bims-moremu 2024-06-16 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2024–06–16
twenty-two papers selected by
Anna Vainshtein, Craft Science Inc.

C16ORF70/Mytho promotes healthy ageing in C. elegans and prevents cellular senescence in mammals.
Inflammatory pathway communication with skeletal muscle-Does aging play a role? A topical review of the current evidence.
Microbial-Derived Exerkines Prevent Skeletal Muscle Atrophy.
Superoxide is an intrinsic signaling molecule triggering muscle hypertrophy.
Short-term aerobic exercise prevents development of glucocorticoid myopathic features in aged skeletal muscle in a sex-dependent manner.
Targeted expression of heme oxygenase-1 in satellite cells improves skeletal muscle pathology in dystrophic mice.
A dual-color PAX7 and MYF5 in vivo reporter to investigate muscle stem cell heterogeneity in regeneration and aging.
Immunomodulatory Role of the Stem Cell Circadian Clock in Muscle Repair.
Modulation of macrophage transcript and secretion profiles by Sargassum Serratifolium extract is associated with the suppression of muscle atrophy.
The TAS1R2 G-protein-coupled receptor is an ambient glucose sensor in skeletal muscle that regulates NAD homeostasis and mitochondrial capacity.
More than the clock: distinct regulation of muscle function and metabolism by PER2 and RORα.
Mini-MEndR: a miniaturized 96-well predictive assay to evaluate muscle stem cell-mediated repair.
Myricanol prevents aging-related sarcopenia by rescuing mitochondrial dysfunction via targeting peroxiredoxin 5.
Interplay between Pitx2 and Pax7 temporally governs specification of extraocular muscle stem cells.
Emerging role of HDAC11 in skeletal muscle biology.
Development of Ryanodine Receptor (RyR) Inhibitors for Skeletal Muscle and Heart Diseases.
Sex Differences in the Association between Skeletal Muscle Energetics and Perceived Physical Fatigability: The Study of Muscle, Mobility and Aging (SOMMA).
Bioreactor development for skeletal muscle hypertrophy and atrophy by manipulating uniaxial cyclic strain: proof of concept.
Single-cell RNA sequencing analysis provides novel insights into the role of apoptosis-related genes in muscle aging.
Long-Term Resistance Trained Human Muscles Have More Fibres, More Myofibrils and Tighter Myofilament Packing than Untrained.
Type 2 diabetes mellitus related sarcopenia: a type of muscle loss distinct from sarcopenia and disuse muscle atrophy.
Aging and putative frailty biomarkers are altered by spaceflight.

J Clin Invest. 2024 Jun 13. pii: e165814. [Epub ahead of print]

C16ORF70/Mytho promotes healthy ageing in C. elegans and prevents cellular senescence in mammals.

Anais Franco-Romero, Valeria Morbidoni, Giulia Milan, Roberta Sartori, Jesper Wulff, Vanina Romanello, Andrea Armani, Leonardo Salviati, Maria Conte, Stefano Salvioli, Claudio Franceschi, Viviana Buonomo, Casey O Swoboda, Paolo Grumati, Luca Pannone, Simone Martinelli, Harold Bj Jefferies, Ivan Dikic, Jennifer van der Laan, Filipe Cabreiro, Douglas P Millay, Sharon A Tooze, Eva Trevisson, Marco Sandri.

  The identification of genes that confer either extension of lifespan or accelerate age-related decline was a step forward in understanding the mechanisms of ageing and revealed that it is partially controlled by genetics and transcriptional programs. Here we discovered that the human DNA sequence C16ORF70 encoded for a protein, named MYTHO (Macroautophagy and YouTH Optimizer), which controls life- and health-span. MYTHO protein is conserved from C. elegans to humans and its mRNA was upregulated in aged mice and elderly people. Deletion of the ortholog myt-1 gene in C. elegans dramatically shortened lifespan and decreased animal survival upon exposure to oxidative stress. Mechanistically, MYTHO is required for autophagy likely because it acts as a scaffold that binds WIPI2 and BCAS3 to recruit and assemble the conjugation system at the phagophore, the nascent autophagosome. We conclude that MYTHO is a transcriptionally regulated initiator of autophagy that is central in promoting stress resistance and healthy ageing.

Keywords:  Aging; Autophagy; Cell biology; Cellular senescence; Skeletal muscle

DOI:  https://doi.org/10.1172/JCI165814
Physiol Rep. 2024 Jun;12(11): e16098

Inflammatory pathway communication with skeletal muscle-Does aging play a role? A topical review of the current evidence.

Stephen M Cornish, Dean M Cordingley.

  Skeletal muscle plays an integral role in locomotion, but also as part of the integrative physiological system. Recent progress has identified crosstalk between skeletal muscle and various physiological systems, including the immune system. Both the musculoskeletal and immune systems are impacted by aging. Increased age is associated with decreased muscle mass and function, while the immune system undergoes "inflammaging" and immunosenescence. Exercise is identified as a preventative medicine that can mitigate loss of function for both systems. This review summarizes: (1) the inflammatory pathways active in skeletal muscle; and (2) the inflammatory and skeletal muscle response to unaccustomed exercise in younger and older adults. Compared to younger adults, it appears older individuals have a muted pro-inflammatory response and elevated anti-inflammatory response to exercise. This important difference could contribute to decreased regeneration and recovery following unaccustomed exercise in older adults, as well as in chronic disease. The current research provides specific information on the role inflammation plays in altering skeletal muscle form and function, and adaptation to exercise; however, the pursuit of more knowledge in this area will delineate specific interventions that may enhance skeletal muscle recovery and promote resiliency in this tissue particularly with aging.

Keywords:  aging; exercise; inflammation; skeletal muscle

DOI:  https://doi.org/10.14814/phy2.16098
bioRxiv. 2024 Jun 02. pii: 2024.05.29.596432. [Epub ahead of print]

Microbial-Derived Exerkines Prevent Skeletal Muscle Atrophy.

Taylor R Valentino, Benjamin I Burke, Gyumin Kang, Jensen Goh, Cory M Dungan, Ahmed Ismaeel, C Brooks Mobley, Michael D Flythe, Yuan Wen, John J McCarthy.

Regular exercise yields a multitude of systemic benefits, many of which may be mediated through the gut microbiome. Here, we report that cecal microbial transplants (CMTs) from exercise-trained vs. sedentary mice have modest benefits in reducing skeletal muscle atrophy using a mouse model of unilaterally hindlimb-immobilization. Direct administration of top microbial-derived exerkines from an exercise-trained gut microbiome preserved muscle function and prevented skeletal muscle atrophy.

DOI: https://doi.org/10.1101/2024.05.29.596432
Antioxid Redox Signal. 2024 Jun 15.

Superoxide is an intrinsic signaling molecule triggering muscle hypertrophy.

Siyu Lu, Yiming Zhou, Mincong Liu, Lijun Gong, Li Liu, Zhigui Duan, Keke Chen, Frank Gonzalez, Fang Wei, Rong Xiang, Guolin Li.

AIMS: Redox signaling plays a key role in skeletal muscle remodeling induced by exercise and prolonged inactivity, but it is unclear which oxidant triggers myofiber hypertrophy due to the lack of strategies to precisely regulate individual oxidants in vivo. In this study, we used tetrathiomolybdate (TM) to dissociate the link between superoxide and H2O2 and thereby to specifically explore the role of superoxide in muscle hypertrophy in C2C12 cells and mice.
RESULTS: TM can linearly regulate intracellular superoxide levels by inhibition of superoxide dismutase 1 (SOD1). A 70% increase in superoxide levels in C2C12 myoblast cells and mice is necessary and sufficient for triggering hypertrophy of differentiated myotubes, and can enhance exercise performance by more than 50% in mice. SOD1 knockout blocks TM-induced superoxide increments and thereby prevents hypertrophy, whereas SOD1 restoration rescues all these effects. Scavenging superoxide with antioxidants abolishes TM-induced hypertrophy and the enhancement of exercise performance, while the restoration of superoxide levels with a superoxide generator promotes muscle hypertrophy independent of SOD1 activity.
INNOVATION AND CONCLUSION: These findings suggest that superoxide is an endogenous initiator of myofiber hypertrophy, and that TM may be used to treat muscle wasting diseases. Our work not only suggests a novel druggable mechanism to increase muscle mass but also provides a tool for precisely regulating superoxide levels in vivo.

DOI: https://doi.org/10.1089/ars.2024.0595
J Physiol. 2024 Jun 11.

Short-term aerobic exercise prevents development of glucocorticoid myopathic features in aged skeletal muscle in a sex-dependent manner.

Grant R Laskin, Liliana I Rentería, Judy M Muller-Delp, Jeong-Su Kim, P Bryant Chase, Hyun Seok Hwang, Bradley S Gordon.

  Older adults are vulnerable to glucocorticoid-induced muscle atrophy and weakness, with sex potentially influencing their susceptibility to those effects. Aerobic exercise can reduce glucocorticoid-induced muscle atrophy in young rodents. However, it is unknown whether aerobic exercise can prevent glucocorticoid myopathy in aged muscle. The objectives of this study were to define the extent to which sex influences the development of glucocorticoid myopathy in aged muscle, and to determine the extent to which aerobic exercise training protects against myopathy development. Twenty-four-month-old female (n = 30) and male (n = 33) mice were randomized to either sedentary or aerobic exercise groups. Within their respective groups, mice were randomized to either daily treatment with dexamethasone (DEX) or saline. Upon completing treatments, the contractile properties of the triceps surae complex were assessed in situ. DEX marginally lowered muscle mass and soluble protein content in both sexes, which was attenuated by aerobic exercise only in females. DEX increased sub-tetanic force and rate of force development only in females, which was not influenced by aerobic exercise. Muscle fatigue was higher in both sexes following DEX, but aerobic exercise prevented fatigue induction only in females. The sex-specific differences to muscle function in response to DEX treatment coincided with sex-specific changes to the content of proteins related to calcium handling, mitochondrial quality control, reactive oxygen species production, and glucocorticoid receptor in muscle. These findings define several important sexually dimorphic changes to aged skeletal muscle physiology in response to glucocorticoid treatment and define the capacity of short-term aerobic exercise to protect against those changes. KEY POINTS: There are sexually dimorphic effects of glucocorticoids on aged skeletal muscle physiology. Glucocorticoid-induced changes to aged muscle contractile properties coincide with sex-specific differences in the content of calcium handling proteins. Aerobic exercise prevents glucocorticoid-induced fatigue only in aged females and coincides with differences in the content of mitochondrial quality control proteins and glucocorticoid receptors.

Keywords:  calcium handling; contractile function; dexamethasone; fatigue

DOI:  https://doi.org/10.1113/JP286334
Skelet Muscle. 2024 Jun 12. 14(1): 13

Targeted expression of heme oxygenase-1 in satellite cells improves skeletal muscle pathology in dystrophic mice.

Urszula Florczyk-Soluch, Katarzyna Polak, Sarka Jelinkova, Iwona Bronisz-Budzyńska, Reece Sabo, Subhashini Bolisetty, Anupam Agarwal, Ewa Werner, Alicja Józkowicz, Jacek Stępniewski, Krzysztof Szade, Józef Dulak.

   BACKGROUND: Adult muscle-resident myogenic stem cells, satellite cells (SCs), that play non-redundant role in muscle regeneration, are intrinsically impaired in Duchenne muscular dystrophy (DMD). Previously we revealed that dystrophic SCs express low level of anti-inflammatory and anti-oxidative heme oxygenase-1 (HO-1, HMOX1). Here we assess whether targeted induction of HMOX1 affect SC function and alleviates hallmark symptoms of DMD.
METHODS: We generated double-transgenic mouse model (mdx;HMOX1Pax7Ind) that allows tamoxifen (TX)-inducible HMOX1 expression in Pax7 positive cells of dystrophic muscles. Mdx;HMOX1Pax7Ind and control mdx mice were subjected to 5-day TX injections (75 mg/kg b.w.) followed by acute exercise protocol with high-speed treadmill (12 m/min, 45 min) and downhill running to worsen skeletal muscle phenotype and reveal immediate effects of HO-1 on muscle pathology and SC function.
RESULTS: HMOX1 induction caused a drop in SC pool in mdx;HMOX1Pax7Ind mice (vs. mdx counterparts), while not exaggerating the effect of physical exercise. Upon physical exercise, the proliferation of SCs and activated CD34- SC subpopulation, was impaired in mdx mice, an effect that was reversed in mdx;HMOX1Pax7Ind mice, however, both in vehicle- and TX-treated animals. This corresponded to the pattern of HO-1 expression in skeletal muscles. At the tissue level, necrotic events of selective skeletal muscles of mdx mice and associated increase in circulating levels of muscle damage markers were blunted in HO-1 transgenic animals which showed also anti-inflammatory cytokine profile (vs. mdx).
CONCLUSIONS: Targeted expression of HMOX1 plays protective role in DMD and alleviates dystrophic muscle pathology.

Keywords:  Duchenne muscular dystrophy; Heme oxygenase-1; Satellite cells; Skeletal muscle regeneration

DOI:  https://doi.org/10.1186/s13395-024-00346-2
Stem Cell Reports. 2024 Jun 10. pii: S2213-6711(24)00147-4. [Epub ahead of print]

A dual-color PAX7 and MYF5 in vivo reporter to investigate muscle stem cell heterogeneity in regeneration and aging.

Sara Ancel, Joris Michaud, Federico Sizzano, Loic Tauzin, Manuel Oliveira, Eugenia Migliavacca, Svenja C Schüler, Sruthi Raja, Gabriele Dammone, Sonia Karaz, José L Sánchez-García, Sylviane Metairon, Guillaume Jacot, C Florian Bentzinger, Jérôme N Feige, Pascal Stuelsatz.

  Increasing evidence suggests that the muscle stem cell (MuSC) pool is heterogeneous. In particular, a rare subset of PAX7-positive MuSCs that has never expressed the myogenic regulatory factor MYF5 displays unique self-renewal and engraftment characteristics. However, the scarcity and limited availability of protein markers make the characterization of these cells challenging. Here, we describe the generation of StemRep reporter mice enabling the monitoring of PAX7 and MYF5 proteins based on equimolar levels of dual nuclear fluorescence. High levels of PAX7 protein and low levels of MYF5 delineate a deeply quiescent MuSC subpopulation with an increased capacity for asymmetric division and distinct dynamics of activation, proliferation, and commitment. Aging primarily reduces the MYF5Low MuSCs and skews the stem cell pool toward MYF5High cells with lower quiescence and self-renewal potential. Altogether, we establish the StemRep model as a versatile tool to study MuSC heterogeneity and broaden our understanding of mechanisms regulating MuSC quiescence and self-renewal in homeostatic, regenerating, and aged muscles.

Keywords:  MYF5; PAX7; Skeletal muscle; aging; muscle stem cells; quiescence; regeneration; satellite cells; self-renewal; stemness

DOI:  https://doi.org/10.1016/j.stemcr.2024.05.005
bioRxiv. 2024 May 28. pii: 2024.05.24.595728. [Epub ahead of print]

Immunomodulatory Role of the Stem Cell Circadian Clock in Muscle Repair.

Pei Zhu, Eric Pfrender, Adam Steffeck, Colleen Reczek, Yalu Zhou, Abhishek Thakkar, Neha Gupta, Amber Willbanks, Richard Lieber, Ishan Roy, Navdeep S Chandel, Clara B Peek.

The circadian clock orchestrates vital physiological processes such as metabolism, immune function, and tissue regeneration, aligning them with the optimal time of day. This study identifies an intricate interplay between the circadian clock within muscle stem cells (SCs) and their capacity to modulate the immune microenvironment during muscle regeneration. We uncover that the SC clock provokes time of day-dependent induction of inflammatory response genes following injury, particularly those related to neutrophil activity and chemotaxis. These responses are driven by rhythms of cytosolic regeneration of the signaling metabolite NAD+. We demonstrate that genetically enhancing cytosolic NAD+ regeneration in SCs is sufficient to induce robust inflammatory responses that significantly influence muscle regeneration. Furthermore, using mononuclear single-cell sequencing of the regenerating muscle niche, we uncover a key role for the cytokine CCL2 in mediating SC-neutrophil crosstalk in a time of day-dependent manner. Our findings highlight a crucial intersection between SC metabolic shifts and immune responses within the muscle microenvironment, dictated by the circadian rhythms, and underscore the potential for targeting circadian and metabolic pathways to enhance tissue regeneration.

DOI: https://doi.org/10.1101/2024.05.24.595728
Sci Rep. 2024 06 10. 14(1): 13282

Modulation of macrophage transcript and secretion profiles by Sargassum Serratifolium extract is associated with the suppression of muscle atrophy.

Heeyeon Ryu, Hyeon Hak Jeong, Myeong-Jin Kim, Seungjun Lee, Won-Kyo Jung, Bonggi Lee.

  Recent research has emphasized the role of macrophage-secreted factors on skeletal muscle metabolism. We studied Sargassum Serratifolium ethanol extract (ESS) in countering lipopolysaccharide (LPS)-induced changes in the macrophage transcriptome and their impact on skeletal muscle. Macrophage-conditioned medium (MCM) from LPS-treated macrophages (LPS-MCM) and ESS-treated macrophages (ESS-MCM) affected C2C12 myotube cells. LPS-MCM upregulated muscle atrophy genes and reduced glucose uptake, while ESS-MCM reversed these effects. RNA sequencing revealed changes in the immune system and cytokine transport pathways in ESS-treated macrophages. Protein analysis in ESS-MCM showed reduced levels of key muscle atrophy-related proteins, TNF-α, IL-6, IL-1, and GDF-15. These proteins play crucial roles in muscle function. These findings highlight the intricate relationship between the macrophage transcriptome and their secreted factors in either impairing or enhancing skeletal muscle function. ESS treatment has the potential to reduce macrophage-derived cytokines, preserving skeletal muscle function.

Keywords:   Sargassum Serratifolium ; Cytokine; Macrophages; RNA Seq; Skeletal muscle

DOI:  https://doi.org/10.1038/s41598-024-63146-0
Nat Commun. 2024 Jun 08. 15(1): 4915

The TAS1R2 G-protein-coupled receptor is an ambient glucose sensor in skeletal muscle that regulates NAD homeostasis and mitochondrial capacity.

Joan Serrano, Jordan Boyd, Ian S Brown, Carter Mason, Kathleen R Smith, Katalin Karolyi, Santosh K Maurya, Nishita N Meshram, Vanida Serna, Grace M Link, Stephen J Gardell, George A Kyriazis.

The bioavailability of nicotinamide adenine dinucleotide (NAD) is vital for skeletal muscle health, yet the mechanisms or signals regulating NAD homeostasis remain unclear. Here, we uncover a pathway connecting peripheral glucose sensing to the modulation of muscle NAD through TAS1R2, the sugar-sensing G protein-coupled receptor (GPCR) initially identified in taste perception. Muscle TAS1R2 receptor stimulation by glucose and other agonists induces ERK1/2-dependent phosphorylation and activation of poly(ADP-ribose) polymerase1 (PARP1), a major NAD consumer in skeletal muscle. Consequently, muscle-specific deletion of TAS1R2 (mKO) in male mice suppresses PARP1 activity, elevating NAD levels and enhancing mitochondrial capacity and running endurance. Plasma glucose levels negatively correlate with muscle NAD, and TAS1R2 receptor deficiency enhances NAD responses across the glycemic range, implicating TAS1R2 as a peripheral energy surveyor. These findings underscore the role of GPCR signaling in NAD regulation and propose TAS1R2 as a potential therapeutic target for maintaining muscle health.

DOI: https://doi.org/10.1038/s41467-024-49100-8
J Physiol. 2024 Jun 08.

More than the clock: distinct regulation of muscle function and metabolism by PER2 and RORα.

Shivani Mansingh, Geraldine Maier, Julien Delezie, Pål O Westermark, Danilo Ritz, Wandrille Duchemin, Gesa Santos, Bettina Karrer-Cardel, Stefan A Steurer, Urs Albrecht, Christoph Handschin.

  Circadian rhythms, governed by the dominant central clock, in addition to various peripheral clocks, regulate almost all biological processes, including sleep-wake cycles, hormone secretion and metabolism. In certain contexts, the regulation and function of the peripheral oscillations can be decoupled from the central clock. However, the specific mechanisms underlying muscle-intrinsic clock-dependent modulation of muscle function and metabolism remain unclear. We investigated the outcome of perturbations of the primary and secondary feedback loops of the molecular clock in skeletal muscle by specific gene ablation of Period circadian regulator 2 (Per2) and RAR-related orphan receptor alpha (Rorα), respectively. In both models, a dampening of core clock gene oscillation was observed, while the phase was preserved. Moreover, both loops seem to be involved in the homeostasis of amine groups. Highly divergent outcomes were seen for overall muscle gene expression, primarily affecting circadian rhythmicity in the PER2 knockouts and non-oscillating genes in the RORα knockouts, leading to distinct outcomes in terms of metabolome and phenotype. These results highlight the entanglement of the molecular clock and muscle plasticity and allude to specific functions of different clock components, i.e. the primary and secondary feedback loops, in this context. The reciprocal interaction between muscle contractility and circadian clocks might therefore be instrumental to determining a finely tuned adaptation of muscle tissue to perturbations in health and disease. KEY POINTS: Specific perturbations of the primary and secondary feedback loop of the molecular clock result in specific outcomes on muscle metabolism and function. Ablation of Per2 (primary loop) or Rorα (secondary loop) blunts the amplitude of core clock genes, in absence of a shift in phase. Perturbation of the primary feedback loop by deletion of PER2 primarily affects muscle gene oscillation. Knockout of RORα and the ensuing modulation of the secondary loop results in the aberrant expression of a large number of non-clock genes and proteins. The deletion of PER2 and RORα affects muscle metabolism and contractile function in a circadian manner, highlighting the central role of the molecular clock in modulating muscle plasticity.

Keywords:  PER2; RORα; circadian rhythm; exercise; metabolism; molecular clock; skeletal muscle; transcriptional regulation

DOI:  https://doi.org/10.1113/JP285585
BMC Methods. 2024 ;1(1): 5

Mini-MEndR: a miniaturized 96-well predictive assay to evaluate muscle stem cell-mediated repair.

Nitya Gulati, Sadegh Davoudi, Bin Xu, Saifedine T Rjaibi, Erik Jacques, Justin Pham, Amir Fard, Alison P McGuigan, Penney M Gilbert.

   Background: Functional evaluation of molecules that are predicted to promote stem cell mediated endogenous repair often requires in vivo transplant studies that are low throughput and hinder the rate of discovery. To offer greater throughput for functional validation studies, we miniaturized, simplified and expanded the functionality of a previously developed muscle endogenous repair (MEndR) in vitro assay that was shown to capture significant events of in vivo muscle endogenous repair.
Methods: The mini-MEndR assay consists of miniaturized cellulose scaffolds designed to fit in 96-well plates, the pores of which are infiltrated with human myoblasts encapsulated in a fibrin-based hydrogel to form engineered skeletal muscle tissues. Pre-adsorbing thrombin to the cellulose scaffolds facilitates in situ tissue polymerization, a critical modification that enables new users to rapidly acquire assay expertise. Following the generation of the 3D myotube template, muscle stem cells (MuSCs), enriched from digested mouse skeletal muscle tissue using an improved magnetic-activated cell sorting protocol, are engrafted within the engineered template. Murine MuSCs are fluorescently labeled, enabling co-evaluation of human and mouse Pax7+ cell responses to drug treatments. A regenerative milieu is introduced by injuring the muscle tissue with a myotoxin to initiate endogenous repair "in a dish". Phenotypic data is collected at endpoints with a high-content imaging system and is analyzed using ImageJ-based image analysis pipelines.
Results: The miniaturized format and modified manufacturing protocol cuts reagent costs in half and hands-on seeding time ~ threefold, while the image analysis pipelines save 40 h of labour. By evaluating multiple commercially available human primary myoblast lines in 2D and 3D culture, we establish quality assurance metrics for cell line selection that standardizes myotube template quality. In vivo outcomes (enhanced muscle production and Pax7+ cell expansion) to a known modulator of MuSC mediated repair (p38/β MAPK inhibition) are recapitulated in the miniaturized culture assay, but only in the presence of stem cells and the regenerative milieu.
Discussion: The miniaturized predictive assay offers a simple, scaled platform to co-investigate human and mouse skeletal muscle endogenous repair molecular modulators, and thus is a promising strategy to accelerate the muscle endogenous repair discovery pipeline.
Supplementary Information: The online version contains supplementary material available at 10.1186/s44330-024-00005-4.

Keywords:  Endogenous repair; Manufacturing; Predictive assay; Scale-up; Skeletal muscle; Stem cell

DOI:  https://doi.org/10.1186/s44330-024-00005-4
MedComm (2020). 2024 Jun;5(6): e566

Myricanol prevents aging-related sarcopenia by rescuing mitochondrial dysfunction via targeting peroxiredoxin 5.

Shengnan Shen, Qiwen Liao, Peng Lyu, Jigang Wang, Ligen Lin.

  Aging is a process that represents the accumulation of changes in organism overtime. In biological level, accumulations of molecular and cellular damage in aging lead to an increasing risk of diseases like sarcopenia. Sarcopenia reduces mobility, leads to fall-related injuries, and diminishes life quality. Thus, it is meaningful to find out novel therapeutic strategies for sarcopenia intervention that may help the elderly maintain their functional ability. Oxidative damage-induced dysfunctional mitochondria are considered as a culprit of muscle wasting during aging. Herein, we aimed to demonstrate whether myricanol (MY) protects aged mice against muscle wasting through alleviating oxidative damage in mitochondria and identify the direct protein target and its underlying mechanism. We discovered that MY protects aged mice against the loss of muscle mass and strength through scavenging reactive oxygen species accumulation to rebuild the redox homeostasis. Taking advantage of biophysical assays, peroxiredoxin 5 was discovered and validated as the direct target of MY. Through activating peroxiredoxin 5, MY reduced reactive oxygen species accumulation and damaged mitochondrial DNA in C2C12 myotubes. Our findings provide an insight for therapy against sarcopenia through alleviating oxidative damage-induced dysfunctional mitochondria by targeting peroxiredoxin 5, which may contribute an insight for healthy aging.

Keywords:  healthy aging; mitochondria; myricanol; peroxiredoxin 5; redox homeostasis; sarcopenia

DOI:  https://doi.org/10.1002/mco2.566
PLoS Genet. 2024 Jun;20(6): e1010935

Interplay between Pitx2 and Pax7 temporally governs specification of extraocular muscle stem cells.

Mao Kuriki, Amaury Korb, Glenda Comai, Shahragim Tajbakhsh.

Gene regulatory networks that act upstream of skeletal muscle fate determinants are distinct in different anatomical locations. Despite recent efforts, a clear understanding of the cascade of events underlying the emergence and maintenance of the stem cell pool in specific muscle groups remains unresolved and debated. Here, we invalidated Pitx2 with multiple Cre-driver mice prenatally, postnatally, and during lineage progression. We showed that this gene becomes progressively dispensable for specification and maintenance of the muscle stem (MuSC) cell pool in extraocular muscles (EOMs) despite being, together with Myf5, a major upstream regulator during early development. Moreover, constitutive inactivation of Pax7 postnatally led to a greater loss of MuSCs in the EOMs compared to the limb. Thus, we propose a relay between Pitx2, Myf5 and Pax7 for EOM stem cell maintenance. We demonstrate also that MuSCs in the EOMs adopt a quiescent state earlier that those in limb muscles and do not spontaneously proliferate in the adult, yet EOMs have a significantly higher content of Pax7+ MuSCs per area pre- and post-natally. Finally, while limb MuSCs proliferate in the mdx mouse model for Duchenne muscular dystrophy, significantly less MuSCs were present in the EOMs of the mdx mouse model compared to controls, and they were not proliferative. Overall, our study provides a comprehensive in vivo characterisation of MuSC heterogeneity along the body axis and brings further insights into the unusual sparing of EOMs during muscular dystrophy.

DOI: https://doi.org/10.1371/journal.pgen.1010935
Front Cell Dev Biol. 2024 ;12 1368171

Emerging role of HDAC11 in skeletal muscle biology.

Jihong Chen, Qiao Li.

  HDAC11 is an epigenetic repressor of gene transcription, acting through its deacetylase activity to remove functional acetyl groups from the lysine residues of histones at genomic loci. It has been implicated in the regulation of different immune responses, metabolic activities, as well as cell cycle progression. Recent studies have also shed lights on the impact of HDAC11 on myogenic differentiation and muscle development, indicating that HDAC11 is important for histone deacetylation at the promoters to inhibit transcription of cell cycle related genes, thereby permitting myogenic activation at the onset of myoblast differentiation. Interestingly, the upstream networks of HDAC11 target genes are mainly associated with cell cycle regulators and the acetylation of histones at the HDAC11 target promoters appears to be residue specific. As such, selective inhibition, or activation of HDAC11 presents a potential therapeutic approach for targeting distinct epigenetic pathways in clinical applications.

Keywords:  chromatin modification; gene regulation; histone acetylation; histone deacetylase; myogenic differentiation

DOI:  https://doi.org/10.3389/fcell.2024.1368171
Juntendo Iji Zasshi. 2023 ;69(3): 180-187

Development of Ryanodine Receptor (RyR) Inhibitors for Skeletal Muscle and Heart Diseases.

Hiroyuki Matsukawa, Takashi Murayama.

  Ryanodine receptors (RyR) are intracellular calcium (Ca2+) release channels on the sarcoplasmic reticulum of skeletal and cardiac muscles that play a central role in excitation-contraction coupling. Genetic mutations or posttranslational modifications of RyR causes hyperactivation of the channel, leading to various skeletal muscle and heart diseases. Currently, no specific treatments exist for most RyR-associated diseases. Recently, high-throughput screening (HTS) assays have been developed to identify potential candidates for treating RyR-related muscle diseases. These assays have successfully identified several compounds as novel RyR inhibitors, which are effective in animal models. In this review, we will focus on recent progress in HTS assays and discuss future perspectives of these promising approaches.

Keywords:  Ca2+ release channel; drug development; high-throughput screening; ryanodine receptor

DOI:  https://doi.org/10.14789/jmj.JMJ22-0045-R
medRxiv. 2024 May 27. pii: 2024.05.25.24307934. [Epub ahead of print]

Sex Differences in the Association between Skeletal Muscle Energetics and Perceived Physical Fatigability: The Study of Muscle, Mobility and Aging (SOMMA).

Emma L Gay, Paul M Coen, Stephanie Harrison, Reagan E Garcia, Yujia Susanna Qiao, Bret H Goodpaster, Daniel E Forman, Frederico G S Toledo, Giovanna Distefano, Philip A Kramer, Sofhia V Ramos, Anthony J A Molina, Barbara J Nicklas, Steven R Cummings, Peggy M Cawthon, Russell T Hepple, Anne B Newman, Nancy W Glynn.

Greater perceived physical fatigability and lower skeletal muscle energetics are predictors of mobility decline. Characterizing associations between muscle energetics and perceived fatigability may provide insight into potential targets to prevent mobility decline. We examined associations of in vivo (maximal ATP production, ATPmax) and ex vivo (maximal carbohydrate supported oxidative phosphorylation [max OXPHOS] and maximal fatty acid supported OXPHOS [max FAO OXPHOS]) measures of mitochondrial energetics with two measures of perceived physical fatigability, Pittsburgh Fatigability Scale (PFS, 0-50, higher=greater) and Rating of Perceived Exertion (RPE Fatigability, 6-20, higher=greater) after a slow treadmill walk. Participants from the Study of Muscle, Mobility and Aging (N=873) were 76.3±5.0 years old, 59.2% women, and 85.3% White. Higher muscle energetics (both in vivo and ex vivo ) were associated with lower perceived physical fatigability, all p<0.03. When stratified by sex, higher ATPmax was associated with lower PFS Physical for men only; higher max OXPHOS and max FAO OXPHOS were associated with lower RPE fatigability for both sexes. Higher skeletal muscle energetics were associated with 40-55% lower odds of being in the most (PFS≥25, RPE Fatigability≥12) vs least (PFS 0-4, RPE Fatigability 6-7) severe fatigability strata, all p<0.03. Being a woman was associated with 2-3 times higher odds of being in the most severe fatigability strata when controlling for ATPmax but not the in vivo measures (p<0.05). Better mitochondrial energetics were linked to lower fatigability and less severe fatigability in older adults. Findings imply that improving skeletal muscle energetics may mitigate perceived physical fatigability and prolong healthy aging.

DOI: https://doi.org/10.1101/2024.05.25.24307934
NPJ Microgravity. 2024 Jun 11. 10(1): 62

Bioreactor development for skeletal muscle hypertrophy and atrophy by manipulating uniaxial cyclic strain: proof of concept.

Khaled Y Kamal, Mariam Atef Othman, Joo-Hyun Kim, John M Lawler.

Skeletal muscles overcome terrestrial, gravitational loading by producing tensile forces that produce movement through joint rotation. Conversely, the microgravity of spaceflight reduces tensile loads in working skeletal muscles, causing an adaptive muscle atrophy. Unfortunately, the design of stable, physiological bioreactors to model skeletal muscle tensile loading during spaceflight experiments remains challenging. Here, we tested a bioreactor that uses initiation and cessation of cyclic, tensile strain to induce hypertrophy and atrophy, respectively, in murine lineage (C2C12) skeletal muscle myotubes. Uniaxial cyclic stretch of myotubes was conducted using a StrexCell® (STB-1400) stepper motor system (0.75 Hz, 12% strain, 60 min day^-1). Myotube groups were assigned as follows: (a) quiescent over 2- or (b) 5-day (no stretch), (c) experienced 2-days (2dHY) or (d) 5-days (5dHY) of cyclic stretch, or (e) 2-days of cyclic stretch followed by a 3-day cessation of stretch (3dAT). Using ß-sarcoglycan as a sarcolemmal marker, mean myotube diameter increased significantly following 2dAT (51%) and 5dAT (94%) vs. matched controls. The hypertrophic, anabolic markers talin and Akt phosphorylation (Thr308) were elevated with 2dHY but not in 3dAT myotubes. Inflammatory, catabolic markers IL-1ß, IL6, and NF-kappaB p65 subunit were significantly higher in the 3dAT group vs. all other groups. The ratio of phosphorylated FoxO3a/total FoxO3a was significantly lower in 3dAT than in the 2dHY group, consistent with elevated catabolic signaling during unloading. In summary, we demonstrated proof-of-concept for a spaceflight research bioreactor, using uniaxial cyclic stretch to produce myotube hypertrophy with increased tensile loading, and myotube atrophy with subsequent cessation of stretch.

DOI: https://doi.org/10.1038/s41526-023-00320-0
Arch Gerontol Geriatr. 2024 May 27. pii: S0167-4943(24)00175-4. [Epub ahead of print]125 105499

Single-cell RNA sequencing analysis provides novel insights into the role of apoptosis-related genes in muscle aging.

Hua Guo, Yunyun Zhang, Xin Xiang, Na Tang, Wei Gao, Xiaochuan Cui.

   OBJECTIVE: This study employed a comprehensive single-cell analysis approach to explore the role of cell apoptosis-related genes in muscle aging.
METHODS: The single-cell RNA sequencing data from the GSE143704 dataset were used to identify distinct cell clusters and assess gene expression patterns related to apoptosis activation. The "limma" package was used to identify hub genes, after which we performed Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis to identify relevant pathways. Additionally, Gene Set Enrichment Analysis(GSEA) and Gene Set Variation Analysis (GSVA) were used to uncover relevant biological pathways. The Receiver Operating Characteristic Curve (ROC) was used to evaluate the diagnostic value of the hub genes. Single-sample Gene Set Enrichment Analysis (ssGSEA) was used to analyze the immune cell infiltration levels.
RESULTS: Single-cell sequencing data from muscle aging patients allowed the identification of various cell types, including epithelial cells, adipocytes, and tissue-resident macrophages. By conducting a differential expression analysis that intersected active and nonactive apoptosis, as well as comparing elderly and young samples, a total of 22 hub genes were identified (p < 0.05). The 22 hub genes have discriminative ability as potential biomarkers for diagnosing muscle aging. The enrichment analysis indicated that these genes were closely associated with diverse pathways, including "response to UV-B" and "extracellular matrix organization" (p < 0.05). Furthermore, GSEA and GSVA indicated that multiple pathways emerged-for example, the "complement and coagulation cascades", "proteasome", "insulin signaling pathway", and "MAPK signaling pathway". Additionally, the analysis of immune cell infiltration revealed positive correlations between most of the hub genes and immune cells.
CONCLUSION: Our study identified 22 apoptosis-related genes involved in muscle aging and indicated their potential diagnostic value. These findings offer a novel perspective on the pathogenesis of muscle aging and present potential targets for therapeutic interventions.

Keywords:  Apoptosis; Muscle aging; Single-cell RNA sequencing analysis

DOI:  https://doi.org/10.1016/j.archger.2024.105499
Med Sci Sports Exerc. 2024 Jun 12.

Long-Term Resistance Trained Human Muscles Have More Fibres, More Myofibrils and Tighter Myofilament Packing than Untrained.

Sumiaki Maeo, Thomas G Balshaw, Benjamin März, Zhaoxia Zhou, Bill Haug, Neil R W Martin, Nicola Maffulli, Jonathan P Folland.

INTRODUCTION: Increases in skeletal muscle size occur in response to prolonged exposure to resistance training that is typically ascribed to increased muscle fibre size. Whether muscle fibre number also changes remains controversial, and a paucity of data exists about myofibrillar structure. This cross-sectional study compared muscle fibre and myofibril characteristics in long-term resistance-trained (LRT) versus untrained (UNT) individuals.
METHODS: The maximal anatomical cross-sectional area (ACSAmax) of the biceps brachii muscle was measured by MRI in 16 LRT (5.9 ± 3.5 years' experience) and 13 UNT males. A muscle biopsy was taken from the biceps brachii to measure muscle fibre area, myofibril area and myosin spacing. Muscle fibre number, myofibril number in total and per fibre were estimated by dividing ACSAmax by muscle fibre area or myofibril area, and muscle fibre area by myofibril area, respectively.
RESULTS: Compared to UNT, LRT individuals had greater ACSAmax (+70%, P < 0.001), fibre area (+29%, P = 0.028), fibre number (+34%, P = 0.013), and myofibril number per fibre (+49%, P = 0.034) and in total (+105%, P < 0.001). LRT individuals also had smaller myosin spacing (-7%, P = 0.004; i.e. greater packing density) and a tendency towards smaller myofibril area (-16%, P = 0.074). ACSAmax was positively correlated with fibre area (r = 0.526), fibre number (r = 0.445) and myofibril number (in total r = 0.873 and per fibre r = 0.566), and negatively correlated with myofibril area (r = -0.456) and myosin spacing (r = -0.382) (all P < 0.05).
CONCLUSIONS: The larger muscles of LRT individuals exhibited more fibres in cross-section and larger muscle fibres, which contained substantially more total myofibrils and more packed myofilaments than UNT participants, suggesting plasticity of muscle ultrastructure.

DOI: https://doi.org/10.1249/MSS.0000000000003495
Front Endocrinol (Lausanne). 2024 ;15 1375610

Type 2 diabetes mellitus related sarcopenia: a type of muscle loss distinct from sarcopenia and disuse muscle atrophy.

Zhenchao Liu, Yunliang Guo, Chongwen Zheng.

  Muscle loss is a significant health concern, particularly with the increasing trend of population aging, and sarcopenia has emerged as a common pathological process of muscle loss in the elderly. Currently, there has been significant progress in the research on sarcopenia, including in-depth analysis of the mechanisms underlying sarcopenia caused by aging and the development of corresponding diagnostic criteria, forming a relatively complete system. However, as research on sarcopenia progresses, the concept of secondary sarcopenia has also been proposed. Due to the incomplete understanding of muscle loss caused by chronic diseases, there are various limitations in epidemiological, basic, and clinical research. As a result, a comprehensive concept and diagnostic system have not yet been established, which greatly hinders the prevention and treatment of the disease. This review focuses on Type 2 Diabetes Mellitus (T2DM)-related sarcopenia, comparing its similarities and differences with sarcopenia and disuse muscle atrophy. The review show significant differences between the three muscle-related issues in terms of pathological changes, epidemiology and clinical manifestations, etiology, and preventive and therapeutic strategies. Unlike sarcopenia, T2DM-related sarcopenia is characterized by a reduction in type I fibers, and it differs from disuse muscle atrophy as well. The mechanism involving insulin resistance, inflammatory status, and oxidative stress remains unclear. Therefore, future research should further explore the etiology, disease progression, and prognosis of T2DM-related sarcopenia, and develop targeted diagnostic criteria and effective preventive and therapeutic strategies to better address the muscle-related issues faced by T2DM patients and improve their quality of life and overall health.

Keywords:  disuse muscle atrophy; muscle fibers; muscle loss; sarcopenia; type 2 diabetes mellitus

DOI:  https://doi.org/10.3389/fendo.2024.1375610
Sci Rep. 2024 06 11. 14(1): 13098

Aging and putative frailty biomarkers are altered by spaceflight.

Andrea Camera, Marshall Tabetah, Veronica Castañeda, JangKeun Kim, Aman Singh Galsinh, Alissen Haro-Vinueza, Ivonne Salinas, Allen Seylani, Shehbeel Arif, Saswati Das, Marcelo A Mori, Anthony Carano, Lorraine Christine de Oliveira, Masafumi Muratani, Richard Barker, Victoria Zaksas, Chirag Goel, Eleni Dimokidis, Deanne M Taylor, Jisu Jeong, Eliah Overbey, Cem Meydan, D Marshall Porterfield, Juan Esteban Díaz, Andrés Caicedo, Jonathan C Schisler, Evagelia C Laiakis, Christopher E Mason, Man S Kim, Fathi Karouia, Nathaniel J Szewczyk, Afshin Beheshti.

Human space exploration poses inherent risks to astronauts' health, leading to molecular changes that can significantly impact their well-being. These alterations encompass genomic instability, mitochondrial dysfunction, increased inflammation, homeostatic dysregulation, and various epigenomic changes. Remarkably, these changes bear similarities to those observed during the aging process on Earth. However, our understanding of the connection between these molecular shifts and disease development in space remains limited. Frailty syndrome, a clinical syndrome associated with biological aging, has not been comprehensively investigated during spaceflight. To bridge this knowledge gap, we leveraged murine data obtained from NASA's GeneLab, along with astronaut data gathered from the JAXA and Inspiration4 missions. Our objective was to assess the presence of biological markers and pathways related to frailty, aging, and sarcopenia within the spaceflight context. Through our analysis, we identified notable changes in gene expression patterns that may be indicative of the development of a frailty-like condition during space missions. These findings suggest that the parallels between spaceflight and the aging process may extend to encompass frailty as well. Consequently, further investigations exploring the utility of a frailty index in monitoring astronaut health appear to be warranted.

DOI: https://doi.org/10.1038/s41598-024-57948-5