bims-moremu 2022-09-04 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2022–09–04
23 papers selected by
Anna Vainshtein, Craft Science Inc.

The skeletal muscle circadian clock regulates titin splicing through RBM20.
Amelioration of pathologic α-synuclein-induced Parkinson's disease by irisin.
TBX1 regulates myogenic differentiation by activating the TGFβ-Smad2/3 pathway in myoblasts.
Downregulation of Sparc-like protein 1 during cisplatin-induced inhibition of myogenic differentiation of C2C12 myoblasts.
Transplantation of PSC-derived myogenic progenitors counteracts disease phenotypes in FSHD mice.
Macrophage immunomodulation accelerates skeletal muscle functional recovery in aged mice following disuse atrophy.
(-)-Epicatechin and its colonic metabolite hippuric acid protect against dexamethasone-induced atrophy in skeletal muscle cells.
Mineralocorticoid receptor antagonists and glucocorticoids differentially affect skeletal muscle inflammation and pathology in muscular dystrophy.
KMT5B is required for early motor development.
Combinatorial treatment with exercise and AICAR potentiates the rescue of myotonic dystrophy type 1 mouse muscles in a sex-specific manner.
Contribution of muscle satellite cells to sarcopenia.
The mineralocorticoid receptor functions as a key glucose regulator in the skeletal muscle of zebrafish.
Exogenous Oncostatin M induces Cardiac Dysfunction, Musculoskeletal Atrophy, and Fibrosis.
Carbohydrate Intake in Recovery from Aerobic Exercise Differentiates Skeletal Muscle microRNA Expression.
Fission impossible: Mitochondrial dynamics direct muscle stem cell fates.
The emerging role of skeletal muscle as a modulator of lipid profile the role of exercise and nutrition.
Changes in vastus lateralis fiber cross-sectional area, pennation angle, and fascicle length do not predict changes in muscle cross-sectional area.
A humanized knockin mouse model of Duchenne muscular dystrophy and its correction by CRISPR-Cas9 therapeutic gene editing.
The muscle proteome reflects changes in mitochondrial function, cellular stress and proteolysis after 14 days of unilateral lower limb immobilization in active young men.
Involvement of the extracellular matrix and integrin signalling proteins in skeletal muscle glucose uptake.
COVID-19 infection and vaccination in patients with skeletal muscle channelopathies.
The growing field of immunometabolism and exercise: Key findings in the last 5 years.
Exercise as an Aging Mimetic: A New Perspective on the Mechanisms Behind Exercise as Preventive Medicine Against Age-Related Chronic Disease.

Elife. 2022 Sep 01. pii: e76478. [Epub ahead of print]11

The skeletal muscle circadian clock regulates titin splicing through RBM20.

Lance A Riley, Xiping Zhang, Collin M Douglas, Joseph M Mijares, David W Hammers, Christopher A Wolff, Neil B Wood, Hailey R Olafson, Ping Du, Siegfried Labeit, Michael J Previs, Eric T Wang, Karyn A Esser.

  Circadian rhythms are maintained by a cell autonomous, transcriptional-translational feedback loop known as the molecular clock. While previous research suggests a role of the molecular clock in regulating skeletal muscle structure and function, no mechanisms have connected the molecular clock to sarcomere filaments. Utilizing inducible, skeletal muscle specific, Bmal1 knockout (iMSBmal1-/-) mice, we showed that knocking out skeletal muscle clock function alters titin isoform expression using RNAseq, LC-MS, and SDS-VAGE. This alteration in titin's spring length resulted in sarcomere length heterogeneity. We demonstrate the direct link between altered titin splicing and sarcomere length in vitro using U7 snRNPs that truncate the region of titin altered in iMSBmal1-/- muscle. We identified a mechanism whereby the skeletal muscle clock regulates titin isoform expression through transcriptional regulation of Rbm20, a potent splicing regulator of titin. Lastly, we used an environmental model of circadian rhythm disruption and identified significant down-regulation of Rbm20 expression. Our findings demonstrate the importance of the skeletal muscle circadian clock in maintaining titin isoform through regulation of RBM20 expression. Because circadian rhythm disruption is a feature of many chronic diseases, our results highlight a novel pathway that could be targeted to maintain skeletal muscle structure and function in a range of pathologies.

Keywords:  cell biology; mouse

DOI:  https://doi.org/10.7554/eLife.76478
Proc Natl Acad Sci U S A. 2022 Sep 06. 119(36): e2204835119

Amelioration of pathologic α-synuclein-induced Parkinson's disease by irisin.

Tae-In Kam, Hyejin Park, Shih-Ching Chou, Jonathan G Van Vranken, Melanie J Mittenbühler, Hyeonwoo Kim, Mu A, Yu Ree Choi, Devanik Biswas, Justin Wang, Yu Shin, Alexis Loder, Senthilkumar S Karuppagounder, Christiane D Wrann, Valina L Dawson, Bruce M Spiegelman, Ted M Dawson.

  Physical activity provides clinical benefit in Parkinson's disease (PD). Irisin is an exercise-induced polypeptide secreted by skeletal muscle that crosses the blood-brain barrier and mediates certain effects of exercise. Here, we show that irisin prevents pathologic α-synuclein (α-syn)-induced neurodegeneration in the α-syn preformed fibril (PFF) mouse model of sporadic PD. Intravenous delivery of irisin via viral vectors following the stereotaxic intrastriatal injection of α-syn PFF cause a reduction in the formation of pathologic α-syn and prevented the loss of dopamine neurons and lowering of striatal dopamine. Irisin also substantially reduced the α-syn PFF-induced motor deficits as assessed behaviorally by the pole and grip strength test. Recombinant sustained irisin treatment of primary cortical neurons attenuated α-syn PFF toxicity by reducing the formation of phosphorylated serine 129 of α-syn and neuronal cell death. Tandem mass spectrometry and biochemical analysis revealed that irisin reduced pathologic α-syn by enhancing endolysosomal degradation of pathologic α-syn. Our findings highlight the potential for therapeutic disease modification of irisin in PD.

Keywords:  Parkinson’s disease; irisin; neurodegeneration; synuclein

DOI:  https://doi.org/10.1073/pnas.2204835119
Exp Biol Med (Maywood). 2022 Aug 29. 15353702221112087

TBX1 regulates myogenic differentiation by activating the TGFβ-Smad2/3 pathway in myoblasts.

Haimei Cen, Hong Luo, Bin Luo, Pin Fan, Yusheng Zhang, Yu Zhang.

  TBX1 is systematically conserved in the T-box transcription factor family and regulates craniofacial muscle development during various stages of myogenesis, including commitment, proliferation, terminal differentiation, and survival. However, the role and mechanism by which TBX1 regulates the myogenic development of myoblasts remains unclear. In our study, we overexpressed TBX1 in mouse C2C12 myoblasts using a lentivirus method. We found that TBX1 inhibited cell proliferation and muscle differentiation, which had no effect on apoptosis. During myogenic differentiation, we also found that TBX1 overexpressing cells regulate myogenic differentiation by upregulating the expression levels of Smad2 and Smad3 and downregulating the expression level of MEF2C. After treatment with a specific inhibitor of Smad3 (SIS3), the myogenic differentiation of wild-type and TBX1 overexpressing cells increased. Thus, TBX1 may regulate myoblast muscle differentiation by enhancing the expression of Smad2 and Smad3. TBX1 may be a therapeutic target for muscular dystrophy.

Keywords:  SIS3; Smad2/3; TBX1; apoptosis; myogenic differentiation; proliferation

DOI:  https://doi.org/10.1177/15353702221112087
Biochem Pharmacol. 2022 Aug 27. pii: S0006-2952(22)00328-8. [Epub ahead of print]204 115234

Downregulation of Sparc-like protein 1 during cisplatin-induced inhibition of myogenic differentiation of C2C12 myoblasts.

Hiroyasu Sakai, Yuta Suzuki, Yu Miyauchi, Fumiaki Sato, Yusuke Ando, Risako Kon, Nobutomo Ikarashi, Yoshihiko Chiba, Junzo Kamei, Tomoo Hosoe.

  Patients with cancer often experience muscle atrophy, which worsens their prognosis. Decreased muscle regenerative capacity plays an important role in the complex processes involved in muscle atrophy. Administration of cisplatin, a cancer chemotherapeutic agent, has been implicated as a cause of muscle atrophy. In this study, we examined whether cisplatin affects the differentiation of myoblasts into myotubes. We treated C2C12 myoblasts with a differentiation medium containing cisplatin and its vehicle during for 8 days and observed the changes in the expression of myosin heavy chain (MyHC) and myogenin in the myoblasts. Cisplatin was injected in mice for 4 consecutive days; on Day 5, the mice quadriceps muscles were sampled and examined. The expression of MyHCs increased and that of myogenin decreased after cisplatin treatment. The secretion of acidic cysteine-rich proteins (e.g., Sparc proteins) reportedly promotes C2C12 myoblast differentiation. Therefore, we investigated the Sparc family gene expression during myogenesis in C2C12 myoblasts after cisplatin treatment. Of all the genes investigated, Sparc-like protein 1 (Sparcl1) expression was significantly suppressed by cisplatin on Days 4-8. Simultaneous treatment with recombinant mouse Sparcl1 almost inhibited the cisplatin-induced suppression of total MyHC and myogenin protein levels. Moreover, Sparcl1 expression decreased in the skeletal muscles of mice, leading to cisplatin-induced muscle atrophy. Our results suggest that cisplatin-induced myogenesis suppression causes muscle atrophy and inhibits the expression of Sparcl1, which promotes C2C12 cell differentiation during myogenesis.

Keywords:  Cisplatin; MyoD1; Myoblast; Myogenesis; Myogenin; Myosin heavy chain

DOI:  https://doi.org/10.1016/j.bcp.2022.115234
NPJ Regen Med. 2022 Sep 02. 7(1): 43

Transplantation of PSC-derived myogenic progenitors counteracts disease phenotypes in FSHD mice.

Karim Azzag, Darko Bosnakovski, Sudheer Tungtur, Peter Salama, Michael Kyba, Rita C R Perlingeiro.

Facioscapulohumeral muscular dystrophy (FSHD) is a genetically dominant progressive myopathy caused by improper silencing of the DUX4 gene, leading to fibrosis, muscle atrophy, and fatty replacement. Approaches focused on muscle regeneration through the delivery of stem cells represent an attractive therapeutic option for muscular dystrophies. To investigate the potential for cell transplantation in FSHD, we have used the doxycycline-regulated iDUX4pA-HSA mouse model in which low-level DUX4 can be induced in skeletal muscle. We find that mouse pluripotent stem cell (PSC)-derived myogenic progenitors engraft in muscle actively undergoing DUX4-mediated degeneration. Donor-derived muscle tissue displayed reduced fibrosis and importantly, engrafted muscles showed improved contractile specific force compared to non-transplanted controls. These data demonstrate the feasibility of replacement of diseased muscle with PSC-derived myogenic progenitors in a mouse model for FSHD, and highlight the potential for the clinical benefit of such a cell therapy approach.

DOI: https://doi.org/10.1038/s41536-022-00249-0
J Appl Physiol (1985). 2022 Sep 01.

Macrophage immunomodulation accelerates skeletal muscle functional recovery in aged mice following disuse atrophy.

Patrick J Ferrara, Elena M Yee, Jonathan J Petrocelli, Dennis K Fix, Carson T Hauser, Naomi M M P de Hart, Ziad S Mahmassani, Paul T Reidy, Ryan M O'Connell, Micah J Drummond.

  Poor recovery of muscle size and strength with aging coincides with a dysregulated macrophage response during the early stages of regrowth. Immunomodulation in the form of ex vivo cytokine (macrophage-colony stimulating factor) or polarized macrophage delivery has been demonstrated to improve skeletal muscle regeneration. However, it is unclear if these macrophage-promoting approaches would be effective to improve skeletal muscle recovery following disuse in aged animals. Here, we isolated bone marrow-derived macrophages from donor mice of different ages under various experimental conditions and polarized them to pro-inflammatory macrophages. Macrophages were delivered intramuscularly into young adult or aged recipient mice during the early recovery period following a period of hindlimb unloading (HU). Delivery of pro-inflammatory macrophages from donor young adult or aged mice was sufficient to increase muscle function of aged mice during the recovery period. Moreover, pro-inflammatory macrophages derived from aged donor mice collected during recovery were similarly able to increase muscle function of aged mice following disuse. In addition to the delivery of macrophages, we showed that the intramuscular injection of the cytokine, macrophage-colony stimulating factor, to the muscle of aged mice following HU was able to increase muscle macrophage content and muscle force production during recovery. Together, these results suggest that macrophage immunomodulation approaches in the form of ex vivo pro-inflammatory macrophage or macrophage-colony stimulating factor delivery during the early recovery phase following disuse atrophy were sufficient to restore the loss of aged skeletal muscle function.

Keywords:  Aging; immune cells; inflammation; muscle function; sarcopenia

DOI:  https://doi.org/10.1152/japplphysiol.00374.2022
J Nutr Biochem. 2022 Aug 29. pii: S0955-2863(22)00218-2. [Epub ahead of print] 109150

(-)-Epicatechin and its colonic metabolite hippuric acid protect against dexamethasone-induced atrophy in skeletal muscle cells.

Edwards Sj, Carter S, Nicholson T, Allen Sl, Morgan Pt, Jones Sw, Rendeiro C, Breen L.

  Cocoa flavanols have been shown to improve muscle function and may offer a novel approach to protect against muscle atrophy. Hippuric acid (HA) is a colonic metabolite of (-)-epicatechin (EPI), the primary bioactive compound of cocoa, and may be responsible for the associations between cocoa supplementation and muscle metabolic alterations. Accordingly, we investigated the effects of EPI and HA upon skeletal muscle morphology and metabolism within an in vitro model of muscle atrophy. Under atrophy-like conditions (24h 100μM dexamethasone (DEX)), C2C12 myotube diameter was significantly greater following co-incubation with either 25μM HA (11.19±0.39μm) or 25μM EPI (11.01±0.21μm) compared to the vehicle control (VC; 7.61±0.16μm, both P<0.001). In basal and leucine-stimulated states, there was a significant reduction in myotube protein synthesis (MPS) rates following DEX treatment in VC (P=0.024). Interestingly, co-incubation with EPI or HA abrogated the DEX-induced reductions in MPS rates, whereas no significant differences vs. control treated myotubes (CTL) were noted. Furthermore, co-incubation with EPI or HA partially attenuated the increase in proteolysis seen in DEX-treated cells, preserving LC3 α/β II:I and caspase-3 protein expression in atrophy-like conditions. The protein content of PGC1α, ACC and TFAM (regulators of mitochondrial function) were significantly lower in DEX-treated vs. CTL cells (all P<0.050). However, co-incubation with EPI or HA was unable to prevent these DEX-induced alterations. For the first time we demonstrate that EPI and HA exert anti-atrophic effects on C2C12 myotubes, providing novel insight into the association between flavanol supplementation and favourable effects on muscle health.

Keywords:  Muscle atrophy; dexamethasone; epicatechin; flavanols; hippuric acid; mitochondria

DOI:  https://doi.org/10.1016/j.jnutbio.2022.109150
JCI Insight. 2022 Aug 30. pii: e159875. [Epub ahead of print]

Mineralocorticoid receptor antagonists and glucocorticoids differentially affect skeletal muscle inflammation and pathology in muscular dystrophy.

Zachary M Howard, Chetan K Gomatam, Charles P Rabolli, Jeovanna Lowe, Arden B Piepho, Shyam S Bansal, Federica Accornero, Jill A Rafael-Fortney.

  Mineralocorticoid receptor (MR) antagonists (MRAs) slow cardiomyopathy in Duchenne Muscular Dystrophy (DMD) patients and improve skeletal muscle pathology and function in dystrophic mice. However, glucocorticoids, known anti-inflammatory drugs, remain standard-of-care for DMD, despite substantial side effects. Exact mechanisms underlying MR signaling contribution to dystrophy are unknown. Whether MRAs affect inflammation in dystrophic muscles and how they compare to glucocorticoids is unclear. The MRA spironolactone and glucocorticoid prednisolone were each administered for one week to dystrophic mdx mice during peak skeletal muscle necrosis to compare effects on inflammation. Both drugs reduced cytokine levels in mdx quadriceps, but prednisolone elevated diaphragm cytokines. Spironolactone did not alter myeloid populations in mdx quadriceps or diaphragms, but prednisolone increased F4/80Hi macrophages. Both spironolactone and prednisolone reduced inflammatory gene expression in myeloid cells sorted from mdx quadriceps, while prednisolone additionally perturbed cell cycle genes. Spironolactone also repressed myeloid expression of the gene encoding fibronectin, while prednisolone increased its expression. Overall, spironolactone exhibits anti-inflammatory properties without altering leukocyte distribution within skeletal muscles while prednisolone suppresses quadriceps cytokines, but increases diaphragm cytokines and pathology. Anti-inflammatory properties of MRAs and different limb and respiratory muscle responses to glucocorticoids should be considered when optimizing treatments for DMD patients.

Keywords:  Cytokines; Innate immunity; Muscle Biology; Skeletal muscle

DOI:  https://doi.org/10.1172/jci.insight.159875
Front Genet. 2022 ;13 901228

KMT5B is required for early motor development.

Jason Hulen, Dorothy Kenny, Rebecca Black, Jodi Hallgren, Kelley G Hammond, Eric C Bredahl, Rochelle N Wickramasekara, Peter W Abel, Holly A F Stessman.

  Disruptive variants in lysine methyl transferase 5B (KMT5B/SUV4-20H1) have been identified as likely-pathogenic among humans with neurodevelopmental phenotypes including motor deficits (i.e., hypotonia and motor delay). However, the role that this enzyme plays in early motor development is largely unknown. Using a Kmt5b gene trap mouse model, we assessed neuromuscular strength, skeletal muscle weight (i.e., muscle mass), neuromuscular junction (NMJ) structure, and myofiber type, size, and distribution. Tests were performed over developmental time (postnatal days 17 and 44) to represent postnatal versus adult structures in slow- and fast-twitch muscle types. Prior to the onset of puberty, slow-twitch muscle weight was significantly reduced in heterozygous compared to wild-type males but not females. At the young adult stage, we identified decreased neuromuscular strength, decreased skeletal muscle weights (both slow- and fast-twitch), increased NMJ fragmentation (in slow-twitch muscle), and smaller myofibers in both sexes. We conclude that Kmt5b haploinsufficiency results in a skeletal muscle developmental deficit causing reduced muscle mass and body weight.

Keywords:  H4K20; KMT5B; SUV420H; histone methylation; hypertrophy; hypotonia; neuromuscular development; neuromuscular junction

DOI:  https://doi.org/10.3389/fgene.2022.901228
Hum Mol Genet. 2022 Sep 01. pii: ddac222. [Epub ahead of print]

Combinatorial treatment with exercise and AICAR potentiates the rescue of myotonic dystrophy type 1 mouse muscles in a sex-specific manner.

Naomi S Misquitta, Aymeric Ravel-Chapuis, Bernard J Jasmin.

Targeting AMPK is emerging as a promising strategy for treating myotonic dystrophy type 1 (DM1), the most prevalent form of adult-onset muscular dystrophy. We previously demonstrated that AICAR and exercise, two potent AMPK activators, improve disease features in DM1 mouse skeletal muscles. Here, we employed a combinatorial approach with these AMPK activators and examined their joint impact on disease severity in male and female DM1 mice. Our data reveal that swimming exercise additively enhances the effect of AICAR in mitigating the nuclear accumulation of toxic CUGexp RNA foci. In addition, our findings show a trend towards an enhanced reversal of MBNL1 sequestration and correction in pathogenic alternative splicing events. Our results further demonstrate that the combinatorial impact of exercise and AICAR promotes muscle fiber hypertrophy in DM1 skeletal muscle. Importantly, these improvements occur in a sex-specific manner with greater benefits observed in female DM1 mice. Our findings demonstrate that combining AMPK-activating interventions may prove optimal for rescuing the DM1 muscle phenotype and uncover important sex differences in the response to AMPK-based therapeutic strategies in DM1 mice.

DOI: https://doi.org/10.1093/hmg/ddac222
Front Physiol. 2022 ;13 892749

Contribution of muscle satellite cells to sarcopenia.

Fengjiao Huo, Qing Liu, Hailiang Liu.

  Sarcopenia, a disorder characterized by age-related muscle loss and reduced muscle strength, is associated with decreased individual independence and quality of life, as well as a high risk of death. Skeletal muscle houses a normally mitotically quiescent population of adult stem cells called muscle satellite cells (MuSCs) that are responsible for muscle maintenance, growth, repair, and regeneration throughout the life cycle. Patients with sarcopenia are often exhibit dysregulation of MuSCs homeostasis. In this review, we focus on the etiology, assessment, and treatment of sarcopenia. We also discuss phenotypic and regulatory mechanisms of MuSC quiescence, activation, and aging states, as well as the controversy between MuSC depletion and sarcopenia. Finally, we give a multi-dimensional treatment strategy for sarcopenia based on improving MuSC function.

Keywords:  aging; muscle satellite cell; regeneration; rejuvenation; sarcopenia

DOI:  https://doi.org/10.3389/fphys.2022.892749
Endocrinology. 2022 Aug 30. pii: bqac149. [Epub ahead of print]

The mineralocorticoid receptor functions as a key glucose regulator in the skeletal muscle of zebrafish.

Erin Faught, Mathilakath M Vijayan.

  Glucocorticoids (GCs) are essential for maintaining energy homeostasis as part of the adaptive stress response. Most work to date has characterized the metabolic role of GCs via the activation of the glucocorticoid receptor (nr3c1; GR), which is activated under high GC conditions. However, GCs also bind to the mineralocorticoid receptor (nr3c2; MR), a high affinity corticosteroid receptor active under basal GC conditions. Despite the expression of MR in skeletal muscles, almost nothing is known about its physiological role. Here we tested the hypothesis that MR promotes anabolic processes during resting cortisol levels and curtails the catabolic actions of GR during high (stressed) levels of cortisol. To determine the effect of MR, a zebrafish line with a ubiquitous MR knockout (MRca402/ca402) was utilized. The GR was activated in the same group by chronically treating fish with exogenous cortisol. In the muscle, MR primarily promoted nutrient storage, and restricted energy substrate mobilization under resting condition, whereas GR activation resulted in increased nutrient utilization. Interestingly, a loss of MR improved GR-driven metabolic flexibility, suggesting that the activation state of these receptors is a key determinant of skeletal muscle ability to switch fuel sources. To determine if the anabolism-promoting nature of MR was due to an interaction with insulin, fish were co-injected with insulin and a fluorescent glucose analogue 2-NBDG. A loss of MR abolished insulin-stimulated glucose uptake in the skeletal muscle. Taken together, we postulate that MR acts as a key modulator of glucose metabolism in the musculature during basal and stress conditions.

Keywords:  glucocorticoid receptor; glucose; metabolic flexibility; metabolism; mineralocorticoid receptor; triglycerides

DOI:  https://doi.org/10.1210/endocr/bqac149
Cytokine. 2022 Aug 30. pii: S1043-4666(22)00181-8. [Epub ahead of print]159 155972

Exogenous Oncostatin M induces Cardiac Dysfunction, Musculoskeletal Atrophy, and Fibrosis.

Daenique H A Jengelley, Meijing Wang, Ashok Narasimhan, Joseph E Rupert, Andrew R Young, Xiaoling Zhong, Daniel J Horan, Alexander G Robling, Leonidas G Koniaris, Teresa A Zimmers.

  Musculoskeletal diseases such as muscular dystrophy, cachexia, osteoarthritis, and rheumatoid arthritis impair overall physical health and reduce survival. Patients suffer from pain, dysfunction, and dysmobility due to inflammation and fibrosis in bones, muscles, and joints, both locally and systemically. The Interleukin-6 (IL-6) family of cytokines, most notably IL-6, is implicated in musculoskeletal disorders and cachexia. Here we show elevated circulating levels of OSM in murine pancreatic cancer cachexia and evaluate the effects of the IL-6 family member, Oncostatin M (OSM), on muscle and bone using adeno-associated virus (AAV) mediated over-expression of murine OSM in wildtype and IL-6 deficient mice. Initial studies with high titer AAV-OSM injection yielded high circulating OSM and IL-6, thrombocytosis, inflammation, and 60% mortality without muscle loss within 4 days. Subsequently, to mimic OSM levels in cachexia, a lower titer of AAV-OSM was used in wildtype and Il6 null mice, observing effects out to 4 weeks and 12 weeks. AAV-OSM caused muscle atrophy and fibrosis in the gastrocnemius, tibialis anterior, and quadriceps of the injected limb, but these effects were not observed on the non-injected side. In contrast, OSM induced both local and distant trabecular bone loss as shown by reduced bone volume, trabecular number, and thickness, and increased trabecular separation. OSM caused cardiac dysfunction including reduced ejection fraction and reduced fractional shortening. RNA-sequencing of cardiac muscle revealed upregulation of genes related to inflammation and fibrosis. None of these effects were different in IL-6 knockout mice. Thus, OSM induces local muscle atrophy, systemic bone loss, tissue fibrosis, and cardiac dysfunction independently of IL-6, suggesting a role for OSM in musculoskeletal conditions with these characteristics, including cancer cachexia.

Keywords:  AAV; Atrophy; Bone; Cachexia; Cardiac Dysfunction; Fibrosis; IL6ST/GP130; Inflammation; Interleukin-6; Oncostatin M; Skeletal Muscle

DOI:  https://doi.org/10.1016/j.cyto.2022.155972
Am J Physiol Endocrinol Metab. 2022 Aug 31.

Carbohydrate Intake in Recovery from Aerobic Exercise Differentiates Skeletal Muscle microRNA Expression.

Lee M Margolis, Christopher T Carrigan, Nancy E Murphy, Marissa N Dibella, Marques A Wilson, Claire C Whitney, Emily E Howard, Stefan M Pasiakos, Donato A Rivas.

  Post-transcriptional regulation by microRNA (miRNA) facilitates exercise and diet-induced skeletal muscle adaptations. However, the impact of diet on miRNA expression during post-exercise recovery remains unclear. The objective of this study was to examine the effects of consuming carbohydrate or a nutrient free control on skeletal muscle miRNA expression during 3 hours of recovery from aerobic exercise. Using a randomized, crossover design, 7 men (mean±SD, age: 21±3 y; body mass: 83±13 kg; V̇O2peak: 43±2 mL/kg/min) completed 2 cycle ergometry glycogen depletion trials followed by 3 hours of recovery while consuming either carbohydrate (CHO: 1 g/kg/hr) or control (CON: nutrient free). Muscle biopsy samples were obtained under resting fasted conditions at baseline and at the end of the 3 hour recovery (REC) period. miRNA expression was determined using unbiased RT-qPCR microarray analysis. Trials were separated by 7 days. Twenty-five miRNA were different (P<0.05) between CHO and CON at REC, with Let7i-5p and miR-195-5p being the most predictive of treatment. In vitro overexpression of Let7i-5p and miR-195-p5 in C2C12 skeletal muscle cells decreased (P<0.05) the expression of protein breakdown (Foxo1,Trim63, Casp3 and Atf4) genes, ubiquitylation, and protease enzyme activity compared to control. Energy sensing (Prkaa1 and Prkab1) and glycolysis (Gsy1 and Gsk3b) genes were lower (P<0.05) with Let7i-5p overexpression compared to miR-195-5p and control. Fat metabolism (Cpt1a, Scd1, and Hadha) genes were lower (P<0.05) in miR-195-5p compared to control. These data indicate that consuming CHO after aerobic exercise alters miRNA profiles compared to CON, and these difference may govern mechanisms facilitating muscle recovery.

Keywords:  Endurance Exercise; Glycogen; Let7; miR-195

DOI:  https://doi.org/10.1152/ajpendo.00110.2022
Cell Stem Cell. 2022 Sep 01. pii: S1934-5909(22)00346-0. [Epub ahead of print]29(9): 1287-1289

Fission impossible: Mitochondrial dynamics direct muscle stem cell fates.

Ji-Hyung Lee, Foteini Mourkioti.

Muscle stem cells (MuSCs) exhibit different metabolic profiles depending on their activity, however the mechanisms by which mitochondria affect MuSC fate has been understudied. In this issue of Cell Stem Cell, Hong et al. (2022) and Baker et al. (2022) demonstrate that defects in mitochondrial dynamics hinder proper MuSC activation and impair muscle regeneration.

DOI: https://doi.org/10.1016/j.stem.2022.08.010
Lipids Health Dis. 2022 Aug 30. 21(1): 81

The emerging role of skeletal muscle as a modulator of lipid profile the role of exercise and nutrition.

Tzortzis Nomikos, Spyridon Methenitis, Demosthenes B Panagiotakos.

  The present article aims to discuss the hypothesis that skeletal muscle per se but mostly its muscle fiber composition could be significant determinants of lipid metabolism and that certain exercise modalities may improve metabolic dyslipidemia by favorably affecting skeletal muscle mass, fiber composition and functionality. It discusses the mediating role of nutrition, highlights the lack of knowledge on mechanistic aspects of this relationship and proposes possible experimental directions in this field.

Keywords:  Dyslipidemia; Exercise protocols; Intramuscular triglycerides; Lipid profile; Muscle fibers; Skeletal muscle

DOI:  https://doi.org/10.1186/s12944-022-01692-0
Exp Physiol. 2022 Sep 02.

Changes in vastus lateralis fiber cross-sectional area, pennation angle, and fascicle length do not predict changes in muscle cross-sectional area.

Bradley A Ruple, Paulo H C Mesquita, Joshua S Godwin, Casey L Sexton, Shelby C Osburn, Mason C McIntosh, Andreas N Kavazis, Cleiton A Libardi, Kaelin C Young, Michael D Roberts.

   NEW FINDINGS: In pennate muscle, changes in myofiber cross-sectional area (fCSA), fascicle length (Lf ), and pennation angle (PA) with exercise training likely interact to alter whole-muscle cross-sectional area (mCSA). Herein, we are the first to use multiple regression to show that changes in vastus lateralis (VL) mean fCSA, Lf and PA following a period of resistance training did not collectively predict changes in mCSA. Thus, the n-size is limited herein, it remains difficult to generalize the morphological adaptations that predominantly drive tissue-level VL muscle hypertrophy. We also present compelling evidence suggesting the mode of hypertrophy differs between individuals, which requires further interrogation.
ABSTRACT: Myofiber This article is protected by copyright. All rights reserved.

Keywords:  histology; muscle; resistance training; ultrasound

DOI:  https://doi.org/10.1113/EP090666
Mol Ther Nucleic Acids. 2022 Sep 13. 29 525-537

A humanized knockin mouse model of Duchenne muscular dystrophy and its correction by CRISPR-Cas9 therapeutic gene editing.

Yu Zhang, Hui Li, Takahiko Nishiyama, John R McAnally, Efrain Sanchez-Ortiz, Jian Huang, Pradeep P A Mammen, Rhonda Bassel-Duby, Eric N Olson.

  Duchenne muscular dystrophy (DMD) is a lethal neuromuscular disease caused by mutations in the X-linked dystrophin (DMD) gene. Exon deletions flanking exon 51, which disrupt the dystrophin open reading frame (ORF), represent one of the most common types of human DMD mutations. Previously, we used clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated proteins (Cas) gene editing to restore the reading frame of exon 51 in mice and dogs with exon 50 deletions. Due to genomic sequence variations between species, the single guide RNAs (sgRNAs) used for DMD gene editing are often not conserved, impeding direct clinical translation of CRISPR-Cas therapeutic gene-editing strategies. To circumvent this potential obstacle, we generated a humanized DMD mouse model by replacing mouse exon 51 with human exon 51, followed by deletion of mouse exon 50, which disrupted the dystrophin ORF. Systemic CRISPR-Cas9 gene editing using an sgRNA that targets human exon 51 efficiently restored dystrophin expression and ameliorated pathologic hallmarks of DMD, including histopathology and grip strength in this mouse model. This unique DMD mouse model with the human genomic sequence allows in vivo assessment of clinically relevant gene editing strategies as well as other therapeutic approaches and represents a significant step toward therapeutic translation of CRISPR-Cas9 gene editing for correction of DMD.

Keywords:  AAV; CRISPR; Duchenne muscular dystrophy; gene editing; humanized mouse model

DOI:  https://doi.org/10.1016/j.omtn.2022.07.024
PLoS One. 2022 ;17(9): e0273925

The muscle proteome reflects changes in mitochondrial function, cellular stress and proteolysis after 14 days of unilateral lower limb immobilization in active young men.

Thomas M Doering, Jamie-Lee M Thompson, Boris P Budiono, Kristen L MacKenzie-Shalders, Thiri Zaw, Kevin J Ashton, Vernon G Coffey.

Skeletal muscle unloading due to joint immobilization induces muscle atrophy, which has primarily been attributed to reductions in protein synthesis in humans. However, no study has evaluated the skeletal muscle proteome response to limb immobilization using SWATH proteomic methods. This study characterized the shifts in individual muscle protein abundance and corresponding gene sets after 3 and 14 d of unilateral lower limb immobilization in otherwise healthy young men. Eighteen male participants (25.4 ±5.5 y, 81.2 ±11.6 kg) underwent 14 d of unilateral knee-brace immobilization with dietary provision and following four-weeks of training to standardise acute training history. Participant phenotype was characterized before and after 14 days of immobilization, and muscle biopsies were obtained from the vastus lateralis at baseline (pre-immobilization) and at 3 and 14 d of immobilization for analysis by SWATH-MS and subsequent gene-set enrichment analysis (GSEA). Immobilization reduced vastus group cross sectional area (-9.6 ±4.6%, P <0.0001), immobilized leg lean mass (-3.3 ±3.9%, P = 0.002), unilateral 3-repetition maximum leg press (-15.6 ±9.2%, P <0.0001), and maximal oxygen uptake (-2.9 ±5.2%, P = 0.044). SWATH analyses consistently identified 2281 proteins. Compared to baseline, two and 99 proteins were differentially expressed (FDR <0.05) after 3 and 14 d of immobilization, respectively. After 14 d of immobilization, 322 biological processes were different to baseline (FDR <0.05, P <0.001). Most (77%) biological processes were positively enriched and characterized by cellular stress, targeted proteolysis, and protein-DNA complex modifications. In contrast, mitochondrial organization and energy metabolism were negatively enriched processes. This study is the first to use data independent proteomics and GSEA to show that unilateral lower limb immobilization evokes mitochondrial dysfunction, cellular stress, and proteolysis. Through GSEA and network mapping, we identify 27 hub proteins as potential protein/gene candidates for further exploration.

DOI: https://doi.org/10.1371/journal.pone.0273925
J Physiol. 2022 Sep 02.

Involvement of the extracellular matrix and integrin signalling proteins in skeletal muscle glucose uptake.

Fulvia Draicchio, Volker Behrends, Neale A Tillin, Nicholas M Hurren, Lykke Sylow, Richard Mackenzie.

  Whole-body euglycaemia is partly maintained by two cellular processes that encourage glucose uptake in skeletal muscle; 1) the insulin- and 2) contraction-stimulated pathways, with research suggesting convergence between these two previously separate processes. The normal structural integrity of the skeletal muscle requires an intact actin cytoskeleton as well as integrin-associated proteins, thus those structures are likely fundamental for effective glucose uptake in skeletal muscle. In contrast, excessive extracellular matrix (ECM) remodelling and integrin expression in skeletal muscle may contribute to insulin resistance owing to an increased physical barrier causing reduced nutrient and hormonal flux. This review paper explores the role of the ECM and the actin cytoskeleton in insulin- and contraction-mediated glucose uptake in skeletal muscle. This is a clinically important area of research given that defects in the structural integrity of the ECM and integrin-associated proteins may contribute to loss of muscle function and decreased glucose uptake in type 2 diabetes. Abstract figure legend Shows nutrient and hormonal flux impeded by the accumulation of excessive extracellular matrix proteins, causing a physical barrier for glucose uptake in skeletal muscle. Abbreviations: ILK, integrin-linked kinase; FAK, focal adhesion kinase; AKT protein kinase B; Rac1, Ras-related C3 botulinum toxin substrate 1; PINCH, particularly interesting new cysteine- histidine-rich protein; NCK2, noncatalytic region of tyrosine kinase adaptor protein 2; IRS1, insulin receptor substrate 1; PI3K, phosphatidylinositol 3-kinase. This article is protected by copyright. All rights reserved.

Keywords:  ECM; ILK; Rac1; actin cytoskeleton; insulin; insulin resistance; integrin; muscle contraction

DOI:  https://doi.org/10.1113/JP283039
Muscle Nerve. 2022 Aug 10.

COVID-19 infection and vaccination in patients with skeletal muscle channelopathies.

Vinojini Vivekanandam, Dipa Jayaseelan, Michael G Hanna.

   INTRODUCTION/AIMS: Although we have gained insight into coronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome-coronavirus 2 since the beginning of the pandemic, our understanding of the consequences for patients with neuromuscular disorders is evolving. In this study we aimed to study the impact of COVID-19 and COVID-19 vaccination on skeletal muscle channelopathies.
METHODS: We conducted a survey of patients with genetically confirmed skeletal muscle channelopathies seen at the UK Nationally Commissioned Channelopathy Service.
RESULTS: Thirty-eight patient responses were received. Six patients had COVID-19 infection leading to exacerbation of their underlying muscle channelopathy. No major complications were reported. Thirty-six patients had received one or two COVID-19 vaccinations and the majority (68%) had no worsening of their underlying channelopathy. Thirty-two percent reported worsening of their usual symptoms of their muscle channelopathy, but all reported recovery to baseline levels. No serious adverse events were reported.
DISCUSSION: The overall rates of COVID-19 infection were low in our study and COVID-19 vaccine uptake rates were high. Our results have been useful to inform patients that a subset of patients have reversible worsening of their channelopathy post-COVID-19 vaccination. Our study provides information for giving advice to patients with skeletal muscle channelopathies regarding COVID-19 infection and vaccination.

Keywords:  COVID-19; channelopathies; coronavirus; myotonia; neuromuscular disorders

DOI:  https://doi.org/10.1002/mus.27704
J Cell Physiol. 2022 Sep 02.

The growing field of immunometabolism and exercise: Key findings in the last 5 years.

Camila S Padilha, Ana E Von Ah Morano, Karsten Krüger, José C Rosa-Neto, Fabio S Lira.

  This perspective review highlights the impact of physical exercise on immunometabolic responses in the past 5 years. Understanding immunometabolism as a part of immunological research is essential. Furthermore, the roles of both acute and chronic effects of physical exercise on health, aging, and chronic diseases in immunometabolic changes should be elaborated. In immune cells, β2 adrenergic signaling stimulates the preferential mobilization of inflammatory phenotypes, such as CD16+ monocytes and CD8+ T cells, into the bloodstream after a physical exercise session. The mobilization of immune cells is closely related to the availability of energetic substrates for the cell and mechanisms associated with the uptake and oxidation of fatty acids and glucose. These cells, especially senescent T cells, are mobilized to the peripheral tissues and undergo apoptotic signaling, stimulating the creation of a "vacant space" where new cells will be matured and replaced in the circulation. This results in the upregulation of the expression and secretion of anti-inflammatory cytokines (IL-10 and IL-1ra), leading to increased regulatory immune cells that provide immunoregulatory properties. Thus, we suggest that a significant nutrient available to the cell will favor oxidative metabolism, augment ATP production, and consequently maintain the immune cells in their quiescent state, as well as promote rapid activation function. Therefore, based on the studies discussed in this perspective review, we highlight the importance of performing moderate-intensity continuous and high-intensity intermittent aerobic exercises, due to a higher magnitude of energetic demand and release of anti-inflammatory cytokines (IL-6 and IL-10).

Keywords:  exercise; immune system; immunometabolic response; metabolic pathway

DOI:  https://doi.org/10.1002/jcp.30866
Front Physiol. 2022 ;13 866792

Exercise as an Aging Mimetic: A New Perspective on the Mechanisms Behind Exercise as Preventive Medicine Against Age-Related Chronic Disease.

Wesley K Lefferts, Mary M Davis, Rudy J Valentine.

  Age-related chronic diseases are among the most common causes of mortality and account for a majority of global disease burden. Preventative lifestyle behaviors, such as regular exercise, play a critical role in attenuating chronic disease burden. However, the exact mechanism behind exercise as a form of preventative medicine remains poorly defined. Interestingly, many of the physiological responses to exercise are comparable to aging. This paper explores an overarching hypothesis that exercise protects against aging/age-related chronic disease because the physiological stress of exercise mimics aging. Acute exercise transiently disrupts cardiovascular, musculoskeletal, and brain function and triggers a substantial inflammatory response in a manner that mimics aging/age-related chronic disease. Data indicate that select acute exercise responses may be similar in magnitude to changes seen with +10-50 years of aging. The initial insult of the age-mimicking effects of exercise induces beneficial adaptations that serve to attenuate disruption to successive "aging" stimuli (i.e., exercise). Ultimately, these exercise-induced adaptations reduce the subsequent physiological stress incurred from aging and protect against age-related chronic disease. To further examine this hypothesis, future work should more intricately describe the physiological signature of different types/intensities of acute exercise in order to better predict the subsequent adaptation and chronic disease prevention with exercise training in healthy and at-risk populations.

Keywords:  aging; exercise physiology; physiological mechanisms; preventive medicine; stress adaptation

DOI:  https://doi.org/10.3389/fphys.2022.866792