bims-moremu 2022-08-21 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2022‒08‒21
25 papers selected by
Anna Vainshtein
Craft Science Inc.

Dominant-negative p53-overexpression in skeletal muscle induces cell death and fiber atrophy in rats.
Obesity impairs skeletal muscle repair through NID-1 mediated extracellular matrix remodeling by mesenchymal progenitors.
Aerobic exercise prevents apoptosis in skeletal muscles of high-fat-fed ovariectomized rats.
Prolonged FOS activity disrupts a global myogenic transcriptional program by altering 3D chromatin architecture in primary muscle progenitor cells.
Short-term aerobic conditioning prior to resistance training augments muscle hypertrophy and satellite cell content in healthy young men and women.
The NLRP3 inflammasome contributes to inflammation-induced morphological and metabolic alterations in skeletal muscle.
Effects of lifelong spontaneous exercise on skeletal muscle and angiogenesis in super-aged mice.
Superfast fish show superfast coupling.
Inflammaging: The ground for sarcopenia?
The Notch signaling pathway in skeletal muscle health and disease.
Morin improves dexamethasone-induced muscle atrophy by modulating atrophy-related genes and oxidative stress in female mice.
Mutations in proteins involved in E-C coupling and SOCE and congenital myopathies.
Establishment of a system evaluating the contractile force of electrically stimulated myotubes from wrinkles formed on elastic substrate.
What Muscle Signals Mediate the Beneficial Effects of Exercise on Cognition?
The potential for Treg-enhancing therapies in tissue, in particular skeletal muscle, regeneration.
L-Arginine increases AMPK phosphorylation and the oxidation of energy substrates in hepatocytes, skeletal muscle cells, and adipocytes.
Clonal behaviour of myogenic precursor cells throughout the vertebrate lifespan.
The spatial distribution of glycogen and glycogen consumption in muscle cells.
Exercise training enhances muscle mitochondrial metabolism in diet-resistant obesity.
Hydrogen sulfide mitigates skeletal muscle mitophagy-led tissue remodeling via epigenetic regulation of the gene writer and eraser function.
Gene therapy in neuromuscular disorders.
Activity-Dependent Induction of Younger Biological Phenotypes.
Measuring Skeletal Muscle Thermogenesis in Mice and Rats.
Cellular and Molecular Regulation of Exercise-A Neuronal Perspective.
High-efficiency quantitative control of mitochondrial transfer based on droplet microfluidics and its application on muscle regeneration.

Cell Death Dis. 2022 Aug 17. 13(8): 716

Dominant-negative p53-overexpression in skeletal muscle induces cell death and fiber atrophy in rats.

Henning T Langer, Agata A Mossakowski, Rasheed Sule, Aldrin Gomes, Keith Baar.

The tumor suppressor p53 is thought to play a key role in the maintenance of cell size and homeostasis, but relatively little is known about its role in skeletal muscle. Based on its ability to suppress cell growth, we hypothesized that inhibiting the function of wild-type p53 through the overexpression of a dominant-negative p53 mutant (DDp53) could result in muscle fiber hypertrophy. To test this hypothesis, we electroporated adult rat tibialis anterior muscles with DDp53 and collected the tissue three weeks later. We confirmed successful overexpression of DDp53 on a histological and biochemical level and found pronounced changes to muscle architecture, metabolism, and molecular signaling. Muscle mass, fiber cross-sectional area, and fiber diameter significantly decreased with DDp53 overexpression. We found histopathological changes in DDp53 transfected muscle which were accompanied by increased levels of proteins that are associated with membrane damage and repair. In addition, DDp53 decreased oxidative phosphorylation complex I and V protein levels, and despite its negative effects on muscle mass and fiber size, caused an increase in muscle protein synthesis as assessed via the SUnSET technique. Interestingly, the increase in muscle protein synthesis was concomitant with a decrease in phospho-S6K1 (Thr389). Furthermore, the muscle wasting in the DDp53 electroporated leg was accompanied by a decrease in global protein ubiquitination and an increase in proteasome activity. In conclusion, overexpression of a dominant-negative p53 mutant in skeletal muscle results in decreased muscle mass, myofiber size, histological muscle damage, a metabolic phenotype, and perturbed homeostasis between muscle protein synthesis and degradation.

DOI: https://doi.org/10.1038/s41419-022-05160-6
Matrix Biol. 2022 Aug 10. pii: S0945-053X(22)00100-7. [Epub ahead of print]

Obesity impairs skeletal muscle repair through NID-1 mediated extracellular matrix remodeling by mesenchymal progenitors.

Sergio Pérez-Díaz, Zeynab Koumaiha, Matthew Jay Borok, Frederic Aurade, Maria Pini, Baptiste Periou, Christine Rouault, Yasmine Baba-Amer, Karine Clément, Genevieve Derumeaux, François Jérôme Authier, Peggy Lafuste, Frederic Relaix.

  Obesity triggers skeletal muscle physio-pathological alterations. However, the crosstalk between adipose tissue and myogenic cells remains poorly understood during obesity. We identified NID-1 among the adipose tissue secreted factors impairing myogenic potential of human myoblasts and murine muscle stem cells in vitro. Mice under High Fat Diet (HFD) displayed increased NID-1 expression in the skeletal muscle endomysium associated with intramuscular fat adipose tissue expansion and compromised muscle stem cell function. We show that NID-1 is highly secreted by skeletal muscle fibro-adipogenic/mesenchymal progenitors (FAPs) during obesity. We demonstrate that increased muscle NID-1 impairs muscle stem cells proliferation and primes the fibrogenic differentiation of FAPs, giving rise to an excessive deposition of extracellular matrix. Finally, we propose a model in which obesity leads to skeletal muscle extracellular matrix remodeling by FAPs, mediating the alteration of myogenic function by adipose tissue and highlighting the key role of NID-1 in the crosstalk between adipose tissue and skeletal muscle.

Keywords:  FAPs; NID-1; Obesity; adipose tissue; extracellular matrix; mesenchymal progenitors; muscle regeneration; muscle stem cells; skeletal muscle

DOI:  https://doi.org/10.1016/j.matbio.2022.08.006
Phys Act Nutr. 2022 Jun;26(2): 1-7

Aerobic exercise prevents apoptosis in skeletal muscles of high-fat-fed ovariectomized rats.

Hye Jin Kim, Oran Kwon.

  PURPOSE: Aging and obesity are associated with skeletal muscle atrophy-related signaling pathways, including apoptosis. Many studies have shown that menopause is associated with an increased risk of skeletal muscle atrophy. There is an increasing need to develop strategies that will improve the risk of skeletal muscle atrophy through exercise interventions. However, the effect of exercise on estrogen deficiency-induced apoptosis in skeletal muscles is poorly understood. Therefore, we examined the effects of low-intensity exercise on ovariectomy (OVX)-induced apoptosis of the soleus and plantaris muscles.METHODS: The ovaries of all female Sprague-Dawley rats aged 8 weeks, were surgically removed to induce postmenopausal status. The rats were randomly divided into three treatment groups: (1) NSV (normal-diet-sedentary-OVX); (2) HSV (high-fat-diet-sedentary-OVX); and (3) HEV (high-fat-diet-exercise-OVX). The exercise groups were regularly running for 30-40 min/day at 15-18 m/minute, five times/week, for eight weeks.
RESULTS: The mRNA levels of Bax significantly decreased in the exercised soleus muscle, and caspase-3 decreased in the plantaris. The skeletal muscle TUNEL-positive apoptotic cells in the high-fat-diet-sedentary OVX rats improved in the treadmill exercise group. Additionally, nuclear caspase-3 levels decreased in the treadmill exercise group compared to those in both sedentary groups. These results suggest that low-intensity treadmill exercise prevents skeletal muscle apoptosis in HFD-fed OVX rats.
CONCLUSION: Induction of HFD in estrogen-deficient mice increased apoptosis in skeletal muscle, which could also be alleviated by low-intensity aerobic exercise. These results may indicate a crucial therapeutic effect of treadmill exercise in preventing skeletal muscle apoptosis in menopausal or post-menopausal women.

Keywords:  aerobic exercise; apoptosis; menopause; ovariectomy; skeletal muscle

DOI:  https://doi.org/10.20463/pan.2022.0007
Skelet Muscle. 2022 Aug 15. 12(1): 20

Prolonged FOS activity disrupts a global myogenic transcriptional program by altering 3D chromatin architecture in primary muscle progenitor cells.

A Rasim Barutcu, Gabriel Elizalde, Alfredo E Gonzalez, Kartik Soni, John L Rinn, Amy J Wagers, Albert E Almada.

  BACKGROUND: The AP-1 transcription factor, FBJ osteosarcoma oncogene (FOS), is induced in adult muscle satellite cells (SCs) within hours following muscle damage and is required for effective stem cell activation and muscle repair. However, why FOS is rapidly downregulated before SCs enter cell cycle as progenitor cells (i.e., transiently expressed) remains unclear. Further, whether boosting FOS levels in the proliferating progeny of SCs can enhance their myogenic properties needs further evaluation.METHODS: We established an inducible, FOS expression system to evaluate the impact of persistent FOS activity in muscle progenitor cells ex vivo. We performed various assays to measure cellular proliferation and differentiation, as well as uncover changes in RNA levels and three-dimensional (3D) chromatin interactions.
RESULTS: Persistent FOS activity in primary muscle progenitor cells severely antagonizes their ability to differentiate and form myotubes within the first 2 weeks in culture. RNA-seq analysis revealed that ectopic FOS activity in muscle progenitor cells suppressed a global pro-myogenic transcriptional program, while activating a stress-induced, mitogen-activated protein kinase (MAPK) transcriptional signature. Additionally, we observed various FOS-dependent, chromosomal re-organization events in A/B compartments, topologically associated domains (TADs), and genomic loops near FOS-regulated genes.
CONCLUSIONS: Our results suggest that elevated FOS activity in recently activated muscle progenitor cells perturbs cellular differentiation by altering the 3D chromosome organization near critical pro-myogenic genes. This work highlights the crucial importance of tightly controlling FOS expression in the muscle lineage and suggests that in states of chronic stress or disease, persistent FOS activity in muscle precursor cells may disrupt the muscle-forming process.

Keywords:  AP-1; FOS; Hi-C; Muscle progenitor cells; Muscle satellite cells; Myogenic differentiation; Topologically associated domains (TADs), gene loops

DOI:  https://doi.org/10.1186/s13395-022-00303-x
FASEB J. 2022 Sep;36(9): e22500

Short-term aerobic conditioning prior to resistance training augments muscle hypertrophy and satellite cell content in healthy young men and women.

Aaron C Q Thomas, Alex Brown, Aidan A Hatt, Katherine Manta, Anamaria Costa-Parke, Michael Kamal, Sophie Joanisse, Chris McGlory, Stuart M Phillips, Dinesh Kumbhare, Gianni Parise.

  Factors influencing inter-individual variability of responses to resistance training (RT) remain to be fully elucidated. We have proposed the importance of capillarization in skeletal muscle for the satellite cell (SC) response to RT-induced muscle hypertrophy, and hypothesized that aerobic conditioning (AC) would augment RT-induced adaptations. Fourteen healthy young (22 ± 2 years) men and women underwent AC via 6 weeks of unilateral cycling followed by 10 weeks of bilateral RT to investigate how AC alters SC content, activity, and muscle hypertrophy following RT. Muscle biopsies were taken at baseline (unilateral), post AC (bilateral), and post RT (bilateral) in the aerobically conditioned (AC + RT) and unconditioned (RT) legs. Immunofluorescence was used to determine muscle capillarization, fiber size, SC content, and activity. Type I and type II fiber cross-sectional area (CSA) increased following RT, and when legs were analyzed independently, AC + RT increased type I, type II, and mixed-fiber CSA, where the RT leg tended to increase type II (p = .05), but not type I or mixed-fiber CSA. SC content, activation, and differentiation increased with RT, where type I total and quiescent SC content was greater in AC + RT compared to the RT leg. Those with the greatest capillary-to-fiber perimeter exchange index before RT had the greatest change in CSA following RT and a significant relationship was observed between type II fiber capillarization and the change in type II-fiber CSA with RT (r = 0.35). This study demonstrates that AC prior to RT can augment RT-induced muscle adaptions and that these differences are associated with increases in capillarization.

Keywords:  aerobic conditioning; aerobic training; capillarization; muscle stem cells; resistance training; responder; satellite cells; single-leg cycling

DOI:  https://doi.org/10.1096/fj.202200398RR
J Cachexia Sarcopenia Muscle. 2022 Aug 17.

The NLRP3 inflammasome contributes to inflammation-induced morphological and metabolic alterations in skeletal muscle.

Moritz Eggelbusch, Andi Shi, Bonnie C Broeksma, Mariana Vázquez-Cruz, Madu N Soares, Gerard M J de Wit, Bart Everts, Richard T Jaspers, Rob C I Wüst.

  BACKGROUND: Systemic inflammation is associated with skeletal muscle atrophy and metabolic dysfunction. Although the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome contributes to cytokine production in immune cells, its role in skeletal muscle is poorly understood. Here, we studied the link between inflammation, NLRP3, muscle morphology, and metabolism in in vitro cultured C2C12 myotubes, independent of immune cell involvement.METHODS: Differentiated C2C12 myotubes were treated with lipopolysaccharide (LPS; 0, 10, and 100-200 ng/mL) to induce activation of the NLRP3 inflammasome with and without MCC950, a pharmacological inhibitor of NLRP3-induced IL-1β production. We assessed markers of the NLRP3 inflammasome, cell diameter, reactive oxygen species, and mitochondrial function.
RESULTS: NLRP3 gene expression and protein concentrations increased in a time-dependent and dose-dependent manner. Intracellular IL-1β concentration significantly increased (P < 0.0001), but significantly less with MCC950 (P = 0.03), suggestive of moderate activation of the NLRP3 inflammasome in cultured myotubes upon LPS stimulation. LPS suppressed myotube growth after 24 h (P = 0.03), and myotubes remained smaller up to 72 h (P = 0.0009). Exposure of myotubes to IL-1β caused similar alterations in cell morphology, and MCC950 mitigated these LPS-induced differences in cell diameter. NLRP3 appeared to co-localize with mitochondria, more so upon exposure to LPS. Mitochondrial reactive oxygen species were higher after LPS (P = 0.03), but not after addition of MCC950. Myotubes had higher glycolytic rates, and mitochondria were more fragmented upon LPS exposure, which was not altered by MCC950 supplementation.
CONCLUSIONS: LPS-induced activation of the NLRP3 inflammasome in cultured myotubes contributes to morphological and metabolic alterations, likely due to its mitochondrial association.

Keywords:  Metabolism; Morphology; NLRP3 inflammasome; Skeletal muscle; Systemic inflammation

DOI:  https://doi.org/10.1002/jcsm.13062
PLoS One. 2022 ;17(8): e0263457

Effects of lifelong spontaneous exercise on skeletal muscle and angiogenesis in super-aged mice.

Kyung-Wan Baek, So-Jeong Kim, Bo-Gyu Kim, Youn-Kwan Jung, Young-Sool Hah, Hyo Youl Moon, Jun-Il Yoo, Jin Sung Park, Ji-Seok Kim.

There has been an increasing awareness of sarcopenia, which is characterized by a concomitant decrease in skeletal muscle mass and quality due to aging. Resistance exercise is considered more effective than aerobic exercise in terms of therapeutic exercise. To confirm the effect of long-term aerobic exercise in preventing sarcopenia, we evaluated the skeletal muscle mass, quality, and angiogenic capacity of super-aged mice that had undergone lifelong spontaneous exercise (LSE) through various experiments. Our findings show that LSE could maintain skeletal muscle mass, quality, and fitness levels in super-aged mice. In addition, ex vivo experiments showed that the angiogenic capacity was maintained at a high level. However, these results were not consistent with the related changes in the expression of genes and/or proteins involved in protein synthesis or angiogenesis. Based on the results of previous studies, it seems certain that the expression at the molecular level does not represent the phenotypes of skeletal muscle and angiogenesis. This is because aging and long-term exercise are variables that can affect both protein synthesis and the expression patterns of angiogenesis-related genes and proteins. Therefore, in aging and exercise-related research, various physical fitness and angiogenesis variables and phenotypes should be analyzed. In conclusion, LSE appears to maintain the potential of angiogenesis and slow the aging process to maintain skeletal muscle mass and quality. Aerobic exercise may thus be effective for the prevention of sarcopenia.

DOI: https://doi.org/10.1371/journal.pone.0263457
J Gen Physiol. 2022 Sep 05. pii: e202213236. [Epub ahead of print]154(9):

Superfast fish show superfast coupling.

Ben Short.

JGP study reveals that adult zebrafish skeletal muscle fibers display the fastest kinetics of excitation-contraction coupling ever measured in vertebrate locomotor muscles.

DOI: https://doi.org/10.1085/jgp.202213236
Exp Gerontol. 2022 Aug 16. pii: S0531-5565(22)00239-X. [Epub ahead of print] 111931

Inflammaging: The ground for sarcopenia?

Zejun Liang, Tianxiao Zhang, Honghong Liu, Zhenlin Li, Lihong Peng, Changyi Wang, Tiantian Wang.

  Sarcopenia is a progressive skeletal muscle disease that occurs most commonly in the elderly population, contributing to increased costs and hospitalization. Exercise and nutritional therapy have been proven to be effective for sarcopenia, and some drugs can also alleviate declines in muscle mass and function due to sarcopenia. However, there is no specific pharmacological treatment for sarcopenia at present. This review will mainly discuss the relationship between inflammaging and sarcopenia. The increased secretion of proinflammatory cytokines with aging may be because of cellular senescence, immunosenescence, alterations in adipose tissue, damage-associated molecular patterns (DAMPs), and gut microbes due to aging. These sources of inflammaging can impact the sarcopenia process through direct or indirect pathways. Conversely, sarcopenia can also aggravate the process of inflammaging, creating a vicious cycle. Targeting sources of inflammaging can influence muscle function, which could be considered a therapeutic target for sarcopenia. Moreover, not only proinflammatory cytokines but also anti-inflammatory cytokines can influence muscle and inflammation and participate in the progression of sarcopenia. This review focuses on the effects of TNF-α, IL-6, and IL-10, which can be detected in plasma. Therefore, clearing chronic inflammation by targeting proinflammatory cytokines (TNF-α, IL-1, IL-6) and the inflammatory pathway (JAK/STAT, autophagy, NF-κB) may be effective in treating sarcopenia.

Keywords:  Anti-inflammatory cytokines; Inflammaging; Proinflammatory cytokines; Sarcopenia; Skeletal muscle

DOI:  https://doi.org/10.1016/j.exger.2022.111931
Muscle Nerve. 2022 Aug 15.

The Notch signaling pathway in skeletal muscle health and disease.

Dorianmarie Vargas-Franco, Raghav Kalra, Isabelle Draper, Christina A Pacak, Atsushi Asakura, Peter B Kang.

  The Notch signaling pathway is a key regulator of skeletal muscle development and regeneration. Over the past decade, the discoveries of three new muscle disease genes have added a new dimension to the relationship between the Notch signaling pathway and skeletal muscle: MEGF10, POGLUT1, and JAG2. We review the clinical syndromes associated with pathogenic variants in each of these genes, known molecular and cellular functions of their protein products with a particular focus on the Notch signaling pathway, and potential novel therapeutic targets that may emerge from further investigations of these diseases. The phenotypes associated with two of these genes, POGLUT1 and JAG2, clearly fall within the realm of muscular dystrophy, whereas the third, MEGF10, is associated with a congenital myopathy/muscular dystrophy overlap syndrome classically known as early-onset myopathy, areflexia, respiratory distress, and dysphagia. JAG2 is a canonical Notch ligand, POGLUT1 glycosylates the extracellular domain of Notch receptors, and MEGF10 interacts with the intracellular domain of NOTCH1. Additional genes and their encoded proteins relevant to muscle function and disease with links to the Notch signaling pathway include TRIM32, ATP2A1 (SERCA1), JAG1, PAX7, and NOTCH2NLC. There is enormous potential to identify convergent mechanisms of skeletal muscle disease and new therapeutic targets through further investigations of the Notch signaling pathway in the context of skeletal muscle development, maintenance, and disease.

Keywords:  JAG2; MEGF10; Notch signaling pathway; POGLUT1; muscular dystrophy

DOI:  https://doi.org/10.1002/mus.27684
Biosci Biotechnol Biochem. 2022 Aug 17. pii: zbac140. [Epub ahead of print]

Morin improves dexamethasone-induced muscle atrophy by modulating atrophy-related genes and oxidative stress in female mice.

Anayt Ulla, Kanae Ozaki, Md Mizanur Rahman, Reiko Nakao, Takayuki Uchida, Isafumi Maru, Kazuaki Mawatari, Tomoya Fukawa, Hiro-Omi Kanayama, Iori Sakakibara, Katsuya Hirasaka, Takeshi Nikawa.

  This study investigated the effect of morin, a flavonoid, on dexamethasone-induced muscle atrophy in C57BL/6J female mice. Dexamethasone (10 mg/kg body weight) for 10 days significantly reduced body weight, gastrocnemius and tibialis anterior muscle mass, and muscle protein in mice. Dexamethasone significantly upregulated muscle atrophy-associated ubiquitin ligases, including atrogin-1 and MuRF-1, and the upstream transcription factors FoxO3a and Klf15. Additionally, dexamethasone significantly induced the expression of oxidative stress-sensitive ubiquitin ligase Cbl-b and the accumulation of the oxidative stress markers malondialdehyde and advanced protein oxidation products in both the plasma and skeletal muscle samples. Intriguingly, morin treatment (20 mg/kg body weight) for 17 days effectively attenuated the loss of muscle mass and muscle protein and suppressed the expression of ubiquitin ligases while reducing the expression of upstream transcriptional factors. Therefore, morin might act as a potential therapeutic agent to attenuate muscle atrophy by modulating atrophy inducing genes and preventing oxidative stress.

Keywords:  C57BL/6J mouse; glucocorticoid; muscle atrophy; oxidative stress; ubiquitin ligase

DOI:  https://doi.org/10.1093/bbb/zbac140
J Gen Physiol. 2022 Sep 05. pii: e202213115. [Epub ahead of print]154(9):

Mutations in proteins involved in E-C coupling and SOCE and congenital myopathies.

Daniela Rossi, Maria Rosaria Catallo, Enrico Pierantozzi, Vincenzo Sorrentino.

In skeletal muscle, Ca2+ necessary for muscle contraction is stored and released from the sarcoplasmic reticulum (SR), a specialized form of endoplasmic reticulum through the mechanism known as excitation-contraction (E-C) coupling. Following activation of skeletal muscle contraction by the E-C coupling mechanism, replenishment of intracellular stores requires reuptake of cytosolic Ca2+ into the SR by the activity of SR Ca2+-ATPases, but also Ca2+ entry from the extracellular space, through a mechanism called store-operated calcium entry (SOCE). The fine orchestration of these processes requires several proteins, including Ca2+ channels, Ca2+ sensors, and Ca2+ buffers, as well as the active involvement of mitochondria. Mutations in genes coding for proteins participating in E-C coupling and SOCE are causative of several myopathies characterized by a wide spectrum of clinical phenotypes, a variety of histological features, and alterations in intracellular Ca2+ balance. This review summarizes current knowledge on these myopathies and discusses available knowledge on the pathogenic mechanisms of disease.

DOI: https://doi.org/10.1085/jgp.202213115
Sci Rep. 2022 Aug 15. 12(1): 13818

Establishment of a system evaluating the contractile force of electrically stimulated myotubes from wrinkles formed on elastic substrate.

Hiroki Hamaguchi, Tsubasa S Matsui, Shinji Deguchi, Yasuro Furuichi, Nobuharu L Fujii, Yasuko Manabe.

Muscle weakness is detrimental not only to quality of life but also life expectancy. However, effective drugs have still not been developed to improve and prevent muscle weakness associated with aging or diseases. One reason for the delay in drug discovery is that no suitable in vitro screening system has been established to test whether drugs improve muscle strength. Here, we used a specific deformable silicone gel substrate to effectively and sensitively evaluate the contractile force generated by myotubes from wrinkles formed on the substrate. Using this system, it was found that the contractile force generated by an atrophic phenotype of myotubes induced by dexamethasone or cancer cell-conditioned medium treatment significantly decreased while that generated by hypertrophic myotubes induced by insulin-like growth factor-1 significantly increased. Notably, it was found that changes in the index related to contractile force can detect atrophic or hypertrophic phenotypes more sensitively than changes in myotube diameter or myosin heavy chain expression, both commonly used to evaluate myotube function. These results suggest that our proposed system will be an effective tool for assessing the contractile force-related state of myotubes, which are available for the development of drugs to prevent and/or treat muscle weakness.

DOI: https://doi.org/10.1038/s41598-022-17548-7
Neurology. 2022 Aug 16. 99(7): 298-304

What Muscle Signals Mediate the Beneficial Effects of Exercise on Cognition?

Eduardo Benarroch.

DOI: https://doi.org/10.1212/WNL.0000000000201049
Clin Exp Immunol. 2022 Aug 16. pii: uxac076. [Epub ahead of print]

The potential for Treg-enhancing therapies in tissue, in particular skeletal muscle, regeneration.

Bola S Hanna, Omar K Yaghi, P Kent Langston, Diane Mathis.

  Foxp3 +CD4 + regulatory T cells (Tregs) are famous for their role in maintaining immunological tolerance. With their distinct transcriptomes, growth-factor dependencies and T-cell receptor (TCR) repertoires, Tregs in nonlymphoid tissues, termed "tissue-Tregs", also perform a variety of functions to help assure tissue homeostasis. For example, they are important for tissue repair and regeneration after various types of injury, both acute and chronic. They exert this influence by controlling both the inflammatory tenor and the dynamics of the parenchymal progenitor-cell pool in injured tissues, thereby promoting efficient repair and limiting fibrosis. Thus, tissue-Tregs are seemingly attractive targets for immunotherapy in the context of tissue regeneration, offering several advantages over existing therapies. Using skeletal muscle as a model system, we discuss the existing literature on Tregs' role in tissue regeneration in acute and chronic injuries, and various approaches for their therapeutic modulation in such contexts, including exercise as a natural Treg modulator.

Keywords:  Tregs; exercise; muscular dystrophy; skeletal muscle; tissue regeneration; tissue repair

DOI:  https://doi.org/10.1093/cei/uxac076
Amino Acids. 2022 Aug 16.

L-Arginine increases AMPK phosphorylation and the oxidation of energy substrates in hepatocytes, skeletal muscle cells, and adipocytes.

Wenjuan S Jobgen, Guoyao Wu.

  Previous work has shown that dietary L-arginine (Arg) supplementation reduced white fat mass in obese rats. The present study was conducted with cell models to define direct effects of Arg on energy-substrate oxidation in hepatocytes, skeletal muscle cells, and adipocytes. BNL CL.2 mouse hepatocytes, C2C12 mouse myotubes, and 3T3-L1 mouse adipocytes were treated with different extracellular concentrations of Arg (0, 15, 50, 100 and 400 µM) or 400 µM Arg + 0.5 mM NG-nitro-L-arginine methyl ester (L-NAME; an NOS inhibitor) for 48 h. Increasing Arg concentrations in culture medium dose-dependently enhanced (P < 0.05) the oxidation of glucose and oleic acid to CO2 in all three cell types, lactate release from C2C12 cells, and the incorporation of oleic acid into esterified lipids in BNL CL.2 and 3T3-L1 cells. Arg at 400 µM also stimulated (P < 0.05) the phosphorylation of AMP-activated protein kinase (AMPK) in all three cell types and increased (P < 0.05) NO production in C2C12 and BNL CL.2 cells. The inhibition of NOS by L-NAME moderately reduced (P < 0.05) glucose and oleic acid oxidation, lactate release, and the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) in BNL CL.2 cells, but had no effect (P > 0.05) on these variables in C2C12 or 3T3-L1 cells. Collectively, these results indicate that Arg increased AMPK activity and energy-substrate oxidation in BNL CL.2, C2C12, and 3T3-L1 cells through both NO-dependent and NO-independent mechanisms.

Keywords:  Arginine; Metabolism; Muscle cells; Nitric oxide; Substrate oxidation; White adipocytes

DOI:  https://doi.org/10.1007/s00726-022-03195-9
Biol Open. 2022 Aug 15. pii: bio059476. [Epub ahead of print]11(8):

Clonal behaviour of myogenic precursor cells throughout the vertebrate lifespan.

Simon M Hughes, Roberta C Escaleira, Kees Wanders, Jana Koth, David G Wilkinson, Qiling Xu.

  To address questions of stem cell diversity during skeletal myogenesis, a Brainbow-like genetic cell lineage tracing method, dubbed Musclebow2, was derived by enhancer trapping in zebrafish. It is shown that, after initial formation of the primary myotome, at least 15 muscle precursor cells (mpcs) seed each somite, where they proliferate but contribute little to muscle growth prior to hatching. Thereafter, dermomyotome-derived mpc clones rapidly expand while some progeny undergo terminal differentiation, leading to stochastic clonal drift within the mpc pool. No evidence of cell-lineage-based clonal fate diversity was obtained. Neither fibre nor mpc death was observed in uninjured animals. Individual marked muscle fibres persist across much of the lifespan indicating low rates of nuclear turnover. In adulthood, early-marked mpc clones label stable blocks of tissue comprising a significant fraction of either epaxial or hypaxial somite. Fusion of cells from separate early-marked clones occurs in regions of clone overlap. Wounds are regenerated from several local mpcs; no evidence for specialised stem mpcs was obtained. In conclusion, our data indicate that most mpcs in muscle tissue contribute to local growth and repair and suggest that cellular turnover is low in the absence of trauma.

Keywords:  Dermomyotome; Muscle; Stem cell; Zebrafish

DOI:  https://doi.org/10.1242/bio.059476
J Gen Physiol. 2022 Sep 05. pii: e202213238. [Epub ahead of print]154(9):

The spatial distribution of glycogen and glycogen consumption in muscle cells.

David G Allen.

DOI: https://doi.org/10.1085/jgp.202213238
EBioMedicine. 2022 Aug 01. pii: S2352-3964(22)00373-5. [Epub ahead of print] 104192

Exercise training enhances muscle mitochondrial metabolism in diet-resistant obesity.

Chantal A Pileggi, Denis P Blondin, Breana G Hooks, Gaganvir Parmar, Irina Alecu, David A Patten, Alexanne Cuillerier, Conor O'Dwyer, A Brianne Thrush, Morgan D Fullerton, Steffany Al Bennett, Éric Doucet, François Haman, Miroslava Cuperlovic-Culf, Ruth McPherson, Robert R M Dent, Mary-Ellen Harper.

  BACKGROUND: Current paradigms for predicting weight loss in response to energy restriction have general validity but a subset of individuals fail to respond adequately despite documented diet adherence. Patients in the bottom 20% for rate of weight loss following a hypocaloric diet (diet-resistant) have been found to have less type I muscle fibres and lower skeletal muscle mitochondrial function, leading to the hypothesis that physical exercise may be an effective treatment when diet alone is inadequate. In this study, we aimed to assess the efficacy of exercise training on mitochondrial function in women with obesity with a documented history of minimal diet-induced weight loss.METHODS: From over 5000 patient records, 228 files were reviewed to identify baseline characteristics of weight loss response from women with obesity who were previously classified in the top or bottom 20% quintiles based on rate of weight loss in the first 6 weeks during which a 900 kcal/day meal replacement was consumed. A subset of 20 women with obesity were identified based on diet-resistance (n=10) and diet sensitivity (n=10) to undergo a 6-week supervised, progressive, combined aerobic and resistance exercise intervention.
FINDINGS: Diet-sensitive women had lower baseline adiposity, higher fasting insulin and triglycerides, and a greater number of ATP-III criteria for metabolic syndrome. Conversely in diet-resistant women, the exercise intervention improved body composition, skeletal muscle mitochondrial content and metabolism, with minimal effects in diet-sensitive women. In-depth analyses of muscle metabolomes revealed distinct group- and intervention- differences, including lower serine-associated sphingolipid synthesis in diet-resistant women following exercise training.
INTERPRETATION: Exercise preferentially enhances skeletal muscle metabolism and improves body composition in women with a history of minimal diet-induced weight loss. These clinical and metabolic mechanism insights move the field towards better personalised approaches for the treatment of distinct obesity phenotypes.
FUNDING: Canadian Institutes of Health Research (CIHR-INMD and FDN-143278; CAN-163902; CIHR PJT-148634).

Keywords:  Exercise; Metabolomics; Mitochondria; Mitochondrial supercomplexes; Muscle physiology; Obesity; Serine; Sphingolipids; Uncoupling; Weight loss

DOI:  https://doi.org/10.1016/j.ebiom.2022.104192
Physiol Rep. 2022 Aug;10(16): e15422

Hydrogen sulfide mitigates skeletal muscle mitophagy-led tissue remodeling via epigenetic regulation of the gene writer and eraser function.

Mahavir Singh, Sathnur Pushpakumar, Yuting Zheng, Rubens P Homme, Irina Smolenkova, Sri Prakash L Mokshagundam, Suresh C Tyagi.

  Ketone bodies (KB) serve as the food for mitochondrial biogenetics. Interestingly, probiotics are known to promote KB formation in the gut (especially those that belong to the Lactobacillus genus). Furthermore, Lactobacillus helps produce folate that lowers the levels of homocysteine (Hcy); a hallmark non-proteinogenic amino acid that defines the importance of epigenetics, and its landscape. In this study, we decided to test whether hydrogen sulfide (H2 S), another Hcy lowering agent regulates the epigenetic gene writer DNA methyltransferase (DNMT), eraser FTO and TET2, and thus mitigates the skeletal muscle remodeling. We treated hyperhomocysteinemic (HHcy, cystathionine beta-synthase heterozygote knockout; CBS+/- ) mice with NaHS (the H2 S donor). The results suggested multi-organ damage by HHcy in the CBS+/- mouse strain compared with WT control mice (CBS+/+ ). H2 S treatment abrogated most of the HHcy-induced damage. The levels of gene writer (DNMT2) and H3K9 (methylation) were higher in the CBS+/- mice, and the H2 S treatment normalized their levels. More importantly, the levels of eraser FTO, TET, and associated GADD45, and MMP-13 were decreased in the CBS+/- mice; however, H2 S treatment mitigated their respective decrease. These events were associated with mitochondrial fission, i.e., an increase in DRP1, and mitophagy. Although the MMP-2 level was lower in CBS+/- compared to WT but H2 S could further lower it in the CBS+/- mice. The MMPs levels were associated with an increase in interstitial fibrosis in the CBS+/- skeletal muscle. Due to fibrosis, the femoral artery blood flow was reduced in the CBS+/- mice, and that was normalized by H2 S. The bone and muscle strengths were found to be decreased in the CBS+/- mice but the H2 S treatment normalized skeletal muscle strength in the CBS+/- mice. Our findings suggest that H2 S mitigates the mitophagy-led skeletal muscle remodeling via epigenetic regulation of the gene writer and eraser function.

Keywords:  1-carbon metabolism; cystathionine β synthase; homocysteine; mitochondria

DOI:  https://doi.org/10.14814/phy2.15422
Arq Neuropsiquiatr. 2022 May;pii: S0004-282X2022000700249. [Epub ahead of print]80(5 Suppl 1): 249-256

Gene therapy in neuromuscular disorders.

Rodrigo Holanda Mendonça, Edmar Zanoteli.

Monogenic neuromuscular disorders are potentially treatable through gene therapy. Using viral vectors, a therapeutic transgene aims to restore normal levels of a protein not produced by the defective gene, or to silence a gene whose expression leads to toxic effects. Spinal Muscular Atrophy (SMA) is a good example of a monogenic disease that currently has an AAV9-based vector gene therapy as a therapeutic option. In this review, we intend to discuss the viral vectors and their mechanisms of action, in addition to reviewing the clinical trials that supported the approval of gene therapy (AVXS-101) for SMA as well as neuromuscular diseases that are potentially treatable with gene replacement therapy.

DOI: https://doi.org/10.1590/0004-282X-ANP-2022-S135
Adv Biol (Weinh). 2022 Aug 17. e2200119

Activity-Dependent Induction of Younger Biological Phenotypes.

Thomas Lissek.

  In several mammalian species, including humans, complex stimulation patterns such as cognitive and physical exercise lead to improvements in organ function, organism health and performance, as well as possibly longer lifespans. A framework is introduced here in which activity-dependent transcriptional programs, induced by these environmental stimuli, move somatic cells such as neurons and muscle cells toward a state that resembles younger cells to allow remodeling and adaptation of the organism. This cellular adaptation program targets several process classes that are heavily implicated in aging, such as mitochondrial metabolism, cell-cell communication, and epigenetic information processing, and leads to functional improvements in these areas. The activity-dependent gene program (ADGP) can be seen as a natural, endogenous cellular reprogramming mechanism that provides deep insight into the principles of inducible improvements in cell and organism function and can guide the development of therapeutic approaches for longevity. Here, these ADGPs are analyzed, exemplary critical molecular nexus points such as cAMP response element-binding protein, myocyte enhancer factor 2, serum response factor, and c-Fos are identified, and it is explored how one may leverage them to prevent, attenuate, and reverse human aging-related decline of body function.

Keywords:  activity; aging; exercise; longevity; rejuvenation; therapy; transcription

DOI:  https://doi.org/10.1002/adbi.202200119
J Vis Exp. 2022 Jul 27.

Measuring Skeletal Muscle Thermogenesis in Mice and Rats.

Christina A Watts, Alexandra Haupt, Jordan Smith, Emily Welch, Aalia Malik, Roman Giacomino, Dinah Walter, Nhlalala Mavundza, Ashley Shemery, Heather K Caldwell, Colleen M Novak.

Skeletal muscle thermogenesis provides a potential avenue for better understanding metabolic homeostasis and the mechanisms underlying energy expenditure. Surprisingly little evidence is available to link the neural, myocellular, and molecular mechanisms of thermogenesis directly to measurable changes in muscle temperature. This paper describes a method in which temperature transponders are utilized to retrieve direct measurements of mouse and rat skeletal muscle temperature. Remote transponders are surgically implanted within the muscle of mice and rats, and the animals are given time to recover. Mice and rats must then be repeatedly habituated to the testing environment and procedure. Changes in muscle temperature are measured in response to pharmacological or contextual stimuli in the home cage. Muscle temperature can also be measured during prescribed physical activity (i.e., treadmill walking at a constant speed) to factor out changes in activity as contributors to the changes in muscle temperature induced by these stimuli. This method has been successfully used to elucidate mechanisms underlying muscle thermogenic control at the level of the brain, sympathetic nervous system, and skeletal muscle. Provided are demonstrations of this success using predator odor (PO; ferret odor) as a contextual stimulus and injections of oxytocin (Oxt) as a pharmacological stimulus, where predator odor induces muscle thermogenesis, and Oxt suppresses muscle temperature. Thus, these datasets display the efficacy of this method in detecting rapid changes in muscle temperature.

DOI: https://doi.org/10.3791/64264
Cell Mol Neurobiol. 2022 Aug 20.

Cellular and Molecular Regulation of Exercise-A Neuronal Perspective.

Ishitha Reddy, Yamini Yadav, Chinmoy Sankar Dey.

  The beneficial effects of exercise on the proper functioning of the body have been firmly established. Multi-systemic metabolic regulation of exercise is the consequence of multitudinous changes that occur at the cellular level. The exercise responsome comprises all molecular entities including exerkines, miRNA species, growth factors, signaling proteins that are elevated and activated by physical exercise. Exerkines are secretory molecules released by organs such as skeletal muscle, adipose tissue, liver, and gut as a function of acute/chronic exercise. Exerkines such as FNDC5/irisin, Cathepsin B, Adiponectin, and IL-6 circulate through the bloodstream, cross the blood-brain barrier, and modulate the expression of important signaling molecules such as AMPK, SIRT1, PGC1α, BDNF, IGF-1, and VEGF which further contribute to improved energy metabolism, glucose homeostasis, insulin sensitivity, neurogenesis, synaptic plasticity, and overall well-being of the body and brain. These molecules are also responsible for neuroprotective adaptations that exercise confers on the brain and potentially ameliorate neurodegeneration. This review aims to detail important cellular and molecular species that directly or indirectly mediate exercise-induced benefits in the body, with an emphasis on the central nervous system.

Keywords:  Exercise; Exercise mimetics; Exerkines; Metabolism; Neuron

DOI:  https://doi.org/10.1007/s10571-022-01272-x
Sci Adv. 2022 Aug 19. 8(33): eabp9245

High-efficiency quantitative control of mitochondrial transfer based on droplet microfluidics and its application on muscle regeneration.

Jiayu Sun, Hiu Tung Jessica Lo, Lei Fan, Tsz Lam Yiu, Adnan Shakoor, Gang Li, Wayne Y W Lee, Dong Sun.

Mitochondrial transfer is a spontaneous process to restore damaged cells in various pathological conditions. The transfer of mitochondria to cell therapy products before their administration can enhance therapeutic outcomes. However, the low efficiency of previously reported methods limits their clinical application. Here, we developed a droplet microfluidics-based mitochondrial transfer technique that can achieve high-efficiency and high-throughput quantitative mitochondrial transfer to single cells. Because mitochondria are essential for muscles, myoblast cells and a muscle injury model were used as a proof-of-concept model to evaluate the proposed technique. In vitro and in vivo experiments demonstrated that C2C12 cells with 31 transferred mitochondria had significant improvements in cellular functions compared to those with 0, 8, and 14 transferred mitochondria and also had better therapeutic effects on muscle regeneration. The proposed technique can considerably promote the clinical application of mitochondrial transfer, with optimized cell function improvements, for the cell therapy of mitochondria-related diseases.

DOI: https://doi.org/10.1126/sciadv.abp9245