bims-moremu 2022-08-07 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2022‒08‒07
37 papers selected by
Anna Vainshtein
Craft Science Inc.

Mechanisms of skeletal muscle repair and regeneration in health and disease.
The role of the aging microenvironment on the fate of PDGFRβ lineage cells in skeletal muscle repair.
From cyclins to CDKIs: Cell cycle regulation of skeletal muscle stem cell quiescence and activation.
A Preclinical Systematic Review of the Effects of Chronic Exercise on Autophagy-Related Proteins in Aging Skeletal Muscle.
Molecular and biochemical regulation of skeletal muscle metabolism.
Dissociation of SH3 and cysteine rich domain 3 and junctophilin 1 from dihydropyridine receptor in dystrophin-deficient muscles.
Septin7 is indispensable for proper skeletal muscle architecture and function.
Altered muscle oxidative phenotype impairs exercise tolerance but does not improve after exercise training in multiple sclerosis.
Notch1 and Notch2 Signaling Exclusively but Cooperatively Maintain Fetal Myogenic Progenitors.
An analysis of lncRNA-miRNA-mRNA networks to investigate the effects of HDAC4 inhibition on skeletal muscle atrophy caused by peripheral nerve injury.
Exercise timing influences multi-tissue metabolome and skeletal muscle proteome profiles in type 2 diabetic patients - A randomized crossover trial.
Regulation of myogenic gene expression.
NR1D1 controls skeletal muscle calcium homeostasis through myoregulin repression.
Hypoxic Training Ameliorates Skeletal Muscle Microcirculation Vascular Function in a Sirt3-Dependent Manner.
Outrunning obesity with Lac-Phe?
Activation of the myosin motors in fast-twitch muscle of the mouse is controlled by mechano-sensing in the myosin filaments.
Histone-mediated skeletal muscle adaptations to exercise: insights into a new era of epigenome-based personalized medicine.
Gene Editing to Tackle Facioscapulohumeral Muscular Dystrophy.
Age-dependent impact of two exercise training regimens on genomic and metabolic remodeling in skeletal muscle and liver of male mice.
Micro(RNA)-cloud can perpetuate physiological adaptation of skeletal muscle to exercise and energy imbalance.
Phytochemical compound PB125 attenuates skeletal muscle mitochondrial dysfunction and impaired proteostasis in a model of musculoskeletal decline.
P2X7 Purinoceptor Affects Ectopic Calcification of Dystrophic Muscles.
A preliminary study on the role of Piezo1 channels in myokine release from cultured mouse myotubes.
The Whole-transcriptome Landscape of Diabetes-related Sarcopenia Reveals the Specific Function of Novel lncRNA Gm20743.
Hypothalamus-Muscle Parallel Induction of Metabolic Pathways Following Physical Exercise.
Regulatory T cells in skeletal muscle repair and regeneration: recent insights.
Tension-driven multi-scale self-organisation in human iPSC-derived muscle fibers.
Towards Soft Wearable Strain Sensors for Muscle Activity Monitoring.
Kynurenine metabolism is altered in mdx mice: A potential muscle to brain connection.
Irisin/FNDC5 influences myogenic markers on skeletal muscle following high and moderate-intensity exercise training in STZ-diabetic rats.
Neuromuscular denervation and deafferentation but not motor neuron death are disease features in the Smn2B/- mouse model of SMA.
JMJD3 activated hyaluronan synthesis drives muscle regeneration in an inflammatory environment.
Preliminary Study of S100B and Sema3A Expression Patterns in Regenerating Muscle Implicates P75-Expressing Terminal Schwann Cells and Muscle Satellite Cells in Neuromuscular Junction Restoration.
A regenerative niche for stem cells.
Spinal muscular atrophy.
The molecular mechanism of snake short-chain α-neurotoxin binding to muscle-type nicotinic acetylcholine receptors.
Reply to 'Lactate as a major myokine and exerkine'.

FEBS J. 2022 Aug 05.

Mechanisms of skeletal muscle repair and regeneration in health and disease.

Daniel E Michele.

  Skeletal muscle is a structurally and functionally remarkable tissue composed of multinucleated post-mitotic muscle fibres. These fibres are filled with an exquisite, near crystalline array of assembled contractile proteins, capable of coupling ATP utilization to mechanical muscle contraction. Fully differentiated muscle has an incredible ability to protect and repair itself from significant muscle injuries. In fact, through activation of a resident population of stem cells known as satellite cells, muscle fibres can be completely regenerated, and normal function can be restored in a matter of a few weeks after a major myocellular necrotic injury. The loss of key mechanisms to protect muscle from injuries or loss of the capacity to repair muscle after injury is thought to underlie several forms of muscular dystrophy and also the age-related decline of muscle function. In this Subject Collection, The FEBS Journal highlights articles that review or investigate key mechanisms of muscle repair and regeneration in response to injuries, and the contributions of these pathways to health and disease of skeletal muscle.

Keywords:  muscle biology; muscle disease; muscle regeneration; skeletal muscle

DOI:  https://doi.org/10.1111/febs.16577
Stem Cell Res Ther. 2022 Aug 05. 13(1): 405

The role of the aging microenvironment on the fate of PDGFRβ lineage cells in skeletal muscle repair.

Aiping Lu, Chieh Tseng, Ping Guo, Zhanguo Gao, Kaitlyn E Whitney, Mikhail G Kolonin, Johnny Huard.

  BACKGROUND: During aging, perturbation of muscle progenitor cell (MPC) constituents leads to progressive loss of muscle mass and accumulation of adipose and fibrotic tissue. Mesenchymal stem cells (MSCs) give rise to adipocytes and fibroblasts that accumulate in injured and pathological skeletal muscle through constitutive activation of platelet-derived growth factor receptors (PDGFRs). Although the role of the PDGFRα has been widely explored, there is a paucity of evidence demonstrating the role of PDGFRβ in aged skeletal muscle.METHODS: In this study, we investigated the role of PDGFRβ lineage cells in skeletal muscle during aging by using Cre/loxP lineage tracing technology. The PDGFR-Cre mice were crossed with global double-fluorescent Cre reporter mice (mTmG) that indelibly marks PDGFRβ lineage cells. Those cells were analyzed and compared at different ages in the skeletal muscle of the mice.
RESULTS: Our results demonstrated that PDGFRβ lineage cells isolated from the muscles of young mice are MPC-like cells that exhibited satellite cell morphology, expressed Pax7, and undergo myogenic differentiation producing myosin heavy chain expressing myotubes. Conversely, the PDGFRβ lineage cells isolated from muscles of old mice displayed MSC morphology with a reduced myogenic differentiation potential while expressing adipogenic and fibrotic differentiation markers. PDGFRβ lineage cells also gave rise to newly regenerated muscle fibers in young mice after muscle injury, but their muscle regenerative process is reduced in old mice.
CONCLUSIONS: Our data suggest that PDGFRβ lineage cells function as MPCs in young mice, while the same PDGFRβ lineage cells from old mice undergo a fate switch participating in adipose and fibrotic tissue infiltration in aged muscle. The inhibition of fate-switching in PDGFRβ lineage cells may represent a potential approach to prevent fibrosis and fatty infiltration in skeletal muscle during the aging process.

Keywords:  Aging; Fibrosis and fatty infiltration; Mesenchymal stem cells; Muscle progenitor cell; PDGFRβ lineage cells; Skeletal muscle injury

DOI:  https://doi.org/10.1186/s13287-022-03072-y
Exp Cell Res. 2022 Aug 02. pii: S0014-4827(22)00268-3. [Epub ahead of print] 113275

From cyclins to CDKIs: Cell cycle regulation of skeletal muscle stem cell quiescence and activation.

Despoina Madamtzoglou, Frederic Relaix.

  After extensive proliferation during development, the adult skeletal muscle cells remain outside the cell cycle, either as post-mitotic myofibers or as quiescent muscle stem cells (MuSCs). Despite its terminally differentiated state, adult skeletal muscle has a remarkable regeneration potential, driven by MuSCs. Upon injury, MuSC quiescence is reversed to support tissue growth and repair and it is re-established after the completion of muscle regeneration. The distinct cell cycle states and transitions observed in the different myogenic populations are orchestrated by elements of the cell cycle machinery. This consists of i) complexes of cyclins and Cyclin-Dependent Kinases (CDKs) that ensure cell cycle progression and ii) their negative regulators, the Cyclin-Dependent Kinase Inhibitors (CDKIs). In this review we discuss the roles of these factors in developmental and adult myogenesis, with a focus on CDKIs that have emerging roles in stem cell functions.

Keywords:  CDK; CDKI; Cell cycle; Cyclins; Growth arrest; Muscle satellite cells; Muscle stem cells; Myogenesis; Proliferation; Quiescence; Skeletal muscle

DOI:  https://doi.org/10.1016/j.yexcr.2022.113275
Front Physiol. 2022 ;13 930185

A Preclinical Systematic Review of the Effects of Chronic Exercise on Autophagy-Related Proteins in Aging Skeletal Muscle.

Cenyi Wang, Jiling Liang, Yuanyuan Ren, Jielun Huang, Baoming Jin, Guodong Wang, Ning Chen.

  Background: Exercise is one of the most effective interventions for preventing and treating skeletal muscle aging. Exercise-induced autophagy is widely acknowledged to regulate skeletal muscle mass and delay skeletal muscle aging. However, the mechanisms underlying of the effect of different exercises on autophagy in aging skeletal muscle remain unclear. Methods: A systematic review was performed following an electronic search of SCOPUS, PubMed, Web of Science, ScienceDirect, and Google Scholar and two Chinese electronic databases, CNKI and Wan Fang. All articles published in English and Chinese between January 2010 and January 2022 that quantified autophagy-related proteins in aging skeletal muscle models. Results: The primary outcome was autophagy assessment, indicated by changes in the levels of any autophagy-associated proteins. A total of fifteen studies were included in the final review. Chronic exercise modes mainly comprise aerobic exercise and resistance exercise, and the intervention types include treadmill training, voluntary wheel running, and ladder training. LC3, Atg5-Atg7/9/12, mTOR, Beclin1, Bcl-2, p62, PGC-1α, and other protein levels were quantified, and the results showed that long-term aerobic exercise and resistance exercise could increase the expression of autophagy-related proteins in aging skeletal muscle (p < 0.05). However, there was no significant difference in short term or high-intensity chronic exercise, and different types and intensities of exercise yielded different levels of significance for autophagy-related protein expression. Conclusion: Existing evidence reveals that high-intensity exercise may induce excessive autophagy, while low-intensity exercise for a short period (Intervention duration <12 weeks, frequency <3 times/week) may not reach the threshold for exercise-induced autophagy. Precise control of the exercise dose is essential in the long term to maximize the benefits of exercise. Further investigation is warranted to explore the relationship between chronic exercise and different exercise duration and types to substantiate the delaying of skeletal muscle aging by exercise.

Keywords:  aging; autophagy; chronic exercise; skeletal muscle; systematic review

DOI:  https://doi.org/10.3389/fphys.2022.930185
J Anim Sci. 2022 Aug 01. pii: skac035. [Epub ahead of print]100(8):

Molecular and biochemical regulation of skeletal muscle metabolism.

Morgan D Zumbaugh, Sally E Johnson, Tim H Shi, David E Gerrard.

  Skeletal muscle hypertrophy is a culmination of catabolic and anabolic processes that are interwoven into major metabolic pathways, and as such modulation of skeletal muscle metabolism may have implications on animal growth efficiency. Muscle is composed of a heterogeneous population of muscle fibers that can be classified by metabolism (oxidative or glycolytic) and contractile speed (slow or fast). Although slow fibers (type I) rely heavily on oxidative metabolism, presumably to fuel long or continuous bouts of work, fast fibers (type IIa, IIx, and IIb) vary in their metabolic capability and can range from having a high oxidative capacity to a high glycolytic capacity. The plasticity of muscle permits continuous adaptations to changing intrinsic and extrinsic stimuli that can shift the classification of muscle fibers, which has implications on fiber size, nutrient utilization, and protein turnover rate. The purpose of this paper is to summarize the major metabolic pathways in skeletal muscle and the associated regulatory pathways.

Keywords:  metabolism; muscle; nutrients; satellite cells

DOI:  https://doi.org/10.1093/jas/skac035
Am J Physiol Cell Physiol. 2022 Aug 01.

Dissociation of SH3 and cysteine rich domain 3 and junctophilin 1 from dihydropyridine receptor in dystrophin-deficient muscles.

Yuki Ashida, Koichi Himori, Nao Tokuda, Azuma Naito, Nao Yamauchi, Nana Takenaka-Ninagawa, Yoshitsugu Aoki, Hidetoshi Sakurai, Takashi Yamada.

  The disruption of excitation-contraction (EC) coupling and subsequent reduction in Ca2+ release from the sarcoplasmic reticulum (SR) have been shown to account for muscle weakness seen in patients with Duchenne muscular dystrophy (DMD). Here, we examined the mechanisms underlying EC uncoupling in skeletal muscles from mdx52 and DMD-null/NSG mice, animal models for DMD, focusing on the SH3 and cysteine rich domain 3 (STAC3) and junctophilin 1 (JP1), which link the dihydropyridine receptor (DHPR) in the transverse tubule and the ryanodine receptor 1 in the SR. The isometric plantarflexion torque normalized to muscle weight of whole plantar flexor muscles was depressed in mdx52 and DMD-null/NSG mice compared to their control mice. This was accompanied by increased autolysis of calpain-1, decreased levels of STAC3 and JP1 content, and dissociation of STAC3 and JP1 from DHPR-α1s in gastrocnemius muscles. Moreover, in vitro mechanistic experiments demonstrated that STAC3 and JP1 underwent Ca2+-dependent proteolysis which was less pronounced in dystrophin-deficient muscles where calpastatin, the endogenous calpain inhibitor, was upregulated. Eccentric contractions further enhanced autolysis of calpain-1 and proteolysis of STAC3 and JP1 that were associated with severe torque depression in gastrocnemius muscles from DMD-null/NSG mice. These data suggest that Ca2+-dependent proteolysis of STAC3 and JP1 may be an essential factor causing muscle weakness due to EC coupling failure in dystrophin-deficient muscles.

Keywords:  STAC3; calpain; eccentric contraction; junctophilin 1; muscular dystrophy

DOI:  https://doi.org/10.1152/ajpcell.00163.2022
Elife. 2022 Aug 05. pii: e75863. [Epub ahead of print]11

Septin7 is indispensable for proper skeletal muscle architecture and function.

Mónika Gönczi, Zsolt Ráduly, László Szabó, János Fodor, Andrea Telek, Nóra Dobrosi, Norbert Balogh, Péter Szentesi, Gréta Kis, Miklós Antal, György Trencsenyi, Beatrix Dienes, László Csernoch.

  Today septins are considered as the fourth component of the cytoskeleton, with the Septin7 isoform playing a critical role in the formation of higher-order structures. While its importance has already been confirmed in several intracellular processes of different organs, very little is known about its role in skeletal muscle. Here, using Septin7 conditional knockdown (KD) mouse model, the C2C12 cell line, and enzymatically isolated adult muscle fibers, the organization and localization of septin filaments are revealed, and an ontogenesis-dependent expression of Septin7 is demonstrated. KD mice displayed a characteristic hunchback phenotype with skeletal deformities, reduction in in vivo and in vitro force generation, and disorganized mitochondrial networks. Furthermore, knockout of Septin7 in C2C12 cells resulted in complete loss of cell division while KD cells provided evidence that Septin7 is essential for proper myotube differentiation. These and the transient increase in Septin7 expression following muscle injury suggest that it may be involved in muscle regeneration and development.

Keywords:  cell biology; cytoskeleton; development; human; mitochondria; mouse; regeneration; septins; skeletal muscle

DOI:  https://doi.org/10.7554/eLife.75863
J Cachexia Sarcopenia Muscle. 2022 Aug 04.

Altered muscle oxidative phenotype impairs exercise tolerance but does not improve after exercise training in multiple sclerosis.

Jan Spaas, Richie P Goulding, Charly Keytsman, Lena Fonteyn, Jack van Horssen, Richard T Jaspers, Bert O Eijnde, Rob C I Wüst.

  BACKGROUND: Patients with multiple sclerosis (MS) experience reduced exercise tolerance that substantially reduces quality of life. The mechanisms underpinning exercise intolerance in MS are not fully clear. This study aimed to determine the contributions of the cardiopulmonary system and peripheral muscle in MS-induced exercise intolerance before and after exercise training.METHODS: Twenty-three patients with MS (13 women) and 20 age-matched and sex-matched healthy controls (13 women) performed a cardiopulmonary exercise test. Muscle fibre type composition, size, succinate dehydrogenase (SDH) activity, capillarity, and gene expression and proteins related to mitochondrial density were determined in vastus lateralis muscle biopsies. Nine MS patients (five women) were re-examined following a 12 week exercise training programme consisting of high-intensity cycling interval and resistance training.
RESULTS: Patients with MS had lower maximal oxygen uptake compared with healthy controls (V̇O2peak , 25.0 ± 8.5 vs. 35.7 ± 6.4 mL/kg/min, P < 0.001). The lower gas exchange threshold (MS: 14.5 ± 5.5 vs. controls: 19.7 ± 2.9 mL/kg/min, P = 0.01) and slope of V̇O2 versus work rate (MS: 9.5 ± 1.7 vs. controls: 10.8 ± 1.1 mL/min/W, P = 0.01) suggested an intramuscular contribution to exercise intolerance in patients with MS. Muscle SDH activity was 22% lower in MS (P = 0.004), and strongly correlated with several indices of whole-body exercise capacity in MS patients (e.g. V̇O2peak , Spearman's ρ = 0.81, P = 0.002), but not healthy controls (ρ = 0.24, P = 0.38). In addition, protein levels of mitochondrial OXPHOS complexes I (-40%, P = 0.047) and II (-45%, P = 0.026) were lower in MS patients versus controls. Muscle capillary/fibre ratio correlated with V̇O2peak in healthy controls (ρ = 0.86, P < 0.001) but not in MS (ρ = 0.35, P = 0.22), and did not differ between groups (1.41 ± 0.30 vs. 1.47 ± 0.38, P = 0.65). Expression of genes involved in mitochondrial function, such as PPARA, PPARG, and TFAM, was markedly reduced in muscle tissue samples of MS patients (all P < 0.05). No differences in muscle fibre type composition or size were observed between groups (all P > 0.05). V̇O2peak increased by 23% following exercise training in MS (P < 0.001); however, no changes in muscle capillarity, SDH activity, gene or protein expression were observed (all P > 0.05).
CONCLUSIONS: Skeletal muscle oxidative phenotype (mitochondrial complex I and II content, SDH activity) is lower in patients with MS, contributing to reduced exercise tolerance. However, skeletal muscle mitochondria appeared resistant to the beneficial effects of exercise training, suggesting that other physiological systems, at least in part, drive the improvements in exercise capacity following exercise training in MS.

Keywords:  Exercise capacity; Exercise therapy; Mitochondria; Multiple sclerosis; Oxidative metabolism; Skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.13050
Stem Cells. 2022 Aug 03. pii: sxac056. [Epub ahead of print]

Notch1 and Notch2 Signaling Exclusively but Cooperatively Maintain Fetal Myogenic Progenitors.

Young-Woo Jo, Inkuk Park, Kyusang Yoo, Hyun-Young Woo, Ye Lynne Kim, Yea-Eun Kim, Ji-Hoon Kim, Young-Yun Kong.

  Myogenic progenitors (MPs) generate myocytes that fuse to form myofibers during skeletal muscle development while maintaining the progenitor pool, which is crucial for generating sufficient muscle. Notch signaling has been known to reserve a population of embryonic MPs during primary myogenesis by promoting cell cycle exit and suppressing premature differentiation. However, the roles of individual Notch receptors (Notch1-4) during embryonic/fetal myogenesis are still elusive. In this study, we found that Notch1 and Notch2, which exhibit the highest structural similarity among Notch receptors, maintain the MP population by distinct mechanisms: Notch1 induces cell cycle exit and Notch2 suppresses premature differentiation. Moreover, genetic and cell culture studies showed that Notch1 and Notch2 signaling in MPs are distinctively activated by interacting with Notch ligand-expressing myofibers and MP-lineage cells, respectively. These results suggest that through different activation modes, Notch1 and Notch2 distinctively and cooperatively maintain MP population during fetal myogenesis for proper muscle development.

Keywords:  Fetal myogenesis; Myogenic progenitor; Notch signaling; Skeletal muscle; Stem cell maintenance

DOI:  https://doi.org/10.1093/stmcls/sxac056
Ann Transl Med. 2022 May;10(9): 516

An analysis of lncRNA-miRNA-mRNA networks to investigate the effects of HDAC4 inhibition on skeletal muscle atrophy caused by peripheral nerve injury.

Yuming Gu, Yinghao Lin, Ming Li, Chenyu Zong, Hualin Sun, Yuntian Shen, Jianwei Zhu.

  Background: Muscle atrophy caused by peripheral nerve injury is a common clinical disease, with no effective treatments currently available. Our previous studies have found that denervation-induced muscle atrophy can be alleviated by inhibiting histone deacetylase 4 (HDAC4). An increasing amount of evidence shows that microRNA (miRNA) and long noncoding RNA (lncRNA) are involved in the occurrence of muscle atrophy. This study aimed to find the mechanism by which HDAC4 regulates denervation-induced muscle atrophy based on lncRNA-associated competing endogenous RNA (ceRNA) networks.Methods: We analyzed the influence of short hairpin RNA (shRNA) knockdown of HDAC4 on lncRNAs and miRNAs after denervated muscle atrophy using RNA sequencing. A Pearson's correlation heat map and principal component analysis were employed to analyze differentially expressed miRNAs and lncRNAs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses of target genes were conducted. The ceRNA network of lncRNA-miRNA-mRNA was constructed, and the core regulatory molecules in the ceRNA network were analyzed.
Results: We found 32 miRNAs and 111 lncRNAs related to denervated muscle atrophy regulated by HDAC4. Moreover, 15 downregulated lncRNAs, 14 upregulated miRNAs, and 61 downregulated mRNAs constituted a ceRNA regulatory network, participating in the biological processes including response to denervation involved in regulation of muscle adaptation, along with the signaling pathways including autophagy, FoxO signaling pathways, and Jak-STAT signaling pathways. Additionally, 6 upregulated lncRNAs, 8 downregulated miRNAs, and 66 upregulated mRNAs constituted another ceRNA regulatory network, which was mainly involved in cell cycle-related biological processes and pathways. Finally, 3 lncRNAs, 4 miRNAs, and 12 mRNAs constituted a ceRNA sub-network, and XR_377582.2 and ENSMUST00000143649 were considered to be the key lncRNAs.
Conclusions: In the ceRNA network, all nodes are directly or indirectly involved in the process by which HDAC4 regulates skeletal muscle atrophy caused by peripheral nerve injury. XR_377582.2 and ENSMUST00000143649 may be the key lncRNAs related to HDAC4 involved in the regulation of muscle atrophy.

Keywords:  Denervation; competing endogenous RNA (ceRNA); histone deacetylase 4 (HDAC4); muscle atrophy; transcriptome sequencing

DOI:  https://doi.org/10.21037/atm-21-6512
Metabolism. 2022 Jul 28. pii: S0026-0495(22)00146-9. [Epub ahead of print] 155268

Exercise timing influences multi-tissue metabolome and skeletal muscle proteome profiles in type 2 diabetic patients - A randomized crossover trial.

Mladen Savikj, Ben Stocks, Shogo Sato, Kenneth Caidahl, Anna Krook, Atul S Desmukh, Juleen R Zierath, Harriet Wallberg-Henriksson.

  AIMS/HYPOTHESIS: Metabolic effects of exercise may partly depend on the time-of-day when exercise is performed. We tested the hypothesis that exercise timing affects the adaptations in multi-tissue metabolome and skeletal muscle proteome profiles in men with type 2 diabetes.METHODS: Men fitting the inclusion (type 2 diabetes, age 45-68 years and body mass index 23-33 kg/m2) and exclusion criteria (insulin treatment, smoking, concurrent systemic disease, and regular exercise training) were included in a randomized crossover trial (n = 15). Participants included in this metabolomics and proteomics analysis fully completed all exercise sessions (n = 8). The trial consisted of two weeks of high-intensity interval training (HIT) (three sessions/week) either in the morning (08:00, n = 5) or afternoon (16:45, n = 3), a two-week wash-out period, and an additional two weeks of HIT at the opposing time. Participants and researchers were not blinded to group allocation. Blood, skeletal muscle and subcutaneous adipose tissue were obtained before the first, and after each training period. Broad-spectrum, untargeted proteomic analysis was performed on skeletal muscle, and metabolomic analysis was performed on all biosamples. Differential content was assessed by linear regression and pathway set enrichment analyses were performed. Coordinated metabolic changes across tissues were identified by Spearman correlation analysis.
RESULTS: Metabolic and proteomic profiles remained stable after two weeks of HIT, and individual metabolites and proteins were not altered, irrespective of the time of day at which the training was performed. However, coordinated changes in relevant metabolic pathways and protein categories were identified. Morning and afternoon HIT similarly increased plasma diacylglycerols, skeletal muscle acyl-carnitines, and subcutaneous adipose tissue sphingomyelins and lysophospholipids. Acyl-carnitines were central to training-induced metabolic cross-talk across tissues. Plasma carbohydrates, via the penthose phosphate pathway, were increased and skeletal muscle lipids were decreased after morning compared to afternoon HIT. Skeletal muscle lipoproteins were higher, and mitochondrial complex III abundance was lower after morning compared to afternoon HIT.
CONCLUSIONS/INTERPRETATION: We provide a comprehensive analysis of a multi-tissue metabolomic and skeletal muscle proteomic responses to training at different times of the day in men with type 2 diabetes. Increased circulating lipids and changes in adipose tissue lipid composition were common between morning and afternoon HIT. However, afternoon HIT increased skeletal muscle lipids and mitochondrial content to a greater degree than morning training. Thus, there is a diurnal component in the metabolomic and proteomic response to exercise in men with type 2 diabetes. The clinical relevance of this response warrants further investigation.

Keywords:  Circadian rhythm; Exercise; High-intensity interval training; Metabolome; Proteome; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.metabol.2022.155268
Exp Cell Res. 2022 Aug 01. pii: S0014-4827(22)00292-0. [Epub ahead of print] 113299

Regulation of myogenic gene expression.

Cristina Vicente-García, Juan Diego Hernández-Camacho, Jaime J Carvajal.

  Skeletal muscle development and regeneration is governed by the combined action of Myf5, MyoD, Mrf4 and MyoG, also known as the myogenic regulatory factors (MRFs). These transcription factors are expressed in a highly spatio-temporal restricted manner, ensuring the significant functional and metabolic diversity observed between the different muscle groups. In this review, we will discuss the multiple layers of regulation that contribute to the control of the exquisite expression patterns of the MRFs in particular, and of myogenic genes in general. We will highlight all major regulatory processes that play a role in myogenesis: from those that modulate chromatin status and transcription competence, such as DNA methylation, histone modification, chromatin remodeling, or non-coding RNAs, to those that control transcript and protein processing and modification, such as alternative splicing, polyadenylation, other mRNA modifications, or post-translational protein modifications. All these processes are exquisitely and tightly coordinated to ensure the proper activation, maintenance and termination of the myogenic process.

Keywords:  Epigenetics; Gene expression regulation; Myogenesis; Myogenic regulatory factors; Post-transcriptional modifications; Post-translational modifications

DOI:  https://doi.org/10.1016/j.yexcr.2022.113299
JCI Insight. 2022 Aug 02. pii: e153584. [Epub ahead of print]

NR1D1 controls skeletal muscle calcium homeostasis through myoregulin repression.

Alexis Boulinguiez, Christian Duhem, Alicia Mayeuf-Louchart, Benoit Pourcet, Yasmine Sebti, Kateryna Kondratska, Valérie Montel, Stéphane Delhaye, Quentin Thorel, Justine Beauchamp, Aurore Hebras, Marion Gimenez, Marie Couvelaere, Mathilde Zecchin, Lise Ferri, Natalia Prevarskaya, Anne Forand, Christel Gentil, Jessica Ohana, France Piétri-Rouxel, Bruno Bastide, Bart Staels, Helene Duez, Steve Lancel.

  The sarcoplasmic reticulum (SR) plays an important role in calcium homeostasis. SR calcium mishandling is described in pathological conditions such as myopathies. Here, we investigated whether the nuclear receptor subfamily 1 group D member (NR1D1, also called REV-ERBα) regulates skeletal muscle SR calcium homeostasis. Our data demonstrate that NR1D1 deficiency in mice impairs SERCA-dependent SR calcium uptake. NR1D1 acts on calcium homeostasis by repressing the SERCA inhibitor myoregulin through direct binding to its promoter. Restoration of myoregulin counteracts the effects of NR1D1 overexpression on SR calcium content. Interestingly, myoblasts from Duchenne myopathy patients display lower NR1D1 expression, whereas pharmacological NR1D1 activation ameliorates SR calcium homeostasis, and improves muscle structure and function in dystrophic mdx/Utr+/- mice. Our findings demonstrate that NR1D1 regulates muscle SR calcium homeostasis, pointing to its therapeutic interest for mitigating myopathy.

Keywords:  Calcium; Cell Biology; Muscle; Muscle Biology

DOI:  https://doi.org/10.1172/jci.insight.153584
Front Physiol. 2022 ;13 921763

Hypoxic Training Ameliorates Skeletal Muscle Microcirculation Vascular Function in a Sirt3-Dependent Manner.

Chunwei Ma, Yongcai Zhao, Xiaoqing Ding, Binghong Gao.

  Hypoxic training improves the microcirculation function of human skeletal muscle, but its mechanism is still unclear. Silent information regulator 2 homolog 3 (Sirt3) can improve mitochondrial function and oxidative status. We aimed to examine the role of Sirt3 in the process of hypoxic training, which affects skeletal muscle microcirculation. C57BL/6 mice were assigned to control (C), hypoxic training (HT), Sirt3 inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP), and 3-TYP + hypoxic training (3-TYP + HT) groups (n = 6/group). Sirt3 inhibition was induced by intraperitoneal injection of Sirt3 inhibitor 3-TYP. After 6 weeks of intervention, microcirculatory capillary formation and vasomotor capacity were evaluated using immunofluorescence, Western blot, biochemical tests, and transmission electron microscopy (TEM). Laser Doppler flowmetry was used to evaluate skeletal muscle microcirculation blood flow characteristics. Six weeks of hypoxic training enhanced skeletal muscle microcirculation function and increased microcirculatory vasodilation capacity and capillary formation. After the pharmacological inhibition of Sirt3, the reserve capacity of skeletal muscle microcirculation was reduced to varying degrees. After the inhibition of Sirt3, mice completed the same hypoxic training, and we failed to observe the microcirculation function adaptation like that observed in hypoxic training alone. The microcirculation vasodilation and the capillaries number did not improve. Hypoxic training improved skeletal muscle microcirculation vasodilation capacity and increased skeletal muscle microcirculation capillary density. Sirt3 is involved in the adaptation of skeletal muscle microcirculation induced by hypoxic training.

Keywords:  Sirt3; hypoxic training; microcirculation; skeletal muscle; vascular function

DOI:  https://doi.org/10.3389/fphys.2022.921763
Cell Metab. 2022 Aug 02. pii: S1550-4131(22)00306-0. [Epub ahead of print]34(8): 1085-1087

Outrunning obesity with Lac-Phe?

Jens Lund, Christoffer Clemmensen, Thue W Schwartz.

Lactate released from skeletal muscle during high-intensity exercise gives rise to a surge in circulating lactate-derived pseudo-dipeptide metabolites including N-lactoyl-phenylalanine (Lac-Phe). In a recent Nature paper, Li et al. use genetic and pharmacological evidence to now propose Lac-Phe to be an "exercise hormone" that suppresses appetite and obesity.

DOI: https://doi.org/10.1016/j.cmet.2022.07.007
J Physiol. 2022 Aug 01.

Activation of the myosin motors in fast-twitch muscle of the mouse is controlled by mechano-sensing in the myosin filaments.

Cameron Hill, Elisabetta Brunello, Luca Fusi, Jesús Garcia Ovejero, Malcolm Irving.

  KEY POINTS: Activation of myosin filaments in extensor digitorum longus muscles of the mouse is delayed by imposing rapid shortening from the start of stimulation. Stress is the major mechanism of myosin filament activation in these muscles, but there is a small component of filament activation during electrical stimulation at zero stress. Myosin motors switch rapidly from the folded inhibited conformation to the actin-attached force-generating conformation early in force development.ABSTRACT: Myosin motors in resting muscle are inactivated by folding against the backbone of the myosin filament in an ordered helical array and must be released from that conformation to engage in force generation. Time-resolved X-ray diffraction from single fibres of amphibian muscle showed that myosin filament activation could be inhibited by imposing unloaded shortening at the start of stimulation, suggesting that filaments were activated by mechanical stress. Here we improved the signal-to-noise of that approach using whole extensor digitorum longus (EDL) muscles of the mouse contracting tetanically at 28°C. Changes in X-ray signals associated with myosin filament activation, including the decrease in the first-order myosin layer line associated with the helical motor array, increase in the spacing of a myosin-based reflection associated with packing of myosin tails in the filament backbone and increase in the ratio of the 1,1 and 1,0 equatorial reflections associated with movement of motors away from the backbone, were delayed by imposing 10-ms unloaded shortening at the start of stimulation. These results show that myosin filaments are predominantly activated by filament stress, as in amphibian muscle. However, a small component of filament activation at zero load was detected, implying an independent mechanism of partial filament activation. X-ray interference measurements indicated a switch-like change in myosin motor conformation at the start of force development, accompanied by transient disordering of motors in the regions of the myosin filament near its midpoint, suggesting that filament zonal dynamics also play a role in its activation. Abstract figure legend Mechano-sensing in the thick filament of mammalian skeletal muscle. Time-resolved X-ray diffraction allows changes in the structure of the myosin-containing thick filaments and actin-containing thin filaments during contraction to be followed in an intact working muscle. In resting muscle (cyan), thin filaments are OFF because no calcium is bound to troponin (hexagons), and myosin motors are inhibited by folding back against the thick filament backbone in a helical array (gray). During contraction at high load (purple), most myosin motors leave the helical array, and some (green) bind to the thin filament to generate force, whilst others (yellow) become disordered. When a period of rapid shortening is imposed at the start of electrical stimulation to keep the load on the muscle very low (low-load; solid black force trace), nearly all motors remain in the helical folded state (grey) even though the thin filament is ON and two calcium ions (white) are bound to each troponin (hexagons). These results show that activation of myosin motors in mammalian skeletal muscle is controlled by mechanical stress in the thick filament. This article is protected by copyright. All rights reserved.

Keywords:  muscle regulation; myosin; skeletal muscle

DOI:  https://doi.org/10.1113/JP283048
J Physiol. 2022 Jul 31.

Histone-mediated skeletal muscle adaptations to exercise: insights into a new era of epigenome-based personalized medicine.

Tomer Jordi Chaffer, Felipe E Broering, Sami Sedraoui.



Keywords:  epigenetics; exercise; personalized medicine; skeletal muscle

DOI:  https://doi.org/10.1113/JP283434
Front Genome Ed. 2022 ;4 937879

Gene Editing to Tackle Facioscapulohumeral Muscular Dystrophy.

Virginie Mariot, Julie Dumonceaux.

  Facioscapulohumeral dystrophy (FSHD) is a skeletal muscle disease caused by the aberrant expression of the DUX4 gene in the muscle tissue. To date, different therapeutic approaches have been proposed, targeting DUX4 at the DNA, RNA or protein levels. The recent development of the clustered regularly interspaced short-palindromic repeat (CRISPR) based technology opened new avenues of research, and FSHD is no exception. For the first time, a cure for genetic muscular diseases can be considered. Here, we describe CRISPR-based strategies that are currently being investigated for FSHD. The different approaches include the epigenome editing targeting the DUX4 gene and its promoter, gene editing targeting the polyadenylation of DUX4 using TALEN, CRISPR/cas9 or adenine base editing and the CRISPR-Cas9 genome editing for SMCHD1. We also discuss challenges facing the development of these gene editing based therapeutics.

Keywords:  CRISPR; DUX4; FSHD; TALEN; cas9; gene editing; muscle; therapy

DOI:  https://doi.org/10.3389/fgeed.2022.937879
NPJ Aging. 2022 Jun 27. 8(1): 8

Age-dependent impact of two exercise training regimens on genomic and metabolic remodeling in skeletal muscle and liver of male mice.

Michel Bernier, Ignacio Navas Enamorado, Mari Carmen Gómez-Cabrera, Miguel Calvo-Rubio, Jose Antonio González-Reyes, Nathan L Price, Ana Belén Cortés-Rodríguez, Juan Carlos Rodríguez-Aguilera, Sandra Rodríguez-López, Sarah J Mitchell, Kelsey N Murt, Krystle Kalafut, Katrina M Williams, Christopher W Ward, Joseph P Stains, Gloria Brea-Calvo, Jose M Villalba, Sonia Cortassa, Miguel A Aon, Rafael de Cabo.

Skeletal muscle adapts to different exercise training modalities with age; however, the impact of both variables at the systemic and tissue levels is not fully understood. Here, adult and old C57BL/6 male mice were assigned to one of three groups: sedentary, daily high-intensity intermittent training (HIIT), or moderate intensity continuous training (MICT) for 4 weeks, compatible with the older group's exercise capacity. Improvements in body composition, fasting blood glucose, and muscle strength were mostly observed in the MICT old group, while effects of HIIT training in adult and old animals was less clear. Skeletal muscle exhibited structural and functional adaptations to exercise training, as revealed by electron microscopy, OXPHOS assays, respirometry, and muscle protein biomarkers. Transcriptomics analysis of gastrocnemius muscle combined with liver and serum metabolomics unveiled an age-dependent metabolic remodeling in response to exercise training. These results support a tailored exercise prescription approach aimed at improving health and ameliorating age-associated loss of muscle strength and function in the elderly.

DOI: https://doi.org/10.1038/s41514-022-00089-8
J Physiol. 2022 Aug 06.

Micro(RNA)-cloud can perpetuate physiological adaptation of skeletal muscle to exercise and energy imbalance.

Filip Kolodziej, Aoife McLysaght, Katarzyna Goljanek-Whysall.



Keywords:  circulating microRNAs; energy imbalance; exercise; microRNA; muscle

DOI:  https://doi.org/10.1113/JP283547
J Physiol. 2022 Aug 04.

Phytochemical compound PB125 attenuates skeletal muscle mitochondrial dysfunction and impaired proteostasis in a model of musculoskeletal decline.

Robert V Musci, Kendra M Andrie, Maureen A Walsh, Zackary J Valenti, Melissa A Linden, Maryam F Afzali, Sydney Bork, Margaret Campbell, Taylor Johnson, Thomas E Kail, Richard Martinez, Tessa Nguyen, Joseph Sanford, Sara Wist, Meredith D Murrell, Joe M McCord, Brooks M Hybertson, Qian Zhang, Martin A Javors, Kelly S Santangelo, Karyn L Hamilton.

  KEY POINTS: Aside from exercise, there are no effective interventions for musculoskeletal decline, which begins in the fifth decade of life and contributes to disability and cardiometabolic diseases. Targeting both mitochondrial dysfunction and impaired protein homeostasis (proteostasis), which contribute to the age and disease process, may mitigate the progressive decline in overall musculoskeletal function (e.g. gait, strength). A potential intervention to target disease drivers is to stimulate Nrf2 activation, which leads to the transcription of genes responsible for redox homeostasis, proteome maintenance, and mitochondrial energetics. Here, we tested a purported phytochemical Nrf2 activator, PB125, to improve mitochondrial function and proteostasis in male and female Hartley guinea pigs, which are a model for musculoskeletal aging. PB125 improved mitochondrial respiration and attenuated disease- and age-related declines in skeletal muscle protein synthesis, a component of proteostasis, in both male and female Hartley guinea pigs.ABSTRACT: Impaired mitochondrial function and disrupted proteostasis contribute to musculoskeletal dysfunction. However, few interventions simultaneously target these two drivers to prevent musculoskeletal decline. Nuclear factor erythroid 2-related factor 2 (Nrf2) activates a transcriptional program promoting cytoprotection, metabolism, and proteostasis. We hypothesized daily treatment with a purported Nrf2 activator, PB125, in Hartley guinea pigs, a model of musculoskeletal decline, would attenuate the progression of skeletal muscle mitochondrial dysfunction and impaired proteostasis and preserve musculoskeletal function. We treated 2-month- and 5-month-old male and female Hartley guinea pigs for 3 and 10 months, respectively, with the phytochemical compound PB125. Longitudinal assessments of voluntary mobility were measured using Any-MazeTM open-field enclosure monitoring. Cumulative skeletal muscle protein synthesis rates were measured using deuterium oxide over the final 30 days of treatment. Mitochondrial oxygen consumption in soleus muscles was measured using high resolution respirometry. In both sexes, PB125 1) increased electron transfer system capacity; 2) attenuated the disease/age-related decline in coupled and uncoupled mitochondrial respiration; and 3) attenuated declines in protein synthesis in the myofibrillar, mitochondrial, and cytosolic subfractions of the soleus. These effects were not associated with statistically significant prolonged maintenance of voluntary mobility in guinea pigs. Collectively, treatment with PB125 contributed to maintenance of skeletal muscle mitochondrial respiration and proteostasis in a pre-clinical model of musculoskeletal decline. Further investigation is necessary to determine if these documented effects of PB125 are also accompanied by slowed progression of other aspects of musculoskeletal dysfunction. Abstract figure legend Musculoskeletal decline is an age-related multifactorial syndrome that is characterized by joint degeneration and loss of skeletal muscle function. Mitochondrial dysfunction and impaired protein turnover are two causative factors of musculoskeletal decline. 10 months of daily oral PB125 supplementation attenuated disease-related declines in mitochondrial respiration and protein synthesis in both male and female Hartley guinea pigs, which are a preclinical model of spontaneous and progressive musculoskeletal decline. Despite the attenuation of mitochondrial dysfunction and impaired protein turnover, there was not a statistically significant effect on the maintenance of mobility over the 10-month trial. This article is protected by copyright. All rights reserved.

Keywords:  ageing; chronic disease; healthspan; lifespan; longevity; mitochondria; musculoskeletal; proteostasis; skeletal muscle

DOI:  https://doi.org/10.1113/JP282273
Front Pharmacol. 2022 ;13 935804

P2X7 Purinoceptor Affects Ectopic Calcification of Dystrophic Muscles.

Robin M H Rumney, Justyna Róg, Natalia Chira, Alexander P Kao, Rasha Al-Khalidi, Dariusz C Górecki.

  Ectopic calcification (EC) of myofibers is a pathological feature of muscle damage in Duchenne muscular dystrophy (DMD). Mineralisation of muscle tissue occurs concomitantly with macrophage infiltration, suggesting a link between ectopic mineral deposition and inflammation. One potential link is the P2X7 purinoceptor, a key trigger of inflammation, which is expressed on macrophages but also up-regulated in dystrophic muscle cells. To investigate the role of P2X7 in dystrophic calcification, we utilised the Dmd mdx-βgeo dystrophin-null mouse model of DMD crossed with a global P2X7 knockout (P2rx7 -/- ) or with our novel P2X7 knockin-knockout mouse (P2x7 KiKo ), which expresses P2X7 in macrophages but not muscle cells. Total loss of P2X7 increased EC, indicating that P2X7 overexpression is a protective mechanism against dystrophic mineralisation. Given that muscle-specific P2X7 ablation did not affect dystrophic EC, this underlined the role of P2X7 receptor expression on the inflammatory cells. Serum phosphate reflected dystrophic calcification, with the highest serum phosphate levels found in genotypes with the most ectopic mineral. To further investigate the underlying mechanisms, we measured phosphate release from cells in vitro, and found that dystrophic myoblasts released less phosphate than non-dystrophic cells. Treatment with P2X7 antagonists increased phosphate release from both dystrophic and control myoblasts indicating that muscle cells are a potential source of secreted phosphate while macrophages protect against ectopic mineralisation. Treatment of cells with high phosphate media engendered mineral deposition, which was decreased in the presence of the P2X7 agonist BzATP, particularly in cultures of dystrophic cells, further supporting a protective role for P2X7 against ectopic mineralisation in dystrophic muscle.

Keywords:  P2X7; P2X7 purinoceptor protects against ectopic calcification of dystrophic muscles duchenne muscular dystrophy; ectopic calcification; knockin; knockout; macrophage

DOI:  https://doi.org/10.3389/fphar.2022.935804
Biochem Biophys Res Commun. 2022 Jul 19. pii: S0006-291X(22)01028-2. [Epub ahead of print]623 148-153

A preliminary study on the role of Piezo1 channels in myokine release from cultured mouse myotubes.

Marina Sciancalepore, Gabriele Massaria, Federica Tramer, Paola Zacchi, Paola Lorenzon, Annalisa Bernareggi.

  It has long been known that regular physical exercise induces short and long term benefits reducing the risk of cardiovascular disease, diabetes, osteoporosis, cancer and improves sleep quality, cognitive level, mobility, autonomy in enderly. More recent is the evidence on the endocrine role of the contracting skeletal muscle. Exercise triggers the release of miokines, which act in autocrine, paracrine and endocrine ways controlling the activity of muscles but also of other tissues and organs such as adipose tissue, liver, pancreas, bones, and brain. The mechanism of release is still unclear. Neuromuscular electrical stimulation reproduces the beneficial effects of physical activity producing physiological metabolic, cardiovascular, aerobic responses consistent with those induced by exercise. In vitro, Electrical Pulse Stimulations (EPS) of muscle cells elicit cell contraction and mimic miokine release in the external medium. Here we show that, in cultured mouse myotubes, EPS induce contractile activity and the release of the myokine IL-6. Gadolinium highly reduces EPS-induced IL-6 release, suggesting the involvement of mechanical activated ion channels. The chemical activation of mechanosensitive Piezo1 channels with the specific agonist Yoda1 stimulates IL-6 release similarly to EPS, suggesting the involvement of Piezo1 channels in the control of the myokine release. The expression of Piezo1 protein in myotubes was confirmed by the Western blot analysis. To the best of our knowledge, this is the first evidence of a Piezo1-mediated effect in myokine release and suggests a potential translational use of specific Piezo1 agonists for innovative therapeutic treatments reproducing/enhancing the benefits of exercise mediated by myokines.

Keywords:  Electrical pulse stimulation; IL-6; Piezo1; Skeletal muscle cells; Yoda1

DOI:  https://doi.org/10.1016/j.bbrc.2022.07.059
Commun Biol. 2022 Aug 01. 5(1): 774

The Whole-transcriptome Landscape of Diabetes-related Sarcopenia Reveals the Specific Function of Novel lncRNA Gm20743.

Jing Yu, Kim Loh, He-Qin Yang, Meng-Ran Du, Yong-Xin Wu, Zhi-Yin Liao, Ai Guo, Yun-Fei Yang, Bo Chen, Yu-Xing Zhao, Jin-Liang Chen, Jing Zhou, Yue Sun, Qian Xiao.

While the exact mechanism remains unclear, type 2 diabetes mellitus increases the risk of sarcopenia which is characterized by decreased muscle mass, strength, and function. Whole-transcriptome RNA sequencing and informatics were performed on the diabetes-induced sarcopenia model of db/db mice. To determine the specific function of lncRNA Gm20743, the detection of Mito-Sox, reactive oxygen species, Ethynyl-2'-deoxyuridine, and myosin heavy chain was performed in overexpressed and knockdown-Gm20743 C2C12 cells. RNA-seq data and informatics revealed the key lncRNA-mRNA interactions and indicated a potential regulatory role of lncRNAs. We characterized three core candidate lncRNAs Gm20743, Gm35438, 1700047G03Rik, and their potential function. Furthermore, the results suggested lncRNA Gm20743 may be involved in regulating mitochondrial function, oxidative stress, cell proliferation, and myotube differentiation in skeletal muscle cells. These findings significantly improve our understanding of lncRNAs that may mediate muscle mass, strength, and function in diabetes and represent potential therapeutic targets for diabetes-induced sarcopenia.

DOI: https://doi.org/10.1038/s42003-022-03728-8
Front Neurosci. 2022 ;16 897005

Hypothalamus-Muscle Parallel Induction of Metabolic Pathways Following Physical Exercise.

Almog Katz, Meital Gonen, Yael Shahar, Asael Roichman, Batia Lerrer, Haim Yosef Cohen.

  The modern lifestyle requires less physical activity and skills during our daily routine, leading to multiple pathologies related to physical disabilities and energy accessibility. Thus, exploring the mechanisms underlying the metabolic regulation of exercise is crucial. Here, we characterized the effect of forced and voluntary endurance exercises on three key metabolic signaling pathways, sirtuins, AMPK, and mTOR, across several metabolic tissues in mice: brain, muscles, and liver. Both voluntary and forced exercises induced AMPK with higher intensity in the first. The comparison between those metabolic tissues revealed that the hypothalamus and the hippocampus, two brain parts, showed different metabolic signaling activities. Strikingly, despite the major differences in the physiology of muscles and hypothalamic tissues, the hypothalamus replicates the metabolic response of the muscle in response to physical exercise. Specifically, muscles and hypothalamic tissues showed an increase and a decrease in AMPK and mTOR signaling, respectively. Overall, this study reveals new insight into the relation between the hypothalamus and muscles, which enhances the coordination within the muscle-brain axis and potentially improves the systemic response to physical activity performance and delaying health inactivity disorders.

Keywords:  exercise; hippocampus; hypothalamus; metabolic pathways; muscle

DOI:  https://doi.org/10.3389/fnins.2022.897005
Cell Death Dis. 2022 Aug 05. 13(8): 680

Regulatory T cells in skeletal muscle repair and regeneration: recent insights.

Jianhui Wu, Bowen Ren, Daochao Wang, Hui Lin.

Skeletal muscle repair and regeneration after injury is a multi-stage process, involving a dynamic inflammatory microenvironment consisting of a complex network formed by the interaction of immune cells and their secreted cytokines. The homeostasis of the inflammatory microenvironment determines whether skeletal muscle repair tissues will ultimately form scar tissue or regenerative tissue. Regulatory T cells (Tregs) regulate homeostasis within the immune system and self-immune tolerance, and play a crucial role in skeletal muscle repair and regeneration. Dysregulated Tregs function leads to abnormal repair. In this review, we discuss the role and mechanisms of Tregs in skeletal muscle repair and regeneration after injury and provide new strategies for Treg immunotherapy in skeletal muscle diseases.

DOI: https://doi.org/10.1038/s41419-022-05142-8
Elife. 2022 Aug 03. pii: e76649. [Epub ahead of print]11

Tension-driven multi-scale self-organisation in human iPSC-derived muscle fibers.

Qiyan Mao, Achyuth Acharya, Alejandra Rodríguez-delaRosa, Fabio Marchiano, Benoit Dehapiot, Ziad Al Tanoury, Jyoti Rao, Margarete Díaz-Cuadros, Arian Mansur, Erica Wagner, Claire Chardes, Vandana Gupta, Pierre-François Lenne, Bianca H Habermann, Olivier Theodoly, Olivier Pourquié, Frank Schnorrer.

  Human muscle is a hierarchically organised tissue with its contractile cells called myofibers packed into large myofiber bundles. Each myofiber contains periodic myofibrils built by hundreds of contractile sarcomeres that generate large mechanical forces. To better understand the mechanisms that coordinate human muscle morphogenesis from tissue to molecular scales, we adopted a simple in vitro system using induced pluripotent stem cell-derived human myogenic precursors. When grown on an unrestricted two-dimensional substrate, developing myofibers spontaneously align and self-organise into higher-order myofiber bundles, which grow and consolidate to stable sizes. Following a transcriptional boost of sarcomeric components, myofibrils assemble into chains of periodic sarcomeres that emerge across the entire myofiber. More efficient myofiber bundling accelerates the speed of sarcomerogenesis suggesting that tension generated by bundling promotes sarcomerogenesis. We tested this hypothesis by directly probing tension and found that tension build-up precedes sarcomere assembly and increases within each assembling myofibril. Furthermore, we found that myofiber ends stably attach to other myofibers using integrin-based attachments and thus myofiber bundling coincides with stable myofiber bundle attachment in vitro. A failure in stable myofiber attachment results in a collapse of the myofibrils. Overall, our results strongly suggest that mechanical tension across sarcomeric components as well as between differentiating myofibers is key to coordinate the multi-scale self-organisation of muscle morphogenesis.

Keywords:  developmental biology; human

DOI:  https://doi.org/10.7554/eLife.76649
IEEE Trans Neural Syst Rehabil Eng. 2022 Aug 04. PP

Towards Soft Wearable Strain Sensors for Muscle Activity Monitoring.

Jonathan T Alvarez, Lucas F Gerez, Oluwaseun A Araromi, Jessica G Hunter, Dabin K Choe, Christopher J Payne, Robert J Wood, Conor J Walsh.

The force-generating capacity of skeletal muscle is an important metric in the evaluation and diagnosis of musculoskeletal health. Measuring changes in muscle force exertion is essential for tracking the progress of athletes during training, for evaluating patients' recovery after muscle injury, and also for assisting the diagnosis of conditions such as muscular dystrophy, multiple sclerosis, or Parkinson's disease. Traditional hardware for strength evaluation requires technical training for operation, generates discrete time points for muscle assessment, and is implemented in controlled settings. The ability to continuously monitor muscle force without restricting the range of motion or adapting the exercise protocol to suit specific hardware would allow for a richer dataset that can help unlock critical features of muscle health and strength evaluation. In this paper, we employ wearable, ultra-sensitive soft strain sensors for tracking changes in muscle deformation during contractions. We demonstrate the sensors' sensitivity to isometric contractions, as well as the sensors' capacity to track changes in peak torque over the course of an isokinetic fatiguing protocol for the knee extensors. The wearable soft system was able to efficiently estimate peak joint torque reduction caused by muscle fatigue (mean NRMSE = 0.15±0.03).

DOI: https://doi.org/10.1109/TNSRE.2022.3196501
Exp Physiol. 2022 Aug 01.

Kynurenine metabolism is altered in mdx mice: A potential muscle to brain connection.

Emily N Copeland, Colton J F Watson, Kennedy C Whitley, Bradley J Baranowski, Nigel Kurgan, Adam J MacNeil, Rebecca E K MacPherson, Val A Fajardo, David J Allison.

  NEW FINDINGS: Research has shown that promoting muscle health with regular aerobic exercise can improve mental health through a kynurenine metabolic pathway. With regular aerobic exercise, kynurenine metabolism is favourably altered towards a neuroprotective pathway that promotes kynurenic acid production through increased expression of PGC-1α, kynurenine amino acid transferase (KAT) enzymes, and lowered inflammation. Whether conditions of muscle disease such as muscular dystrophy can negatively influence this pathway remains unknown. We show that the DBA/2J mdx model of Duchenne muscular dystrophy exhibit altered kynurenine metabolism with less KYNA and PGC-1α and the highest level of TNF-a mRNA - results associated with anxiety-like behaviour.ABSTRACT: Regular exercise can direct muscle kynurenine (KYN) metabolism toward the neuroprotective branch of the kynurenine pathway thereby limiting the accumulation of neurotoxic metabolites in the brain and contributing to mental resilience. However, the effect of muscle disease on KYN metabolism has not yet been investigated. Previous work has highlighted anxiety-like behaviors in approximately 25% of patients with Duchenne muscular dystrophy (DMD), possibly due to altered KYN metabolism. Here, we characterized KYN metabolism in mdx mouse models of DMD. Young (8-10 week old) DBA/2J (D2) mdx mice, but not age-matched C57BL/10 (C57) mdx mice, had lower levels of circulating KYNA and KYNA:KYN ratio compared with their respective wild-type (WT) controls. While both C57 and D2 mdx mice displayed signs of anxiety-like behaviour, spending more time in the corners of the arena during a novel object recognition test, this effect was more prominent in D2 mdx mice. Correlational analysis detected a significant negative association between KYNA:KYN levels and time spent in corners in D2 mice, but not C57 mice. In extensor digitorum longus muscles from D2 mdx mice, but not C57 mdx mice, we found lowered protein levels of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha and kynurenine amino transferase-1 enzyme when compared with WT. Furthermore, D2 mdx quadricep muscles had the highest level of TNF-α expression, which is suggestive of enhanced inflammation. Thus, our pilot work shows that KYN metabolism is altered in D2 mdx mice, with a potential contribution from altered muscle health. This article is protected by copyright. All rights reserved.

Keywords:  KYNA; anxiety; mental health; muscular dystrophy

DOI:  https://doi.org/10.1113/EP090381
3 Biotech. 2022 Sep;12(9): 193

Irisin/FNDC5 influences myogenic markers on skeletal muscle following high and moderate-intensity exercise training in STZ-diabetic rats.

Ehsan Arabzadeh, Hossein Shirvani, Masoumeh Ebadi Zahmatkesh, Shahin Riyahi Malayeri, Gholam Hossein Meftahi, Fatemeh Rostamkhani.

  In the present study, we investigated the effects of high-intensity interval training (HIIT) versus moderate-intensity continuous training (MICT) on irisin and expression of myogenic markers (paired box 7 (Pax7), myogenic differentiation 1 (MyoD), myogenin) in skeletal muscle of diabetic rats. Eighty-four male Wistar rats (6 weeks of age) were randomly divided into seven groups (n = 12): basic control (Co Basic), 8 weeks control (Co 8w), diabetes mellitus (DM), HIIT, DM + HIIT, MICT, and DM + MICT groups. Diabetes was induced by intraperitoneal injection of streptozotocin (STZ). The V ˙ o 2 max protocol was characterized by running on a rodent treadmill with moderate intensity (60-70% V ˙ o 2 max ), 60 min per session, 5 days/week, for 6 weeks. HIIT consisted of six 3-min runs at a high intensity (80-90% V ˙ o 2 max ) alternated with 2-min running at low intensity (50% V ˙ o 2 max ), 30 min per session, 5 days/week, for 6 weeks. Results showed that DM decreased myoblast markers compared to Co Basic and Co 8w groups. Fibronectin type III domain-containing protein 5 (FNDC5) mRNA decrease was correlated with myoblast markers (Pax7 r = 0.632, p = 0.027; MyoD r = 0.999, p = 0.001; myogenin r = 1.000, p = 0.001) in DM group. DM + MICT significantly increased gene expression of MyoD, myogenin, and FNDC5 compared to DM and DM + HIIT. The results also showed that the intensity and duration of exercise on the treadmill were effective in stimulating irisin and myogenic markers after DM.

Keywords:  Diabetes; Exercise training; Irisin; Muscle cell; Pax7; Satellite cells

DOI:  https://doi.org/10.1007/s13205-022-03253-9
PLoS One. 2022 ;17(8): e0267990

Neuromuscular denervation and deafferentation but not motor neuron death are disease features in the Smn2B/- mouse model of SMA.

Maria J Carlini, Marina K Triplett, Livio Pellizzoni.

Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by loss of motor neurons and skeletal muscle atrophy which is caused by ubiquitous deficiency in the survival motor neuron (SMN) protein. Several cellular defects contribute to sensory-motor circuit pathology in SMA mice, but the underlying mechanisms have often been studied in one mouse model without validation in other available models. Here, we used Smn2B/- mice to investigate specific behavioral, morphological, and functional aspects of SMA pathology that we previously characterized in the SMNΔ7 model. Smn2B/- SMA mice on a pure FVB/N background display deficits in body weight gain and muscle strength with onset in the second postnatal week and median survival of 19 days. Morphological analysis revealed severe loss of proprioceptive synapses on the soma of motor neurons and prominent denervation of neuromuscular junctions (NMJs) in axial but not distal muscles. In contrast, no evidence of cell death emerged from analysis of several distinct pools of lumbar motor neurons known to be lost in the disease. Moreover, SMA motor neurons from Smn2B/- mice showed robust nuclear accumulation of p53 but lack of phosphorylation of serine 18 at its amino-terminal, which selectively marks degenerating motor neurons in the SMNΔ7 mouse model. These results indicate that NMJ denervation and deafferentation, but not motor neuron death, are conserved features of SMA pathology in Smn2B/- mice.

DOI: https://doi.org/10.1371/journal.pone.0267990
Science. 2022 Aug 05. 377(6606): 666-669

JMJD3 activated hyaluronan synthesis drives muscle regeneration in an inflammatory environment.

Kiran Nakka, Sarah Hachmer, Zeinab Mokhtari, Radmila Kovac, Hina Bandukwala, Clara Bernard, Yuefeng Li, Guojia Xie, Chengyu Liu, Magid Fallahi, Lynn A Megeney, Julien Gondin, Bénédicte Chazaud, Marjorie Brand, Xiaohui Zha, Kai Ge, F Jeffrey Dilworth.

Muscle stem cells (MuSCs) reside in a specialized niche that ensures their regenerative capacity. Although we know that innate immune cells infiltrate the niche in response to injury, it remains unclear how MuSCs adapt to this altered environment for initiating repair. Here, we demonstrate that inflammatory cytokine signaling from the regenerative niche impairs the ability of quiescent MuSCs to reenter the cell cycle. The histone H3 lysine 27 (H3K27) demethylase JMJD3, but not UTX, allowed MuSCs to overcome inhibitory inflammation signaling by removing trimethylated H3K27 (H3K27me3) marks at the Has2 locus to initiate production of hyaluronic acid, which in turn established an extracellular matrix competent for integrating signals that direct MuSCs to exit quiescence. Thus, JMJD3-driven hyaluronic acid synthesis plays a proregenerative role that allows MuSC adaptation to inflammation and the initiation of muscle repair.

DOI: https://doi.org/10.1126/science.abm9735
Front Cell Dev Biol. 2022 ;10 874756

Preliminary Study of S100B and Sema3A Expression Patterns in Regenerating Muscle Implicates P75-Expressing Terminal Schwann Cells and Muscle Satellite Cells in Neuromuscular Junction Restoration.

Nasibeh Daneshvar, Judy E Anderson.

  Terminal Schwann cells (TSCs) help regulate the formation, maintenance, function, and repair of neuromuscular junctions (NMJs) and axon guidance after muscle injury. Premature activation of muscle satellite cells (SCs), induced by isosorbide dinitrate (ISDN) before injury, accelerates myogenic regeneration, disrupts NMJ remodeling and maturation, decreases Sema3A protein-induced neuro-repulsion, and is accompanied by time-dependent changes in S100B protein levels. Here, to study the effects of premature SC activation on TSCs and SCs, both expressing P75 nerve growth-factor receptor, in situ hybridization was used to identify transcripts of S100B and Sema3A, and the number, intensity, and diameter of expression sites were analyzed. The number of sites/fields expressing S100B and Sema3A increased with regeneration time (both p < 0.001). Expression-site intensity (S100B) and diameter (S100B and Sema3A) decreased during regeneration (p = 0.005; p < 0.05, p = 0.006, respectively). P75 protein colocalized with a subset of S100B and Sema3A expression sites. Principal component analyses of gene expression, protein levels, and histological variables (fiber diameter, vascular density) in control and ISDN-pretreated groups explained 83% and 64% of the dataset variance, respectively. A very strong loading coefficient for colocalization of P75 protein with S100B and Sema3A mRNAs (0.91) in control regenerating muscle dropped markedly during regeneration disrupted by premature SC activation (-0.10 in Factor 1 to 0.55 in Factor 3). These findings strongly implicate the triple-expression profile by TSCs and/or SCs as a strong correlate of the important synchrony of muscle and nerve regeneration after muscle tissue injury. The results have the potential to focus future research on the complex interplay of TSCs and SCs in neuromuscular tissue repair and help promote effective function after traumatic muscle injury.

Keywords:  P75 nerve growth-factor receptor; S100B; SEMA3A; myogenesis; neuritogenesis; neuromuscular junctions (NMJs); principal component analysis

DOI:  https://doi.org/10.3389/fcell.2022.874756
Science. 2022 Aug 05. 377(6606): 578-579

A regenerative niche for stem cells.

Davide Gabellini.

Production of hyaluronic acid allows regenerative signaling in muscle stem cells after injury.

DOI: https://doi.org/10.1126/science.add6804
Nat Rev Dis Primers. 2022 Aug 04. 8(1): 52

Spinal muscular atrophy.

Eugenio Mercuri, Charlotte J Sumner, Francesco Muntoni, Basil T Darras, Richard S Finkel.

Spinal muscular atrophy (SMA) is a neurodegenerative disorder caused by mutations in SMN1 (encoding survival motor neuron protein (SMN)). Reduced expression of SMN leads to loss of α-motor neurons, severe muscle weakness and often early death. Standard-of-care recommendations for multidisciplinary supportive care of SMA were established in the past few decades. However, improved understanding of the pathogenetic mechanisms of SMA has led to the development of different therapeutic approaches. Three treatments that increase SMN expression by distinct molecular mechanisms, administration routes and tissue biodistributions have received regulatory approval with others in clinical development. The advent of the new therapies is redefining standards of care as in many countries most patients are treated with one of the new therapies, leading to the identification of emerging new phenotypes of SMA and a renewed characterization of demographics owing to improved patient survival.

DOI: https://doi.org/10.1038/s41572-022-00380-8
Nat Commun. 2022 Aug 04. 13(1): 4543

The molecular mechanism of snake short-chain α-neurotoxin binding to muscle-type nicotinic acetylcholine receptors.

Mieke Nys, Eleftherios Zarkadas, Marijke Brams, Aujan Mehregan, Kumiko Kambara, Jeroen Kool, Nicholas R Casewell, Daniel Bertrand, John E Baenziger, Hugues Nury, Chris Ulens.

Bites by elapid snakes (e.g. cobras) can result in life-threatening paralysis caused by venom neurotoxins blocking neuromuscular nicotinic acetylcholine receptors. Here, we determine the cryo-EM structure of the muscle-type Torpedo receptor in complex with ScNtx, a recombinant short-chain α-neurotoxin. ScNtx is pinched between loop C on the principal subunit and a unique hairpin in loop F on the complementary subunit, thereby blocking access to the neurotransmitter binding site. ScNtx adopts a binding mode that is tilted toward the complementary subunit, forming a wider network of interactions than those seen in the long-chain α-Bungarotoxin complex. Certain mutations in ScNtx at the toxin-receptor interface eliminate inhibition of neuronal α7 nAChRs, but not of human muscle-type receptors. These observations explain why ScNtx binds more tightly to muscle-type receptors than neuronal receptors. Together, these data offer a framework for understanding subtype-specific actions of short-chain α-neurotoxins and inspire strategies for design of new snake antivenoms.

DOI: https://doi.org/10.1038/s41467-022-32174-7
Nat Rev Endocrinol. 2022 Aug 01.

Reply to 'Lactate as a major myokine and exerkine'.

Lisa S Chow, Robert E Gerszten, Joan M Taylor, Bente K Pedersen, Henriette van Praag, Scott Trappe, Mark A Febbraio, Zorina S Galis, Yunling Gao, Jacob M Haus, Ian R Lanza, Carl J Lavie, Chih-Hao Lee, Alejandro Lucia, Cedric Moro, Ambarish Pandey, Jeremy M Robbins, Kristin I Stanford, Alice E Thackray, Saul Villeda, Matthew J Watt, Ashley Xia, Juleen R Zierath, Bret H Goodpaster, Michael Snyder.

DOI: https://doi.org/10.1038/s41574-022-00726-y