bims-moremu 2024-03-03 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2024‒03‒03
34 papers selected by
Anna Vainshtein, Craft Science Inc.

Reorganization of mitochondria-organelle interactions during postnatal development in skeletal muscle.
ATF4-dependent increase in mitochondrial-endoplasmic reticulum tethering following OPA1 deletion in skeletal muscle.
Optic atrophy 1 mediates muscle differentiation by promoting a metabolic switch via the supercomplex assembly factor SCAF1.
Denervation alters the secretome of myofibers and thereby affects muscle stem cell lineage progression and functionality.
METTL21C mediates the occurrence of autophagy and formation of slow-twitch muscle fibers after exercise.
Targeted brain-specific tauopathy compromises peripheral skeletal muscle integrity and function.
Prehab? Rehab? Both? Exploring interventions to alleviate disuse-induced muscle atrophy and anabolic resistance in older adults.
The cellular bases of mobility from the Study of Muscle, Mobility and Aging (SOMMA).
Making the case for resistance training in improving vascular function and skeletal muscle capillarization.
Myogenic exosome miR-140-5p modulates skeletal muscle regeneration and injury repair by regulating muscle satellite cells.
SERCA-1 conformational change exerted by the Ca2+-channel blocker diltiazem affects mammalian skeletal muscle function.
Cannabidiol protects C2C12 myotubes against cisplatin-induced atrophy by regulating oxidative stress.
Functional hypoxia reduces mitochondrial calcium uptake.
SIRT1 activation attenuates palmitate induced apoptosis in C2C12 muscle cells.
In vivo PSC differentiation as a platform to identify factors for improving the engraftability of cultured muscle stem cells.
Immortalised murine R349P desmin knock-in myotubes exhibit a reduced proton leak and decreased ADP/ATP translocase levels in purified mitochondria.
Conserved mammalian muscle mechanics during eccentric contractions.
Consequences of GMPPB deficiency for neuromuscular development and maintenance.
The effect of protein or amino acid provision on immobilization-induced muscle atrophy in healthy adults: A systematic review and meta-analysis.
HDAC inhibitors as pharmacological treatment for Duchenne muscular dystrophy: a discovery journey from bench to patients.
The SGLT2 inhibitor empagliflozin inhibits skeletal muscle fibrosis in naturally aging male mice through the AMPKα/MMP9/TGF-β1/Smad pathway.
Mitochondrial fusion and altered beta-oxidation drive muscle wasting in a Drosophila cachexia model.
Flvcr1a deficiency promotes heme-based energy metabolism dysfunction in skeletal muscle.
Podocan promoting skeletal muscle post-injury regeneration by inhibiting TGF-β signaling pathway.
Turning fat into muscle: can this be an alternative to anti-obesity drugs such as semaglutide?
RASGRP1 targeted by H3K27me3 regulates myoblast proliferation and differentiation in mice and pigs.
Lower basal and postprandial muscle protein synthesis after 2 weeks single-leg immobilization in older men: No protective effect of anti-inflammatory medication.
Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.
Aligned Nanofibers Promote Myoblast Polarization and Myogenesis through Activating Rac-Related Signaling Pathways.
Impact of preterm birth on muscle mass and function: a systematic review and meta-analysis.
IGF-1 Regulates Skeletal Muscle Degradation and Remolding in Ventilator-Induced Diaphragmatic Dysfunction by Mediating FOXO1 Expression.
Skeletal muscle estimation: A review of techniques and their applications.
Extracellular Vesicles and Exosomes in the Control of the Musculoskeletal Health.
Cancer cachexia: biomarkers and the influence of age.

J Physiol. 2024 Mar 01.

Reorganization of mitochondria-organelle interactions during postnatal development in skeletal muscle.

Yuho Kim, Hailey A Parry, T Bradley Willingham, Greg Alspaugh, Eric Lindberg, Christian A Combs, Jay R Knutson, Christopher K E Bleck, Brian Glancy.

  Skeletal muscle cellular development requires the integrated assembly of mitochondria and other organelles adjacent to the sarcomere in support of muscle contractile performance. However, it remains unclear how interactions among organelles and with the sarcomere relates to the development of muscle cell function. Here, we combine 3D volume electron microscopy, proteomic analyses, and live cell functional imaging to investigate the postnatal reorganization of mitochondria-organelle interactions in skeletal muscle. We show that while mitochondrial networks are disorganized and loosely associated with the contractile apparatus at birth, contact sites among mitochondria, lipid droplets and the sarcoplasmic reticulum are highly abundant in neonatal muscles. The maturation process is characterized by a transition to highly organized mitochondrial networks wrapped tightly around the muscle sarcomere but also to less frequent interactions with both lipid droplets and the sarcoplasmic reticulum. Concomitantly, expression of proteins involved in mitochondria-organelle membrane contact sites decreases during postnatal development in tandem with a decrease in abundance of proteins associated with sarcomere assembly despite an overall increase in contractile protein abundance. Functionally, parallel measures of mitochondrial membrane potential, NADH redox status, and NADH flux within intact cells revealed that mitochondria in adult skeletal muscle fibres maintain a more activated electron transport chain compared with neonatal muscle mitochondria. These data demonstrate a developmental redesign reflecting a shift from muscle cell assembly and frequent inter-organelle communication toward a muscle fibre with mitochondrial structure, interactions, composition and function specialized to support contractile function. KEY POINTS: Mitochondrial network organization is remodelled during skeletal muscle postnatal development. The mitochondrial outer membrane is in frequent contact with other organelles at birth and transitions to more close associations with the contractile apparatus in mature muscles. Mitochondrial energy metabolism becomes more activated during postnatal development. Understanding the developmental redesign process within skeletal muscle cells may help pinpoint specific areas of deficit in muscles with developmental disorders.

Keywords:  3D mitochondrial structure; functional cellular imaging; organelle interactions; postnatal muscle development; volume electron microscopy

DOI:  https://doi.org/10.1113/JP285014
J Cell Physiol. 2024 Feb 28.

ATF4-dependent increase in mitochondrial-endoplasmic reticulum tethering following OPA1 deletion in skeletal muscle.

Antentor Hinton, Prasanna Katti, Margaret Mungai, Duane D Hall, Olha Koval, Jianqiang Shao, Zer Vue, Edgar Garza Lopez, Rahmati Rostami, Kit Neikirk, Jessica Ponce, Jennifer Streeter, Brandon Schickling, Serif Bacevac, Chad Grueter, Andrea Marshall, Heather K Beasley, Young Do Koo, Sue C Bodine, Nayeli G Reyes Nava, Anita M Quintana, Long-Sheng Song, Isabella M Grumbach, Renata O Pereira, Brian Glancy, E Dale Abel.

  Mitochondria and endoplasmic reticulum (ER) contact sites (MERCs) are protein- and lipid-enriched hubs that mediate interorganellar communication by contributing to the dynamic transfer of Ca2+ , lipid, and other metabolites between these organelles. Defective MERCs are associated with cellular oxidative stress, neurodegenerative disease, and cardiac and skeletal muscle pathology via mechanisms that are poorly understood. We previously demonstrated that skeletal muscle-specific knockdown (KD) of the mitochondrial fusion mediator optic atrophy 1 (OPA1) induced ER stress and correlated with an induction of Mitofusin-2, a known MERC protein. In the present study, we tested the hypothesis that Opa1 downregulation in skeletal muscle cells alters MERC formation by evaluating multiple myocyte systems, including from mice and Drosophila, and in primary myotubes. Our results revealed that OPA1 deficiency induced tighter and more frequent MERCs in concert with a greater abundance of MERC proteins involved in calcium exchange. Additionally, loss of OPA1 increased the expression of activating transcription factor 4 (ATF4), an integrated stress response (ISR) pathway effector. Reducing Atf4 expression prevented the OPA1-loss-induced tightening of MERC structures. OPA1 reduction was associated with decreased mitochondrial and sarcoplasmic reticulum, a specialized form of ER, calcium, which was reversed following ATF4 repression. These data suggest that mitochondrial stress, induced by OPA1 deficiency, regulates skeletal muscle MERC formation in an ATF4-dependent manner.

Keywords:  activating transcription factor 4; endoplasmic reticulum; integrated stress response; interorganelle communication; mitochondria

DOI:  https://doi.org/10.1002/jcp.31204
iScience. 2024 Mar 15. 27(3): 109164

Optic atrophy 1 mediates muscle differentiation by promoting a metabolic switch via the supercomplex assembly factor SCAF1.

Matthew Triolo, Nicole Baker, Soniya Agarwal, Nikita Larionov, Tina Podinić, Mireille Khacho.

  Myogenic differentiation is integral for the regeneration of skeletal muscle following tissue damage. Though high-energy post-mitotic muscle relies predominantly on mitochondrial respiration, the importance of mitochondrial remodeling in enabling muscle differentiation and the players involved are not fully known. Here we show that the mitochondrial fusion protein OPA1 is essential for muscle differentiation. Our study demonstrates that OPA1 loss or inhibition, through genetic and pharmacological means, abolishes in vivo muscle regeneration and in vitro myotube formation. We show that both the inhibition and genetic deletion of OPA1 prevent the early onset metabolic switch required to drive myoblast differentiation. In addition, we observe an OPA1-dependent upregulation of the supercomplex assembly factor, SCAF1, at the onset of differentiation. Importantly, preventing the upregulation of SCAF1, through OPA1 loss or siRNA-mediated SCAF1 knockdown, impairs metabolic reprogramming and muscle differentiation. These findings reveal the integral role of OPA1 and mitochondrial reprogramming at the onset of myogenic differentiation.

Keywords:  Molecular biology; Physiology

DOI:  https://doi.org/10.1016/j.isci.2024.109164
NPJ Regen Med. 2024 Mar 01. 9(1): 10

Denervation alters the secretome of myofibers and thereby affects muscle stem cell lineage progression and functionality.

Henriette Henze, Sören S Hüttner, Philipp Koch, Svenja C Schüler, Marco Groth, Björn von Eyss, Julia von Maltzahn.

Skeletal muscle function crucially depends on innervation while repair of skeletal muscle relies on resident muscle stem cells (MuSCs). However, it is poorly understood how innervation affects MuSC properties and thereby regeneration of skeletal muscle. Here, we report that loss of innervation causes precocious activation of MuSCs concomitant with the expression of markers of myogenic differentiation. This aberrant activation of MuSCs after loss of innervation is accompanied by profound alterations on the mRNA and protein level. Combination of muscle injury with loss of innervation results in impaired regeneration of skeletal muscle including shifts in myogenic populations concomitant with delayed maturation of regenerating myofibers. We further demonstrate that loss of innervation leads to alterations in myofibers and their secretome, which then affect MuSC behavior. In particular, we identify an increased secretion of Osteopontin and transforming growth factor beta 1 (Tgfb1) by myofibers isolated from mice which had undergone sciatic nerve transection. The altered secretome results in the upregulation of early activating transcription factors, such as Junb, and their target genes in MuSCs. However, the combination of different secreted factors from myofibers after loss of innervation is required to cause the alterations observed in MuSCs after loss of innervation. These data demonstrate that loss of innervation first affects myofibers causing alterations in their secretome which then affect MuSCs underscoring the importance of proper innervation for MuSC functionality and regeneration of skeletal muscle.

DOI: https://doi.org/10.1038/s41536-024-00353-3
Genes Genet Syst. 2024 Feb 28.

METTL21C mediates the occurrence of autophagy and formation of slow-twitch muscle fibers after exercise.

Jing Qu, Shuai Dang, Yuan-Yuan Sun, Tao Zhang, Hai Jiang, Hong-Zhao Lu.

  Homeostasis is essential for muscle repair and regeneration after skeletal muscle exercise. This study investigated the role of methyltransferase-like 21C (METTL21C) in skeletal muscle of mice after exercise and the potential mechanism. First, muscle samples were collected at 2, 4, and 6 weeks after exercise, liver glycogen, muscle glycogen, blood lactic acid (BLA) and triglyceride (TG) were assessed. Moreover, the expression levels of autophagy markers and METTL21C in skeletal muscle were analyzed. The results showed that the expressions of METTL21C and MYH7 in the gastrocnemius muscle of mice in the exercise group were significantly higher than that in the control group after exercise, which suggested that long-term exercise promoted the formation of slow-twitch muscle fibers in mouse skeletal muscle. Likewise, the autophagy capacity is enhanced with the extension of exercise in muscles. The findings were further verified in mouse C2C12 cells. We discovered that knockdown of Mettl21c reduced the expression of MYH7 and autophagy level in mouse myoblasts. These findings indicate that METTL21C promotes skeletal muscle homeostasis after exercise by enhancing autophagy, while METTL21C also contributes to differentiation of myogenic and formation of slow muscle fiber.

Keywords:  METTL21C; autophagy; exercise; mice; skeletal muscle

DOI:  https://doi.org/10.1266/ggs.23-00320
Aging Brain. 2024 ;5 100110

Targeted brain-specific tauopathy compromises peripheral skeletal muscle integrity and function.

Bryan Alava, Gabriela Hery, Silvana Sidhom, Miguel Gutierrez-Monreal, Stefan Prokop, Karyn A Esser, Jose Abisambra.

Tauopathies are neurodegenerative disorders in which the pathological intracellular aggregation of the protein tau causes cognitive deficits. Additionally, clinical studies report muscle weakness in populations with tauopathy. However, whether neuronal pathological tau species confer muscle weakness, and whether skeletal muscle maintains contractile capacity in primary tauopathy remains unknown. Here, we identified skeletal muscle abnormalities in a mouse model of primary tauopathy, expressing human mutant P301L-tau using adeno-associated virus serotype 8 (AAV8). AAV8-P301L mice showed grip strength deficits, hyperactivity, and abnormal histological features of skeletal muscle. Additionally, spatially resolved gene expression of muscle cross sections were altered in AAV8-P301L myofibers. Transcriptional changes showed alterations of genes encoding sarcomeric proteins, proposing a weakness phenotype. Strikingly, specific force of the soleus muscle was blunted in AAV8-P301L tau male mice. Our findings suggest tauopathy has peripheral consequences in skeletal muscle that contribute to weakness in tauopathy.

DOI: https://doi.org/10.1016/j.nbas.2024.100110
J Physiol. 2024 Feb 27.

Prehab? Rehab? Both? Exploring interventions to alleviate disuse-induced muscle atrophy and anabolic resistance in older adults.

Nigel L M LeGood, XinYue Li, Michelle Ha, Joshua D R Downer.



Keywords:  anabolic resistance; disuse; muscle atrophy; prehabilitation; rehabilitation; resistance exercise; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1113/JP286231
Aging Cell. 2024 Mar 01. e14129

The cellular bases of mobility from the Study of Muscle, Mobility and Aging (SOMMA).

Steven R Cummings, Paul M Coen, Luigi Ferrucci.

  Findings from the Study of Muscle, Mobility and Aging (SOMMA) in this issue of Aging Cell show that several biological pathways in skeletal muscle cells play an important role in determining mobility in older adults. These are based on assays in skeletal muscle biopsies obtained from participants, aged 70 years and older in SOMMA tested for association with assessments related to mobility, including muscle mass, strength, power, cardiopulmonary fitness, and 400 m walking speed. The papers show that, using mass spectrometry, oxidative modifications of proteins essential to myocellular function are associated with poorer mobility. Using RNA-seq to quantify gene expression, lower levels of expression of antioxidant enzymes located in mitochondria, autophagy, patterns of expression of genes involved in autophagy, and higher levels of RNA transcripts that increase with denervation were associated with poorer performance on tests of mobility. These results extend previous research from the Baltimore Longitudinal Study of Aging and recent studies from SOMMA showing the importance of mitochondrial energetics in mobility. Together, these findings are painting a picture of how fundamental cellular processes influence the loss of mobility with aging. They may also be a window on aging in other cells, tissues, and systems. The data collected in SOMMA are publicly available and SOMMA welcomes collaborations with scientists who are interested in research about human aging.

Keywords:  autophagy; denervation; mobility; oxidative stress; physical fitness; skeletal muscle; strength

DOI:  https://doi.org/10.1111/acel.14129
Front Physiol. 2024 ;15 1338507

Making the case for resistance training in improving vascular function and skeletal muscle capillarization.

Mason C McIntosh, Derick A Anglin, Austin T Robinson, Darren T Beck, Michael D Roberts.

  Through decades of empirical data, it has become evident that resistance training (RT) can improve strength/power and skeletal muscle hypertrophy. Yet, until recently, vascular outcomes have historically been underemphasized in RT studies, which is underscored by several exercise-related reviews supporting the benefits of endurance training on vascular measures. Several lines of evidence suggest large artery diameter and blood flow velocity increase after a single bout of resistance exercise, and these events are mediated by vasoactive substances released from endothelial cells and myofibers (e.g., nitric oxide). Weeks to months of RT can also improve basal limb blood flow and arterial diameter while lowering blood pressure. Although several older investigations suggested RT reduces skeletal muscle capillary density, this is likely due to most of these studies being cross-sectional in nature. Critically, newer evidence from longitudinal studies contradicts these findings, and a growing body of mechanistic rodent and human data suggest skeletal muscle capillarity is related to mechanical overload-induced skeletal muscle hypertrophy. In this review, we will discuss methods used by our laboratories and others to assess large artery size/function and skeletal muscle capillary characteristics. Next, we will discuss data by our groups and others examining large artery and capillary responses to a single bout of resistance exercise and chronic RT paradigms. Finally, we will discuss RT-induced mechanisms associated with acute and chronic vascular outcomes.

Keywords:  angiogenesis; blood flow; brachial artery; capillaries; hypertrophy; resistance training; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2024.1338507
Aging (Albany NY). 2024 Feb 29. 16

Myogenic exosome miR-140-5p modulates skeletal muscle regeneration and injury repair by regulating muscle satellite cells.

Xiaorui Cao, Linli Xue, Xiuju Yu, Yi Yan, Jiayin Lu, Xiaomao Luo, Haidong Wang, Juan Wang.

  Muscle satellite cells (SCs) play a crucial role in the regeneration and repair of skeletal muscle injuries. Previous studies have shown that myogenic exosomes can enhance satellite cell proliferation, while the expression of miR-140-5p is significantly reduced during the repair process of mouse skeletal muscle injuries induced by BaCl2. This study aims to investigate the potential of myogenic exosomes carrying miR-140-5p inhibitors to activate SCs and influence the regeneration of injured muscles. Myogenic progenitor cell exosomes (MPC-Exo) and contained miR-140-5p mimics/inhibitors myogenic exosomes (MPC-Exo140+ and MPC-Exo140-) were employed to treat SCs and use the model. The results demonstrate that miR-140-5p regulates SC proliferation by targeting Pax7. Upon the addition of MPC-Exo and MPC-Exo140-, Pax7 expression in SCs significantly increased, leading to the transition of the cell cycle from G1 to S phase and an enhancement in cell proliferation. Furthermore, the therapeutic effect of MPC-Exo140- was validated in animal model, where the expression of muscle growth-related genes substantially increased in the gastrocnemius muscle. Our research demonstrates that MPC-Exo140- can effectively activate dormant muscle satellite cells, initiating their proliferation and differentiation processes, ultimately leading to the formation of new skeletal muscle cells and promoting skeletal muscle repair and remodeling.

Keywords:  exosomes; miR-140-5p; muscle injury repair; muscle satellite cells; regeneration

DOI:  https://doi.org/10.18632/aging.205617
Cell Calcium. 2024 Feb 08. pii: S0143-4160(24)00010-1. [Epub ahead of print]119 102852

SERCA-1 conformational change exerted by the Ca2+-channel blocker diltiazem affects mammalian skeletal muscle function.

Aura Jiménez-Garduño, Ibrahim Ramirez-Soto, Ileana Miranda-Rodríguez, Sofía Gitler, Alicia Ortega.

  In skeletal muscle (SM), inward Ca2+-currents have no apparent role in excitation-contraction coupling (e-c coupling), however the Ca2+-channel blocker can affect twitch and tetanic muscle in mammalian SM. Experiments were conducted to study how diltiazem (DLZ) facilitates e-c coupling and inhibits contraction. 1) In complete Extensor Digitorum Longus (EDL) muscle and single intact fibres, 0.03 mM DLZ causes twitch potentiation and decreases force during tetanic activity, with increased fatigue. 2) In split open fibres isolated from EDL fibres, DLZ inhibits sarcoplasmic reticulum (SR) Ca2+-loading in a dose-dependent manner and has a potentiating effect on caffeine-induced SR Ca2+-release. 3) In isolated light SR (LSR) vesicles, SERCA1 hydrolytic activity is not affected by DLZ up to 0.2 mM. However, ATP-dependent Ca2+-uptake was inhibited in a dose-dependent manner at a concentration where e-c coupling is changed. 4) The passive Ca2+-efflux from LSR was reduced by half with 0.03 mM diltiazem, indicating that SR leaking does not account for the decreased Ca2+-uptake. 5) The denaturation profile of the SERCA Ca2+-binding domain has lower thermal stability in the presence of DLZ in a concentration-dependent manner, having no effect on the nucleotide-binding domain. We conclude that the effect of DLZ on SM is exerted by crossing the sarcolemma and interacting directly with the SERCA Ca2+-binding domain, affecting SR Ca2+-loading during relaxation, which has a consequence on SM contractility. Diltiazem effect on SM could be utilized as a tool to understand SM e-c coupling and muscle fatigue.

Keywords:  Calcium-channel blocker; Diltiazem; Excitation-contraction coupling; SERCA; Sarcoplasmic reticulum; Skeletal muscle

DOI:  https://doi.org/10.1016/j.ceca.2024.102852
Am J Physiol Cell Physiol. 2024 Feb 26.

Cannabidiol protects C2C12 myotubes against cisplatin-induced atrophy by regulating oxidative stress.

Olivier Le Bacquer, Phelipe Sanchez, Véronique Patrac, César Rivoirad, Nicolas Saroul, Christophe Giraudet, Ayhan Kocer, Stephane Walrand.

  Cancer and chemotherapy can both cause cachexia, a complex multi-organ syndrome characterized by body weight loss, due to adipose tissue and skeletal muscle wasting. Changes in body weight and muscle mass are predictive of response to chemotherapy, incidence of treatment-related complications and, ultimately, patient survival, but there are currently still no clear therapeutic strategies to counteract cachexia. Cannabidiol (CBD) is a bioactive phytocannabinoid produced from a plant named Cannabis sativa. In recent years, CBD has demonstrated beneficial effects on maintaining skeletal muscle mass, function and metabolism in models of muscular dystrophy or diet-induced obesity. Here, we used a model of myotubes in culture to evaluate the potential beneficial effects of CBD on cisplatin-induced skeletal muscle wasting. 24-h cisplatin treatment resulted in a ≈30% reduction in myotube diameter, driven by a drastic reduction in protein synthesis rate and a twofold increase in proteolysis. 24-h cisplatin treatment also significantly increased myotube TBARS content, catalase activity and antioxidant system mRNA levels (GPX1, SOD1, SOD2 and CAT) indicating increased oxidative stress. 24-h cisplatin treatment also increased the mitochondrial protein content of NDUFB8, UQCRC2, COX4 and VDAC1, which are involved in mitochondrial respiration and control of apoptosis. Importantly, CBD was found to antagonize chemotherapy-induced C2C12 myotube atrophy by promoting protein homeostasis and reducing oxidative stress. Our results show that CBD could be used as an adjuvant in the treatment of cancer cachexia to help maintain muscle mass and improve patient quality of life.

Keywords:  cachexia; endocannabinoid system; mitochondrial function; oxidative stress; protein homeostasis

DOI:  https://doi.org/10.1152/ajpcell.00622.2023
Redox Biol. 2024 Jan 17. pii: S2213-2317(24)00013-2. [Epub ahead of print]71 103037

Functional hypoxia reduces mitochondrial calcium uptake.

Chris Donnelly, Timea Komlódi, Cristiane Cecatto, Luiza H D Cardoso, Anne-Claire Compagnion, Alessandro Matera, Daniele Tavernari, Olivier Campiche, Rosa Chiara Paolicelli, Nadège Zanou, Bengt Kayser, Erich Gnaiger, Nicolas Place.

  Mitochondrial respiration extends beyond ATP generation, with the organelle participating in many cellular and physiological processes. Parallel changes in components of the mitochondrial electron transfer system with respiration render it an appropriate hub for coordinating cellular adaption to changes in oxygen levels. How changes in respiration under functional hypoxia (i.e., when intracellular O2 levels limit mitochondrial respiration) are relayed by the electron transfer system to impact mitochondrial adaption and remodeling after hypoxic exposure remains poorly defined. This is largely due to challenges integrating findings under controlled and defined O2 levels in studies connecting functions of isolated mitochondria to humans during physical exercise. Here we present experiments under conditions of hypoxia in isolated mitochondria, myotubes and exercising humans. Performing steady-state respirometry with isolated mitochondria we found that oxygen limitation of respiration reduced electron flow and oxidative phosphorylation, lowered the mitochondrial membrane potential difference, and decreased mitochondrial calcium influx. Similarly, in myotubes under functional hypoxia mitochondrial calcium uptake decreased in response to sarcoplasmic reticulum calcium release for contraction. In both myotubes and human skeletal muscle this blunted mitochondrial adaptive responses and remodeling upon contractions. Our results suggest that by regulating calcium uptake the mitochondrial electron transfer system is a hub for coordinating cellular adaption under functional hypoxia.

Keywords:  Coenzyme Q; Exercise; Membrane potential; Respirometry; Skeletal muscle

DOI:  https://doi.org/10.1016/j.redox.2024.103037
Mol Biol Rep. 2024 Feb 24. 51(1): 354

SIRT1 activation attenuates palmitate induced apoptosis in C2C12 muscle cells.

Gholamreza Taheripak, Niusha Sabeti, Naba Najar, Zahrasadat Razavi, Saber Saharkhiz, Iraj Alipourfard.

  BACKGROUND: Type 2 diabetes is characterized by insulin resistance, which manifests mainly in skeletal muscles. SIRT1 has been found to play a role in the insulin signaling pathway. However, the molecular underpinnings of SIRT1's function in palmitate fatty acid-induced apoptosis still need to be better understood.METHODS: In this research, skeletal muscle cells are treated with palmitate to be insulin resistant. It is approached that SIRT1 is downregulated in C2C12 muscle cells during palmitate-induced apoptosis and that activating SIRT1 mitigates this effect.
RESULTS: Based on these findings, palmitate-induced apoptosis suppressed mitochondrial biogenesis by lowering PGC-1 expression, while SIRT1 overexpression boosted. The SIRT1 inhibitor sirtinol, on the other hand, decreased mitochondrial biogenesis under the same conditions. This research also shows that ROS levels rise in the conditions necessary for apoptosis induction by palmitate, and ROS inhibitors can mitigate this effect. This work demonstrated that lowering ROS levels by boosting SIRT1 expression inhibited apoptotic induction in skeletal muscle cells.
CONCLUSION: This study's findings suggested that SIRT1 can improve insulin resistance in type 2 diabetes by slowing the rate of lipo-apoptosis and boosting mitochondrial biogenesis, among other benefits.

Keywords:  Apoptosis; C2C12 muscle cells; Diabetes type 2; Mitochondrial biogenesis; Palmitate; SIRT1

DOI:  https://doi.org/10.1007/s11033-024-09250-w
Front Cell Dev Biol. 2024 ;12 1362671

In vivo PSC differentiation as a platform to identify factors for improving the engraftability of cultured muscle stem cells.

Ning Xie, Kathryn Robinson, Timothy Sundquist, Sunny S K Chan.

  Producing an adequate number of muscle stem cells (MuSCs) with robust regenerative potential is essential for the successful cell therapy of muscle-wasting disorders. We have recently developed a method to produce skeletal myogenic cells with exceptional engraftability and expandability through an in vivo pluripotent stem cell (PSC) differentiation approach. We have subsequently mapped engraftment and gene expression and found that leukemia inhibitory factor receptor (Lifr) expression is positively correlated with engraftability. We therefore investigated the effect of LIF, the endogenous ligand of LIFR, on cultured MuSCs and examined their engraftment potential. We found that LIF-treated MuSCs exhibited elevated expression of PAX7, formed larger colonies from single cells, and favored the retention of PAX7+ "reserve cells" upon myogenic differentiation. This suggested that LIF promoted the maintenance of cultured MuSCs at a stem cell stage. Moreover, LIF enhanced the engraftment capability of MuSCs that had been expanded in vitro for 12 days by 5-fold and increased the number of MuSCs that repopulated the stem cell pool post-transplantation. These results thereby demonstrated the effectiveness of our in vivo PSC differentiation platform to identify positive regulators of the engraftability of cultured MuSCs.

Keywords:  cell therapy; muscle stem cells; muscular dystrophy; myogenic differentiation; pluripotent stem cells; transplantation

DOI:  https://doi.org/10.3389/fcell.2024.1362671
Eur J Cell Biol. 2024 Feb 20. pii: S0171-9335(24)00016-5. [Epub ahead of print]103(2): 151399

Immortalised murine R349P desmin knock-in myotubes exhibit a reduced proton leak and decreased ADP/ATP translocase levels in purified mitochondria.

Carolin Berwanger, Dominic Terres, Dominik Pesta, Britta Eggers, Katrin Marcus, Ilka Wittig, Rudolf J Wiesner, Rolf Schröder, Christoph S Clemen.

  Desmin gene mutations cause myopathies and cardiomyopathies. Our previously characterised R349P desminopathy mice, which carry the ortholog of the common human desmin mutation R350P, showed marked alterations in mitochondrial morphology and function in muscle tissue. By isolating skeletal muscle myoblasts from offspring of R349P desminopathy and p53 knock-out mice, we established an immortalised cellular disease model. Heterozygous and homozygous R349P desmin knock-in and wild-type myoblasts could be well differentiated into multinucleated spontaneously contracting myotubes. The desminopathy myoblasts showed the characteristic disruption of the desmin cytoskeleton and desmin protein aggregation, and the desminopathy myotubes showed the characteristic myofibrillar irregularities. Long-term electrical pulse stimulation promoted myotube differentiation and markedly increased their spontaneous contraction rate. In both heterozygous and homozygous R349P desminopathy myotubes, this treatment restored a regular myofibrillar cross-striation pattern as seen in wild-type myotubes. High-resolution respirometry of mitochondria purified from myotubes by density gradient ultracentrifugation revealed normal oxidative phosphorylation capacity, but a significantly reduced proton leak in mitochondria from the homozygous R349P desmin knock-in cells. Consistent with a reduced proton flux across the inner mitochondrial membrane, our quantitative proteomic analysis of the purified mitochondria revealed significantly reduced levels of ADP/ATP translocases in the homozygous R349P desmin knock-in genotype. As this alteration was also detected in the soleus muscle of R349P desminopathy mice, which, in contrast to the mitochondria purified from cultured cells, showed a variety of other dysregulated mitochondrial proteins, we consider this finding to be an early step in the pathogenesis of secondary mitochondriopathy in desminopathy.

Keywords:  ADP/ATP translocase; Desminopathy; Electrical pulse stimulation; Immortalised murine myoblasts; Mitochondrial respiration; Myofibrillar maturation

DOI:  https://doi.org/10.1016/j.ejcb.2024.151399
J Physiol. 2024 Feb 24.

Conserved mammalian muscle mechanics during eccentric contractions.

Roger W P Kissane, Graham N Askew.

  Skeletal muscle has a broad range of biomechanical functions, including power generation and energy absorption. These roles are underpinned by the force-velocity relationship, which comprises two distinct components: a concentric and an eccentric force-velocity relationship. The concentric component has been extensively studied across a wide range of muscles with different muscle properties. However, to date, little progress has been made in accurately characterising the eccentric force-velocity relationship in mammalian muscle with varying muscle properties. Consequently, mathematical models of this muscle behaviour are based on a poorly understood phenomenon. Here, we present a comprehensive assessment of the concentric force-velocity and eccentric force-velocity relationships of four mammalian muscles (soleus, extensor digitorum longus, diaphragm and digastric) with varying biomechanical functions, spanning three orders of magnitude in body mass (mouse, rat and rabbits). The force-velocity relationship was characterised using a hyperbolic-linear equation for the concentric component a hyperbolic equation for the eccentric component, at the same time as measuring the rate of force development in the two phases of force development in relation to eccentric lengthening velocity. We demonstrate that, despite differences in the curvature and plateau height of the eccentric force-velocity relationship, the rates of relative force development were consistent for the two phases of the force-time response during isovelocity lengthening ramps, in relation to lengthening velocity, in the four muscles studied. Our data support the hypothesis that this relationship depends on cross-bridge and titin activation. Hill-type musculoskeletal models of the eccentric force-velocity relationship for mammalian muscles should incorporate this biphasic force response. KEY POINTS: The capacity of skeletal muscle to generate mechanical work and absorb energy is underpinned by the force-velocity relationship. Despite identification of the lengthening (eccentric) force-velocity relationship over 80 years ago, no comprehensive study has been undertaken to characterise this relationship in skeletal muscle. We show that the biphasic force response seen during active muscle lengthening is conserved over three orders of magnitude of mammalian skeletal muscle mass. Using mice with a small deletion in titin, we show that part of this biphasic force profile in response to muscle lengthening is reliant on normal titin activation. The rate of force development during muscle stretch may be a more reliable way to describe the forces experienced during eccentric muscle contractions compared to the traditional hyperbolic curve fitting, and functions as a novel predictor of force-velocity characteristics that may be used to better inform hill-type musculoskeletal models and assess pathophysiological remodelling.

Keywords:  force-velocity; lengthening; muscle mechanics; scaling; titin

DOI:  https://doi.org/10.1113/JP285549
Front Mol Neurosci. 2024 ;17 1356326

Consequences of GMPPB deficiency for neuromuscular development and maintenance.

Mona K Schurig, Obinna Umeh, Henriette Henze, M Juliane Jung, Lennart Gresing, Véronique Blanchard, Julia von Maltzahn, Christian A Hübner, Patricia Franzka.

  Guanosine diphosphate-mannose pyrophosphorylase B (GMPPB) catalyzes the conversion of mannose-1-phosphate and GTP to GDP-mannose, which is required as a mannose donor for the biosynthesis of glycan structures necessary for proper cellular functions. Mutations in GMPPB have been associated with various neuromuscular disorders such as muscular dystrophy and myasthenic syndromes. Here, we report that GMPPB protein abundance increases during brain and skeletal muscle development, which is accompanied by an increase in overall protein mannosylation. To model the human disorder in mice, we generated heterozygous GMPPB KO mice using CIRSPR/Cas9. While we were able to obtain homozygous KO mice from heterozygous matings at the blastocyst stage, homozygous KO embryos were absent beyond embryonic day E8.5, suggesting that the homozygous loss of GMPPB results in early embryonic lethality. Since patients with GMPPB loss-of-function manifest with neuromuscular disorders, we investigated the role of GMPPB in vitro. Thereby, we found that the siRNA-mediated knockdown of Gmppb in either primary myoblasts or the myoblast cell line C2C12 impaired myoblast differentiation and resulted in myotube degeneration. siRNA-mediated knockdown of Gmppb also impaired the neuron-like differentiation of N2A cells. Taken together, our data highlight the essential role of GMPPB during development and differentiation, especially in myogenic and neuronal cell types.

Keywords:  GMPPB; glycosylation; mannosylation; myogenesis; nervous system; neurogenesis; skeletal muscle

DOI:  https://doi.org/10.3389/fnmol.2024.1356326
Exp Physiol. 2024 Feb 29.

The effect of protein or amino acid provision on immobilization-induced muscle atrophy in healthy adults: A systematic review and meta-analysis.

Alix K Hughes, Thomas Francis, Jessica Rooney, Ross Pollock, Oliver C Witard.

  Bed rest and limb immobilization are models of muscle disuse associated with skeletal muscle atrophy and reduced strength. The purpose of this systematic review was to examine the impact of protein or amino acid provision before and/or during a period of muscle disuse on muscle atrophy (primary outcome), strength and muscle protein synthesis (secondary outcomes) following a disuse period. We performed a systematic review of Embase, MEDLINE, Web of Science, PubMed and Clinical Trials in December 2022. Eligible studies were randomized controlled trials that combined a dietary protein or amino acid intervention versus control during an experimental model of disuse (bed rest or unilateral limb immobilization) in healthy individuals aged ≥18 years. Nine articles from eight independent trials were identified and rated for risk of bias by two authors. A meta-analysis of muscle mass data revealed no effect (standardized mean difference: 0.2; 95% confidence interval: -0.18 to 0.57, P = 0.31) of protein/amino acid intervention in preventing disuse-induced muscle atrophy. Although the meta-analysis was not conducted on strength or muscle protein synthesis data, there was insufficient evidence in the reviewed articles to support the use of protein/amino acid provision in mitigating the disuse-induced decline in either outcome measurement. Additional high-quality studies, including the reporting of randomization procedures and blinding procedures and the provision of statistical analysis plans, might be required to determine whether protein or amino acid provision serves as an effective strategy to attenuate muscle atrophy during periods of disuse.

Keywords:  muscle atrophy; muscle disuse; muscle mass; nutrition; protein

DOI:  https://doi.org/10.1113/EP090434
Trends Mol Med. 2024 Feb 25. pii: S1471-4914(24)00007-8. [Epub ahead of print]

HDAC inhibitors as pharmacological treatment for Duchenne muscular dystrophy: a discovery journey from bench to patients.

Chiara Mozzetta, Vittorio Sartorelli, Christian Steinkuhler, Pier Lorenzo Puri.

  Earlier evidence that targeting the balance between histone acetyltransferases (HATs) and deacetylases (HDACs), through exposure to HDAC inhibitors (HDACis), could enhance skeletal myogenesis, prompted interest in using HDACis to promote muscle regeneration. Further identification of constitutive HDAC activation in dystrophin-deficient muscles, caused by dysregulated nitric oxide (NO) signaling, provided the rationale for HDACi-based therapeutic interventions for Duchenne muscular dystrophy (DMD). In this review, we describe the molecular, preclinical, and clinical evidence supporting the efficacy of HDACis in countering disease progression by targeting pathogenic networks of gene expression in multiple muscle-resident cell types of patients with DMD. Given that givinostat is paving the way for HDACi-based interventions in DMD, next-generation HDACis with optimized therapeutic profiles and efficacy could be also explored for synergistic combinations with other therapeutic strategies.

Keywords:  HDAC inhibitors; duchenne muscular dystrophy; fibro-adipogenic degeneration; histone acetylation; muscle regeneration

DOI:  https://doi.org/10.1016/j.molmed.2024.01.007
Biogerontology. 2024 Feb 26.

The SGLT2 inhibitor empagliflozin inhibits skeletal muscle fibrosis in naturally aging male mice through the AMPKα/MMP9/TGF-β1/Smad pathway.

Qixuan Huang, Jie Chen, Siqi Liao, Jiangchuan Long, Ronghua Fang, Yusen He, Peiyun Chen, Dongfang Liu.

  ABSTACT: With advancing age, the incidence of sarcopenia increases, eventually leading to a cascade of adverse events. However, there is currently a lack of effective pharmacological treatment for sarcopenia. Sodium-glucose co-transporter 2 inhibitor (SGLT2i) empagliflozin demonstrates anti-fibrotic capabilities in various organs. This study aims to determine whether empagliflozin can improve skeletal muscle fibrosis induced by sarcopenia in naturally aging mice. A natural aging model was established by feeding male mice from 13 months of age to 19 months of age. A fibrosis model was created by stimulating skeletal muscle fibroblasts with TGF-β1. The Forelimb grip strength test assessed skeletal muscle function, and expression levels of COL1A1, COL3A1, and α-SMA were analyzed by western blot, qPCR, and immunohistochemistry. Additionally, levels of AMPKα/MMP9/TGFβ1/Smad signaling pathways were examined. In naturally aging mice, skeletal muscle function declines, expression of muscle fibrosis markers increases, AMPKα expression is downregulated, and MMP9/TGFβ1/Smad signaling pathways are upregulated. However, treatment with empagliflozin reverses this phenomenon. At the cellular level, empagliflozin exhibits similar anti-fibrotic effects, and these effects are attenuated by Compound C and siAMPKα. Empagliflozin exhibits anti-fibrotic effects, possibly associated with the AMPK/MMP9/TGFβ1/Smad signaling pathways.

Keywords:  AMPKα; Empagliflozin; Fibrosis; Sarcopenia; Smad; TGFβ1

DOI:  https://doi.org/10.1007/s10522-024-10093-y
EMBO Rep. 2024 Mar 01.

Mitochondrial fusion and altered beta-oxidation drive muscle wasting in a Drosophila cachexia model.

Callum Dark, Nashia Ali, Sofya Golenkina, Vaibhav Dhyani, Ronnie Blazev, Benjamin L Parker, Kate T Murphy, Gordon S Lynch, Tarosi Senapati, S Sean Millard, Sarah M Judge, Andrew R Judge, Lopamudra Giri, Sarah M Russell, Louise Y Cheng.

  Cancer cachexia is a tumour-induced wasting syndrome, characterised by extreme loss of skeletal muscle. Defective mitochondria can contribute to muscle wasting; however, the underlying mechanisms remain unclear. Using a Drosophila larval model of cancer cachexia, we observed enlarged and dysfunctional muscle mitochondria. Morphological changes were accompanied by upregulation of beta-oxidation proteins and depletion of muscle glycogen and lipid stores. Muscle lipid stores were also decreased in Colon-26 adenocarcinoma mouse muscle samples, and expression of the beta-oxidation gene CPT1A was negatively associated with muscle quality in cachectic patients. Mechanistically, mitochondrial defects result from reduced muscle insulin signalling, downstream of tumour-secreted insulin growth factor binding protein (IGFBP) homologue ImpL2. Strikingly, muscle-specific inhibition of Forkhead box O (FOXO), mitochondrial fusion, or beta-oxidation in tumour-bearing animals preserved muscle integrity. Finally, dietary supplementation with nicotinamide or lipids, improved muscle health in tumour-bearing animals. Overall, our work demonstrates that muscle FOXO, mitochondria dynamics/beta-oxidation and lipid utilisation are key regulators of muscle wasting in cancer cachexia.

Keywords:   Drosophila ; Cachexia; Lipid Metabolism; Muscle

DOI:  https://doi.org/10.1038/s44319-024-00102-z
Cell Rep. 2024 Feb 26. pii: S2211-1247(24)00182-7. [Epub ahead of print]43(3): 113854

Flvcr1a deficiency promotes heme-based energy metabolism dysfunction in skeletal muscle.

Miriam Mistretta, Veronica Fiorito, Anna Lucia Allocco, Giorgia Ammirata, Myriam Y Hsu, Sabrina Digiovanni, Marzia Belicchi, Laura Napoli, Michela Ripolone, Elena Trombetta, PierLuigi Mauri, Andrea Farini, Mirella Meregalli, Chiara Villa, Paolo Ettore Porporato, Barbara Miniscalco, Simonetta Geninatti Crich, Chiara Riganti, Yvan Torrente, Emanuela Tolosano.

  The definition of cell metabolic profile is essential to ensure skeletal muscle fiber heterogeneity and to achieve a proper equilibrium between the self-renewal and commitment of satellite stem cells. Heme sustains several biological functions, including processes profoundly implicated with cell metabolism. The skeletal muscle is a significant heme-producing body compartment, but the consequences of impaired heme homeostasis on this tissue have been poorly investigated. Here, we generate a skeletal-muscle-specific feline leukemia virus subgroup C receptor 1a (FLVCR1a) knockout mouse model and show that, by sustaining heme synthesis, FLVCR1a contributes to determine the energy phenotype in skeletal muscle cells and to modulate satellite cell differentiation and muscle regeneration.

Keywords:  ALAS1; CP: Metabolism; FLVCR1; FLVCR1a; heme; metabolism; skeletal muscle

DOI:  https://doi.org/10.1016/j.celrep.2024.113854
FASEB J. 2024 Mar 15. 38(5): e23502

Podocan promoting skeletal muscle post-injury regeneration by inhibiting TGF-β signaling pathway.

Huaixin Teng, Jingxian Zheng, Yanyan Liang, Jingwen Zhao, Yunqin Yan, Shufeng Li, Shuang Li, Huili Tong.

  Podocan, the fifth member of Small Leucine-Rich Proteoglycan (SLRP) family of extracellular matrix components, is poorly known in muscle development. Previous studies have shown that Podocan promotes C2C12 differentiation in mice. In this study, we elucidated the effect of Podocan on skeletal muscle post-injury regeneration and its underlying mechanism. Injection of Podocan protein promoted the process of mice skeletal muscle post-injury regeneration. This effect seemed to be from the acceleration of muscle satellite cell differentiation in vivo. Meanwhile, Podocan promoted myogenic differentiation in vitro by binding with TGF-β1 to inhibit the activity of the TGF-β signaling pathway. These results indicated that Podocan had the potential roles to enhance skeletal muscle post-injury regeneration. Its mechanism is likely the regulation of the expression of p-Smad2 and p-Smad4 related to the TGF-β signaling pathway by interacting with TGF-β1.

Keywords:  Podocan; TGF-β signaling pathway; differentiation; regeneration; skeletal muscle

DOI:  https://doi.org/10.1096/fj.202302158RR
J Physiol. 2024 Mar 01.

Turning fat into muscle: can this be an alternative to anti-obesity drugs such as semaglutide?

Henning Wackerhage, Arne Hinrichs, Eckhard Wolf, Martin Hrabě de Angelis.



Keywords:  GLP-1 receptor agonists; diabetes mellitus; hypertrophy; muscle atrophy; obesity; skeletal muscle

DOI:  https://doi.org/10.1113/JP286430
Acta Biochim Biophys Sin (Shanghai). 2024 Feb 28.

RASGRP1 targeted by H3K27me3 regulates myoblast proliferation and differentiation in mice and pigs.

Liyao Xiao, Jiaxin Qiao, Yiyang Huang, Baohua Tan, Linjun Hong, Zicong Li, Gengyuan Cai, Zhenfang Wu, Enqin Zheng, Shanshan Wang, Ting Gu.

  Skeletal muscle is not only the largest organ in the body that is responsible for locomotion and exercise but also crucial for maintaining the body's energy metabolism and endocrine secretion. The trimethylation of histone H3 lysine 27 (H3K27me3) is one of the most important histone modifications that participates in muscle development regulation by repressing the transcription of genes. Previous studies indicate that the RASGRP1 gene is regulated by H3K27me3 in embryonic muscle development in pigs, but its function and regulatory role in myogenesis are still unclear. In this study, we verify the crucial role of H3K27me3 in RASGRP1 regulation. The gain/loss function of RASGRP1 in myogenesis regulation is performed using mouse myoblast C2C12 cells and primarily isolated porcine skeletal muscle satellite cells (PSCs). The results of qPCR, western blot analysis, EdU staining, CCK-8 assay and immunofluorescence staining show that overexpression of RASGRP1 promotes cell proliferation and differentiation in both skeletal muscle cell models, while knockdown of RASGRP1 leads to the opposite results. These findings indicate that RASGRP1 plays an important regulatory role in myogenesis in both mice and pigs.

Keywords:  H3K27me3; RASGRP1; cell proliferation; myoblasts; skeletal muscle

DOI:  https://doi.org/10.3724/abbs.2024011
Physiol Rep. 2024 Feb;12(4): e15958

Lower basal and postprandial muscle protein synthesis after 2 weeks single-leg immobilization in older men: No protective effect of anti-inflammatory medication.

K Dideriksen, S Reitelseder, A P Boesen, M Zillmer, J Agergaard, M Kjaer, L Holm.

  Muscle inactivity may reduce basal and postprandial muscle protein synthesis (MPS) rates in humans. Anti-inflammatory treatment alleviates the MPS impairments in younger individuals. The present study explored the influence of nonsteroidal anti-inflammatory drugs (NSAIDs) upon MPS during a period of inactivity in older humans. Eighteen men (age 60-80 years) were allocated to ibuprofen (1200 mg/day, Ibu) or control (Plc) groups. One lower limb was cast immobilized for 2 weeks. Postabsorptive and postprandial MPS was measured before and after the immobilization by L-[ring-13 C6 ]-phenylalanine infusion. The protein expression of select anabolic signaling molecules was investigated by western blot. Basal (0.038 ± 0.002%/h and 0.039 ± 0.005%/h, Plc and Ibu, respectively) and postprandial (0.064 ± 0.004%/h and 0.067 ± 0.010%/h, Plc and Ibu, respectively) MPS rate were higher pre-immobilization compared to basal (0.019 ± 0.005%/h and 0.020 ± 0.010%/h, Plc and Ibu, respectively) and postprandial (0.033 ± 0.005%/h and 0.037 ± 0.006%/h, Plc and Ibu, respectively) MPS rate post-immobilization (p < 0.001). NSAID treatment did not affect the suppression of MPS (p > 0.05). The anabolic signaling were in general reduced after immobilization (p < 0.05). These changes were unaffected by NSAID treatment (p > 0.05). Basal and postprandial MPS dropped markedly after 2 weeks of lower limb immobilization. NSAID treatment neither influenced the reduction in MPS nor the anabolic signaling after immobilization in healthy older individuals.

Keywords:  anabolic resistance; ibuprofen; muscle disuse; muscle inactivity; muscle protein synthesis signaling; myofibrillar FSR

DOI:  https://doi.org/10.14814/phy2.15958
Nat Genet. 2024 Mar 01.

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.

Ana Töpf, Dan Cox, Irina T Zaharieva, Valeria Di Leo, Jaakko Sarparanta, Per Harald Jonson, Ian M Sealy, Andrei Smolnikov, Richard J White, Anna Vihola, Marco Savarese, Munise Merteroglu, Neha Wali, Kristen M Laricchia, Cristina Venturini, Bas Vroling, Sarah L Stenton, Beryl B Cummings, Elizabeth Harris, Chiara Marini-Bettolo, Jordi Diaz-Manera, Matt Henderson, Rita Barresi, Jennifer Duff, Eleina M England, Jane Patrick, Sundos Al-Husayni, Valerie Biancalana, Alan H Beggs, Istvan Bodi, Shobhana Bommireddipalli, Carsten G Bönnemann, Anita Cairns, Mei-Ting Chiew, Kristl G Claeys, Sandra T Cooper, Mark R Davis, Sandra Donkervoort, Corrie E Erasmus, Mahmoud R Fassad, Casie A Genetti, Carla Grosmann, Heinz Jungbluth, Erik-Jan Kamsteeg, Xavière Lornage, Wolfgang N Löscher, Edoardo Malfatti, Adnan Manzur, Pilar Martí, Tiziana E Mongini, Nuria Muelas, Atsuko Nishikawa, Anne O'Donnell-Luria, Narumi Ogonuki, Gina L O'Grady, Emily O'Heir, Stéphanie Paquay, Rahul Phadke, Beth A Pletcher, Norma B Romero, Meyke Schouten, Snehal Shah, Izelle Smuts, Yves Sznajer, Giorgio Tasca, Robert W Taylor, Allysa Tuite, Peter Van den Bergh, Grace VanNoy, Nicol C Voermans, Julia V Wanschitz, Elizabeth Wraige, Kimihiko Yoshimura, Emily C Oates, Osamu Nakagawa, Ichizo Nishino, Jocelyn Laporte, Juan J Vilchez, Daniel G MacArthur, Anna Sarkozy, Heather J Cordell, Bjarne Udd, Elisabeth M Busch-Nentwich, Francesco Muntoni, Volker Straub.

In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3-/-; ttn.1+/-) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases.

DOI: https://doi.org/10.1038/s41588-023-01651-0
ACS Biomater Sci Eng. 2024 Feb 29.

Aligned Nanofibers Promote Myoblast Polarization and Myogenesis through Activating Rac-Related Signaling Pathways.

Xiangyu Dong, Shan Su, Qian Sun, Peng Wang, Qian Hu, Qiang Wei.

  The extracellular matrix (ECM) plays a crucial role in regulating cellular behaviors and functions. However, the impact of ECM topography on muscle cell adhesion and differentiation remains poorly understood from a mechanosensing perspective. In this study, we fabricated aligned and random electrospun polycaprolactone (PCL) nanofibers to mimic the structural characteristics of ECM. Mechanism investigations revealed that the orientation of nanofibers promoted C2C12 polarization and myogenesis through Rac-related signaling pathways. Conversely, cells cultured on random fibers exhibited spreading behavior mediated by RhoA/ROCK pathways, resulting in enhanced stress fiber formation but reduced capacity for myogenic differentiation. Our findings highlight the critical role of an ECM structure in muscle regeneration and damage repair, providing novel insights into mechanosensing mechanisms underlying muscle injury diseases.

Keywords:  electrospinning; mechanosensing; myoblast; myogenesis; pseudopodia

DOI:  https://doi.org/10.1021/acsbiomaterials.4c00127
Eur J Pediatr. 2024 Feb 28.

Impact of preterm birth on muscle mass and function: a systematic review and meta-analysis.

Alyson Deprez, Jéssica H Poletto Bonetto, Daniela Ravizzoni Dartora, Philippe Dodin, Anne Monique Nuyt, Thuy Mai Luu, Nicolas A Dumont.

  Individuals born preterm present lower exercise capacity. Along with the cardiopulmonary responses and activity level, muscle strength is a key determinant of exercise capacity. This systematic review aimed to summarize the current knowledge on the impact of preterm birth on skeletal muscle mass and function across the lifespan. The databases PubMed, MEDLINE, EBM, Embase, CINAHL Plus, Global Index Medicus, and Google Scholar were searched using keywords and MeSH terms related to skeletal muscle, preterm birth, and low birth weight. Two independent reviewers undertook study selection, data extraction, and quality appraisal using Covidence review management. Data were pooled to estimate the prematurity effect on muscle mass and function using the R software. From 4378 studies retrieved, 132 were full-text reviewed and 25 met the inclusion/exclusion criteria. Five studies presented a low risk of bias, and 5 had a higher risk of bias due to a lack of adjustment for confounding factors and presenting incomplete outcomes. Meta-analyses of pooled data from homogenous studies indicated a significant reduction in muscle thickness and jump test (muscle power) in individuals born preterm versus full-term with standardized mean difference and confidence interval of - 0.58 (0.27, 0.89) and - 0.45 (0.21, 0.69), respectively. Conclusion: Overall, this systematic review summarizing the existing literature on the impact of preterm birth on skeletal muscle indicates emerging evidence that individuals born preterm, display alteration in the development of their skeletal muscle mass and function. This work also highlights a clear knowledge gap in understanding the effect of preterm birth on skeletal muscle development. What is Known: • Preterm birth, which occurs at a critical time of skeletal muscle development and maturation, impairs the development of different organs and tissues leading to a higher risk of comorbidities such as cardiovascular diseases. • Preterm birth is associated with reduced exercise capacity. What is New: • Individuals born preterm display alterations in muscle mass and function compared to individuals born at term from infancy to adulthood. • There is a need to develop preventive or curative interventions to improve skeletal muscle health in preterm-born individuals.

Keywords:  Exercise capacity; Muscle function; Muscle mass; Preterm birth; Skeletal muscle

DOI:  https://doi.org/10.1007/s00431-023-05410-5
Discov Med. 2024 Feb;36(181): 402-414

IGF-1 Regulates Skeletal Muscle Degradation and Remolding in Ventilator-Induced Diaphragmatic Dysfunction by Mediating FOXO1 Expression.

Luyu Yang, Xiaohong Jiang, Shouzhi Fu, Jinhui Tan, Wankang Dian, Yumei Zhou.

  BACKGROUND: Mechanical ventilation (MV) sustains life in critically ill patients by providing adequate alveolar ventilation. However, prolonged MV could induce inspiratory muscle atrophy known as ventilator-induced diaphragmatic dysfunction (VIDD). Insulin-like growth factor (IGF)-1 has been proven to play crucial roles in regulating skeletal muscle size and function. Meanwhile, the forkhead box protein O1 (FOXO1) has been linked to muscle atrophy. This study aimed to explore the effect of IGF-1 on muscle degradation and remodeling in VIDD and delved into the association of the underlying mechanism involving FOXO1.METHODS: VIDD models were established by treating rats with MV. Adeno-associated virus (AAV) was used for transfection to construct IGF-1 and/or FOXO1 overexpressed rats. There were four groups in this study: normal rats (NC), normal rats with MV treatment (MV), IGF-1-overexpressed rats with MV treatment (MV+IGF-1), and rats overexpressing both IGF-1 and FOXO1 with MV treatment (MV+IGF-1+FOXO1). Protein levels were measured by western blot or enzyme-linked immunosorbent assay (ELISA), and mRNA levels were detected by real-time reverse transcriptase-polymerase chain reaction (RT-qPCR). IGF-1 and FOXO1 expression were validated by detecting mRNA and protein levels. Diaphragmatic muscle contractility and morphometry were tested using stimulating electrodes in conjunction with hematoxylin and eosin (H&E) staining. Interleukin (IL)-6 and carbonylated protein were used for evaluating muscle atrophy and oxidation, respectively. Protein degradation was determined by troponin-I level and tyrosine release. Apoptosis was assessed using the terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate (UTP) nick-end labeling (TUNEL) assay, alongside markers like Bax, B-cell lymphoma 2 (BCL-2), and Cleaved Caspase-3. Atrogin-1, muscle RING finger 1 (MURF1), neuronally expressed developmentally downregulated 4 (NEDD4), muscle ubiquitin ligase of SCF complex in atrophy-1 (MUSA1), and ubiquitinated protein was used to determine proteolysis. Additionally, protein synthesis was measured by assessing the rates of mixed muscle protein (MMP) and myosin heavy chain (MHC).
RESULTS: MV treatment caused IGF-1 downregulation (p < 0.01) and FOXO1 upregulation (p < 0.01). The IGF-1 upregulation downregulated FOXO1 in the MV+IGF-1 group (p < 0.001) while IGF-1 and FOXO1 were both upregulated in the MV+IGF-1+FOXO1 group (p < 0.001). The treatment of MV decreased muscle contractility and cross-sectional areas of diaphragm muscle fibers (p < 0.01). Additionally, IL-6, troponin-1, tyrosine release, carbonylated protein, TUNEL positive nuclei, Bax, Cleaved Caspase-3, Atrogin-1, MURF1, neuronally expressed developmentally downregulated 4 (NEDD4), MUSA1, and ubiquitinated protein levels increased significantly in MV group (p < 0.001) while levels of BCL-2, fractional synthetic rate of MMP and MHC, and type I and type II MHC protein mRNA expression decreased in MV group (p < 0.001). All of these alterations were reversed in the MV+IGF-1 group (p < 0.01), while the IGF-1-induced reversion was disrupted in the MV+IGF-1+FOXO1 group (p < 0.01).
CONCLUSIONS: IGF-1 may protect diaphragmatic muscles from VIDD-induced structural damage and function loss by downregulating FOXO1. This action suppresses muscle breakdown and facilitates muscle remodeling in diaphragmatic muscles affected by VIDD.

Keywords:  FOXO1; IGF-1; VIDD; diaphragm; skeletal muscle; ventilator-induced diaphragmatic dysfunction

DOI:  https://doi.org/10.24976/Discov.Med.202436181.38
Clin Physiol Funct Imaging. 2024 Mar 01.

Skeletal muscle estimation: A review of techniques and their applications.

Christian Rodriguez, Jacob D Mota, Ty B Palmer, Steven B Heymsfield, Grant M Tinsley.

  Quantifying skeletal muscle size is necessary to identify those at risk for conditions that increase frailty, morbidity, and mortality, as well as decrease quality of life. Although muscle strength, muscle quality, and physical performance have been suggested as important assessments in the screening, prevention, and management of sarcopenic and cachexic individuals, skeletal muscle size is still a critical objective marker. Several techniques exist for estimating skeletal muscle size; however, each technique presents with unique characteristics regarding simplicity/complexity, cost, radiation dose, accessibility, and portability that are important factors for assessors to consider before applying these modalities in practice. This narrative review presents a discussion centred on the theory and applications of current non-invasive techniques for estimating skeletal muscle size in diverse populations. Common instruments for skeletal muscle assessment include imaging techniques such as computed tomography, magnetic resonance imaging, peripheral quantitative computed tomography, dual-energy X-ray absorptiometry, and Brightness-mode ultrasound, and non-imaging techniques like bioelectrical impedance analysis and anthropometry. Skeletal muscle size can be acquired from these methods using whole-body and/or regional assessments, as well as prediction equations. Notable concerns when conducting assessments include the absence of standardised image acquisition/processing protocols and the variation in cut-off thresholds used to define low skeletal muscle size by clinicians and researchers, which could affect the accuracy and prevalence of diagnoses. Given the importance of evaluating skeletal muscle size, it is imperative practitioners are informed of each technique and their respective strengths and weaknesses.

Keywords:  body composition; cachexia; computed tomography; dual-energy X-ray absorptiometry; magnetic resonance imaging; sarcopenia

DOI:  https://doi.org/10.1111/cpf.12874
Curr Osteoporos Rep. 2024 Mar 01.

Extracellular Vesicles and Exosomes in the Control of the Musculoskeletal Health.

Fabio Penna, Lorena Garcia-Castillo, Paola Costelli.

  PURPOSE OF REVIEW: The present review will highlight recent reports supporting the relevance of extracellular vesicles to the musculoskeletal system in health and disease.RECENT FINDINGS: Preserving the health of the musculoskeletal system is important to maintain a good quality of life, and the bone-muscle crosstalk is crucial in this regard. This latter is largely mediated by extracellular vesicles released by the different cell populations residing in muscle and bone, which deliver cargoes, microRNAs, and proteins being the most relevant ones, to target cells. Extracellular vesicles could be exploited as therapeutic tools, in view of their resistance to destruction in the biological fluid and of the possibility to be functionalized according to the need. Extracellular vesicles are recognized as crucial players in the bone-muscle cross-talk. Additional studies however are required to refine their use as biomarkers of early alterations of the musculoskeletal system, and as potential therapeutic tools.

Keywords:  Bone loss; MicroRNAs; Muscle-bone cross-talk; Sarcopenia; Therapeutic tools

DOI:  https://doi.org/10.1007/s11914-024-00866-2
Mol Oncol. 2024 Feb 27.

Cancer cachexia: biomarkers and the influence of age.

Julia Geppert, Maria Rohm.

  Cancer cachexia (Ccx) is a complex metabolic condition characterized by pronounced muscle and fat wasting, systemic inflammation, weakness and fatigue. Up to 30% of cancer patients succumb directly to Ccx, yet therapies that effectively address this perturbed metabolic state are rare. In recent decades, several characteristics of Ccx have been established in mice and humans, of which we here highlight adipose tissue dysfunction, muscle wasting and systemic inflammation, as they are directly linked to biomarker discovery. To counteract cachexia pathogenesis as early as possible and mitigate its detrimental impact on anti-cancer treatments, identification and validation of clinically endorsed biomarkers assume paramount importance. Ageing was recently shown to affect both the validity of Ccx biomarkers and Ccx development, but the underlying mechanisms are still unknown. Thus, unravelling the intricate interplay between ageing and Ccx can help to counteract Ccx pathogenesis and tailor diagnostic and treatment strategies to individual needs.

Keywords:  ageing; biomarker; cachexia; cancer; inflammation; metabolism

DOI:  https://doi.org/10.1002/1878-0261.13590