle endurance during subacute phase related to mitochondrial function. Muscle mass was reduced without changes in the proportions of fiber type-specific myosin heavy chain isoforms in Nx rats. Pyruvate-malate-driven state 3 respiration in isolated mitochondria were impaired in Nx rats. Protein expression levels of mitochondrial respiratory chain complexes III and V were decreased in Nx rats. Metabolome analysis revealed that the increased supply of acetyl CoA in response to fatigue was blunted in Nx rats. These findings suggest that CKD deteriorates skeletal muscle endurance in association with mitochondrial dysfunction and inadequate supply of acetyl-CoA during muscle fatigue.

Keywords:  Cachexia; Chronic kidney disease; Metabolome; Mitochondria; Muscle fatigue

DOI:  https://doi.org/10.1152/japplphysiol.00226.2023
Acta Physiol (Oxf). 2023 Aug 08. e14031

Automated in-depth fiber and nuclei typing in cross-sectional muscle images can pave the way to a better understanding of skeletal muscle diseases.

Simone Baltrusch.

DOI: https://doi.org/10.1111/apha.14031
Physiol Rep. 2023 Aug;11(15): e15793

Stanniocalcin-2 inhibits skeletal muscle growth and is upregulated in functional overload-induced hypertrophy.

Arimantas Lionikas, Ana I Hernandez Cordero, Audrius Kilikevicius, Andrew M Carroll, Guy S Bewick, Lutz Bunger, Aivaras Ratkevicius, Lora K Heisler, Mette Harboe, Claus Oxvig.

   AIMS: Stanniocalcin-2 (STC2) has recently been implicated in human muscle mass variability by genetic analysis. Biochemically, STC2 inhibits the proteolytic activity of the metalloproteinase PAPP-A, which promotes muscle growth by upregulating the insulin-like growth factor (IGF) axis. The aim was to examine if STC2 affects skeletal muscle mass and to assess how the IGF axis mediates muscle hypertrophy induced by functional overload.
METHODS: We compared muscle mass and muscle fiber morphology between Stc2-/- (n = 21) and wild-type (n = 15) mice. We then quantified IGF1, IGF2, IGF binding proteins -4 and -5 (IGFBP-4, IGFBP-5), PAPP-A and STC2 in plantaris muscles of wild-type mice subjected to 4-week unilateral overload (n = 14).
RESULTS: Stc2-/- mice showed up to 10% larger muscle mass compared with wild-type mice. This increase was mediated by greater cross-sectional area of muscle fibers. Overload increased plantaris mass and components of the IGF axis, including quantities of IGF1 (by 2.41-fold, p = 0.0117), IGF2 (1.70-fold, p = 0.0461), IGFBP-4 (1.48-fold, p = 0.0268), PAPP-A (1.30-fold, p = 0.0154) and STC2 (1.28-fold, p = 0.019).
CONCLUSION: Here we provide evidence that STC2 is an inhibitor of muscle growth upregulated, along with other components of the IGF axis, during overload-induced muscle hypertrophy.

Keywords:  IGF; STC2; resistance training; skeletal muscle

DOI:  https://doi.org/10.14814/phy2.15793
Aging Cell. 2023 Aug 10. e13952

The secretome atlas of two mouse models of progeria.

Diego Quintana-Torres, Alejandra Valle-Cao, Pablo Bousquets-Muñoz, Sandra Freitas-Rodríguez, Francisco Rodríguez, Alejandro Lucia, Carlos López-Otín, Alejandro López-Soto, Alicia R Folgueras.

  Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by nuclear envelope alterations that lead to accelerated aging and premature death. Several studies have linked health and longevity to cell-extrinsic mechanisms, highlighting the relevance of circulating factors in the aging process as well as in age-related diseases. We performed a global plasma proteomic analysis in two preclinical progeroid models (LmnaG609G/G609G and Zmpste24-/- mice) using aptamer-based proteomic technology. Pathways related to the extracellular matrix, growth factor response and calcium ion binding were among the most enriched in the proteomic signature of progeroid samples compared to controls. Despite the global downregulation trend found in the plasma proteome of progeroid mice, several proteins associated with cardiovascular disease, the main cause of death in HGPS, were upregulated. We also developed a chronological age predictor using plasma proteome data from a cohort of healthy mice (aged 1-30 months), that reported an age acceleration when applied to progeroid mice, indicating that these mice exhibit an "old" plasma proteomic signature. Furthermore, when compared to naturally-aged mice, a great proportion of differentially expressed circulating proteins in progeroid mice were specific to premature aging, highlighting secretome-associated differences between physiological and accelerated aging. This is the first large-scale profiling of the plasma proteome in progeroid mice, which provides an extensive list of candidate circulating plasma proteins as potential biomarkers and/or therapeutic targets for further exploration and hypothesis generation in the context of both physiological and premature aging.

Keywords:  HGPS; aging; aging clock; progeria; proteomics; secretome

DOI:  https://doi.org/10.1111/acel.13952