bims-moremu 2023-02-26 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2023–02–26
38 papers selected by
Anna Vainshtein, Craft Science Inc.

Cell selectivity in succinate receptor SUCNR1/GPR91 signaling in skeletal muscle.
Exercise and aging impact kynurenine/tryptophan pathway and acylcarnitine metabolite pools in skeletal muscle of older adults.
Human skeletal muscle-specific atrophy with aging: a comprehensive review.
The dawn of the functional genomics era in muscle physiology.
DNA repair byproduct 8-oxoguanine base promotes myoblast differentiation.
Low-load blood flow-restricted resistance exercise produce fiber type-independent hypertrophy and improves muscle functional capacity in older individuals.
Emerging Mechanisms of Skeletal Muscle Homeostasis and Cachexia: The SUMO Perspective.
Does initial skeletal muscle size or sex affect the magnitude of muscle loss in response to 14 days immobilization?
Systemic γ-sarcoglycan AAV gene transfer results in dose-dependent correction of muscle deficits in the LGMD 2C/R5 mouse model.
Drosophila Tropomodulin is required for multiple actin-dependent processes within developing myofibers.
Cellular interplay in skeletal muscle regeneration and wasting: insights from animal models.
Hox11-expressing interstitial cells contribute to adult skeletal muscle at homeostasis.
Exercise-activated hepatic autophagy via the FN1-α5β1 integrin pathway drives metabolic benefits of exercise.
Deletion of Sod1 in motor neurons exacerbates age-related changes in axons and neuromuscular junctions in mice.
Chronic Stress Induces Type 2b Skeletal Muscle Atrophy via the Inhibition of mTORC1 Signaling in Mice.
Titin activates myosin filaments in skeletal muscle by switching from an extensible spring to a mechanical rectifier.
Sex differences in skeletal muscle-aging trajectory: same processes, but with a different ranking.
The PoWeR of exercise: exploring the anti-ageing effects of exercise through epigenetic modifications to skeletal muscle.
The association between muscle architecture and muscle spindle abundance.
Probenecid affects muscle Ca2+ homeostasis and contraction independently from pannexin channel block.
The Role of Sirtuins in Sarcopenia and Frailty.
11β-HSD1 determines the extent of muscle atrophy in a model of acute exacerbation of COPD.
Endogenous and Exogenous Antioxidants in Skeletal Muscle Fatigue Development during Exercise.
Optogenetic decoding of Akt2-regulated metabolic signaling pathways in skeletal muscle cells using transomics analysis.
Effect of Zbed6 Single-Allele Knockout on the Growth and Development of Skeletal Muscle in Mice.
Spatiotemporal mapping of immune and stem cell dysregulation after volumetric muscle loss.
A role for β-catenin in diet-induced skeletal muscle insulin resistance.
BMP-7 Attenuates Sarcopenia and Adverse Muscle Remodeling in Diabetic Mice via Alleviation of Lipids, Inflammation, HMGB1, and Pyroptosis.
Accumulation of polyunsaturated fatty acid-derived metabolites in the sarcopenic muscle of aging mice.
VEGAN AND OMNIVOROUS HIGH PROTEIN DIETS SUPPORT COMPARABLE DAILY MYOFIBRILLAR PROTEIN SYNTHESIS RATES AND SKELETAL MUSCLE HYPERTROPHY IN YOUNG ADULTS.
Time-restricted feeding promotes muscle function through purine cycle and AMPK signaling in Drosophila obesity models.
Gene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging.
Sex-Specific Patterns of Diaphragm Phospholipid Content and Remodeling during Aging and in a Model of SELENON-Related Myopathy.
When should I run - the role of exercise timing in metabolic health.
Extracellular Vesicles in Aging: An Emerging Hallmark?
TNF-α contributes to sarcopenia through caspase-8/caspase-3/GSDME-mediated pyroptosis.
Inhibition of DDX3X alleviates persistent inflammation, immune suppression and catabolism syndrome in a septic mice model.
Rab8a as a mitochondrial receptor for lipid droplets in skeletal muscle.

Am J Physiol Endocrinol Metab. 2023 Feb 22.

Cell selectivity in succinate receptor SUCNR1/GPR91 signaling in skeletal muscle.

Ahmed M Abdelmoez, Oksana Dmytriyeva, Yasemin-Xiomara Zurke, Mette Trauelsen, Alesandra A Marica, Mladen Savikj, Jonathon A B Smith, Claudia Monaco, Thue W Schwartz, Anna Krook, Nicolas J Pillon.

  Succinate is released by skeletal muscle during exercise and activates SUCNR1/GPR91. Signaling of SUCNR1 is involved in metabolite-sensing paracrine communication in skeletal muscle during exercise. However, the specific cell types responding to succinate and the directionality of communication are unclear. We aim to characterize the expression of SUCNR1 in human skeletal muscle. De novo analysis of transcriptomic datasets demonstrated that SUCNR1 mRNA is expressed in immune, adipose, and liver tissues, but scarce in skeletal muscle. In human tissues, SUCNR1 mRNA was associated with macrophage markers. Single-cell RNA sequencing and fluorescent RNAscope demonstrated that in human skeletal muscle, SUCNR1 mRNA is not expressed in muscle fibers but coincided with macrophage populations. Human M2-polarized macrophages exhibit high levels of SUCNR1 mRNA and stimulation with selective agonists of SUCNR1 triggered Gq- and Gi-coupled signaling. Primary human skeletal muscle cells were unresponsive to SUCNR1 agonists. In conclusion, SUCNR1 is not expressed in muscle cells and its role in the adaptive response of skeletal muscle to exercise is most likely mediated via paracrine mechanisms involving M2-like macrophages within the muscle.

Keywords:  GPR91; Macrophage; SUCNR1; Skeletal muscle; Succinate

DOI:  https://doi.org/10.1152/ajpendo.00009.2023
J Physiol. 2023 Feb 22.

Exercise and aging impact kynurenine/tryptophan pathway and acylcarnitine metabolite pools in skeletal muscle of older adults.

J Matthew Hinkley, GongXin Yu, Robert A Standley, Giovanna Distefano, Vladimir Tolstikov, Niven R Narain, Bennett P Greenwood, Shraddha Karmacharya, Michael A Kiebish, Elvis Alvarez Carnero, Fanchao Yi, Rick B Vega, Bret H Goodpaster, Stephen J Gardell, Paul M Coen.

  Exercise-induced perturbation of skeletal muscle metabolites is a likely mediator of long-term health benefits in older adults. While specific metabolites have been identified to be impacted by age, physical activity, and exercise, the depth of coverage of the muscle metabolome is still limited. Here, we investigated resting and exercise-induced metabolite distribution in muscle from well-phenotyped older adults that were active or sedentary, and a group of active young adults. Percutaneous biopsies of the vastus lateralis were obtained before, immediately after, and 3-hours following a bout of endurance cycling. Metabolite profile in muscle biopsies was determined by tandem mass spectrometry. Mitochondrial energetics in permeabilized fiber bundles was assessed by high resolution respirometry and fiber type proportion was assessed by immunohistology. We found that metabolites of the kynurenine/tryptophan pathway were impacted by age and activity. Specifically, kynurenine was elevated in muscle from older adults, while downstream metabolites of kynurenine (kynurenic acid and nicotinamide adenine dinucleotide (NAD+ )) were elevated in muscle from active adults and associated with cardiorespiratory fitness and muscle oxidative capacity. Acylcarnitines, a potential marker of impaired metabolic health, were elevated in muscle from physically active participants. Surprisingly, despite baseline group difference, acute exercise-induced alterations in whole-body substrate utilization and muscle acylcarnitines and ketone bodies were remarkably similar between groups. Our data identified novel muscle metabolite signatures that associate with the healthy aging phenotype provoked by physical activity and reveal the metabolic responsiveness of muscle to acute endurance exercise is retained with age regardless of activity levels. KEY POINTS: Kynurenine/tryptophan pathway metabolites were impacted by age and physical activity in human muscle, with kynurenine elevated in older muscle, while downstream products kynurenic acid and NAD+ were elevated in exercise-trained muscle regardless of age. Acylcarnitines, a marker of impaired metabolic health when heightened in circulation, was elevated in exercise-trained muscle of young and older adults, suggesting muscle act as a metabolic sink to reduce circulating acylcarnitines observed with unhealthy aging. Despite the phenotypic differences, the exercise-induced response of various muscle metabolite pools, including acylcarnitine and ketone bodies, was similar amongst the groups, suggesting older adults can achieve the metabolic benefits of exercise seen in young counterparts. Abstract figure legend Muscle metabolite profiles at baseline and in response to an acute bout of endurance exercise were examined in three groups: Young Active, Older Active, Older Sedentary. Baseline profiles revealed distinct age- and activity-related metabolite profiles in muscle that associated with clinical and biochemical characteristics of the oxidative phenotype (cardiorespiratory fitness (VO2peak), muscle mitochondrial energetics, and type I fiber type proportion). Specifically, kynurenine-related metabolites (kynurenine, kynurenic acid, and quinolinate) were impacted by age, while nicotinamide adenine dinucleotide (NAD+ ) and acylcarnitines levels were impacted by activity/exercise training. Despite baseline differences, the whole-body and muscle-specific metabolic responses were similarly amongst young and older adults regardless of training status. This article is protected by copyright. All rights reserved.

Keywords:  NAD+; aging; ketones; kynurenic acid

DOI:  https://doi.org/10.1113/JP284142
J Appl Physiol (1985). 2023 Feb 24.

Human skeletal muscle-specific atrophy with aging: a comprehensive review.

Masatoshi Naruse, Scott Trappe, Todd A Trappe.

  Age-related skeletal muscle atrophy appears to be a muscle group-specific process, yet only a few specific muscles have been investigated and our understanding in this area is limited. This review provides a comprehensive summary of the available information on age-related skeletal muscle atrophy in a muscle-specific manner, nearly half of which comes from the quadriceps. Decline in muscle-specific size over ~50yr of aging was determined from 47 cross-sectional studies of 982 young (~25yr) and 1,003 old (~75yr) individuals and nine muscle groups: elbow extensors (-20%, -0.39%/yr), elbow flexors (-19%, -0.38%/yr), paraspinals (-24%, -0.47%/yr), psoas (-29%, -0.58%/yr), hip adductors (-13%, -0.27%/yr), hamstrings (-19%, -0.39%/yr), quadriceps (-27%, -0.53%/yr), dorsiflexors (-9%, -0.19%/yr), and triceps surae (-14%, -0.28%/yr). Muscle-specific atrophy rate was also determined for each of the subcomponent muscles in the hamstrings, quadriceps, and triceps surae. Of all the muscles included in this review, there was more than a 5-fold difference between the least (-6%, -0.13%/yr, soleus) to the most (-33%, -0.66%/yr, rectus femoris) atrophying muscles. Muscle activity level, muscle fiber type, sex, and timeline of the aging process all appeared to have some influence on muscle-specific atrophy. Given the large range of muscle-specific atrophy and the large number of muscles that have not been investigated, more muscle-specific information could expand our understanding of functional deficits that develop with aging and help guide muscle-specific interventions to improve the quality of life of aging women and men.

Keywords:  Skeletal muscle mass; aging; sarcopenia

DOI:  https://doi.org/10.1152/japplphysiol.00768.2022
J Physiol. 2023 Feb 24.

The dawn of the functional genomics era in muscle physiology.

Robert A E Seaborne, Julien Ochala.

  Skeletal muscle represents the most abundant component of the mature mammalian phenotype. Designed to generate contractile force and movement, skeletal muscle is crucial for organism health, function, and development. One of the great interests for muscle biologists is in understanding how skeletal muscle adapts during periods of stress and stimuli, such as disease, disuse and ageing. To this end, genomic based experimental and analytical approaches offer one of the most powerful approaches for comprehensively mapping the molecular paradigms that regulate skeletal muscle. With the power, applicability, and robustness of omic technologies continually being developed, we are now in a position to investigate these molecular mechanisms in skeletal muscle to an unprecedented level of accuracy and precision, dawning a new era of functional genomics in the field of muscle physiology. Abstract figure legend Skeletal muscle samples obtained from human or model organisms are used to study the adaptability of the tissue to differing stimuli. These homogenate samples contain an array of different cells, as well as a variety of different muscle cell types (myofibers), which may lead to the generated data not truly reflecting the molecular adaptations of muscle cells or muscle cell types, specifically. With the continued development of functional genomic approaches however, we now have the capacity to analyse purified myofibers on either a type specific, or individual cell manner potentially enabling more precise and accurate discoveries. This topical review showcases some of first forays into the functional genomics field in muscle physiology. We highlight developments in functional genomic methods, the applicability of these methods to studying skeletal muscle and some of the most promising areas of future research. This article is protected by copyright. All rights reserved.

Keywords:  genomics; molecular physiology; skeletal muscle

DOI:  https://doi.org/10.1113/JP284206
Redox Biol. 2023 Feb 15. pii: S2213-2317(23)00035-6. [Epub ahead of print]61 102634

DNA repair byproduct 8-oxoguanine base promotes myoblast differentiation.

Xu Zheng, Wenhe Zhang, Yinchao Hu, Zhexuan Zhao, Jiaxin Wu, Xiaoqing Zhang, Fengqi Hao, Jinling Han, Jing Xu, Wenjing Hao, Ruoxi Wang, Meihong Tian, Zsolt Radak, Yusaku Nakabeppu, Istvan Boldogh, Xueqing Ba.

  Muscle contraction increases the level of reactive oxygen species (ROS), which has been acknowledged as key signaling entities in muscle remodeling and to underlie the healthy adaptation of skeletal muscle. ROS inevitably endows damage to various cellular molecules including DNA. DNA damage ought to be repaired to ensure genome integrity; yet, how DNA repair byproducts affect muscle adaptation remains elusive. Here, we showed that exercise elicited the generation of 8-oxo-7,8-dihydroguanine (8-oxoG), that was primarily found in mitochondrial genome of myofibers. Upon exercise, TA muscle's 8-oxoG excision capacity markedly enhanced, and in the interstitial fluid of TA muscle from the post-exercise mice, the level of free 8-oxoG base was significantly increased. Addition of 8-oxoG to myoblasts triggered myogenic differentiation via activating Ras-MEK-MyoD signal axis. 8-Oxoguanine DNA glycosylase1 (OGG1) silencing from cells or Ogg1 KO from mice decreased Ras activation, ERK phosphorylation, MyoD transcriptional activation, myogenic regulatory factors gene (MRFs) expression. In reconstruction experiments, exogenously added 8-oxoG base enhanced the expression of MRFs and accelerated the recovery of the injured skeletal muscle. Collectively, these data not only suggest that DNA repair metabolite 8-oxoG function as a signal entity for muscle remodeling and contribute to exercise-induced adaptation of skeletal muscle, but also raised the potential for utilizing 8-oxoG in clinical treatment to skeletal muscle damage-related disorders.

Keywords:  8-Dihydroguanine (8-oxoG); 8-Oxo-7; 8-oxoG glycosylase 1 (OGG1); Guanine nucleotide exchange factor (GEF); Myoblast; Myogenic differentiation

DOI:  https://doi.org/10.1016/j.redox.2023.102634
J Appl Physiol (1985). 2023 Feb 24.

Low-load blood flow-restricted resistance exercise produce fiber type-independent hypertrophy and improves muscle functional capacity in older individuals.

Jakob Wang, Anna-Maria Godsk Mogensen, Frederik Thybo, Magnus Brandbyge, Jonas Brorson Jensen, Gerrit van Hall, Jakob Agergaard, Frank Vincenzo de Paoli, Benjamin F Miller, Hans Erik Bøtker, Jean Farup, Kristian Vissing.

  Low-load blood flow-restricted resistance exercise (BFRRE) constitute an effective means to produce skeletal muscle hypertrophy. Nonetheless, its applicability to counteract the age-related skeletal muscle decay at a cellular level, is not clear. Therefore, we investigated the effect of BFRRE on muscle fiber morphology, integrated muscle protein synthesis, muscle stem cells (MuSCs), myonuclear content and muscle functional capacity in healthy older individuals. Twenty-three participants with a mean age of 66 years (56-75 years) were randomized to six weeks of supervised BFRRE (3 sessions x week) or non-intervention control (CON). Biopsies were collected from vastus lateralis before and after the intervention. Immunofluorescent microscopy was utilized to assess muscle fiber type-specific cross-sectional area (CSA) as well as MuSC and myonuclear content. Deuterium oxide was orally administered throughout the intervention period, enabling assessment of integrated myofibrillar and connective tissue protein fractional synthesis rate (FSR). BFRRE produced uniform ~20% increases in the fiber CSA of both type I and type II fibers (p<0.05). This occurred concomitantly with improvements in both maximal strength and muscle strength-endurance, but in the absence of increased MuSC content and myonuclear addition. The observed muscle fiber hypertrophy was not mirrored by increases in either myofibrillar or connective tissue FSR. In conclusion, BFRRE proved effective in stimulating skeletal muscle growth and increased muscle function in older individuals, which advocates for the use of BFRRE as a countermeasure of age-related deterioration of skeletal muscle mass and function.

Keywords:  Blood flow-restricted exercise; aging; myofibrillar protein synthesis; satellite cells; strength training

DOI:  https://doi.org/10.1152/japplphysiol.00789.2022
Cells. 2023 Feb 17. pii: 644. [Epub ahead of print]12(4):

Emerging Mechanisms of Skeletal Muscle Homeostasis and Cachexia: The SUMO Perspective.

Bushra Khan, Luis Vincens Gand, Mamta Amrute-Nayak, Arnab Nayak.

  Mobility is an intrinsic feature of the animal kingdom that stimulates evolutionary processes and determines the biological success of animals. Skeletal muscle is the primary driver of voluntary movements. Besides, skeletal muscles have an immense impact on regulating glucose, amino acid, and lipid homeostasis. Muscle atrophy/wasting conditions are accompanied by a drastic effect on muscle function and disrupt steady-state muscle physiology. Cachexia is a complex multifactorial muscle wasting syndrome characterized by extreme loss of skeletal muscle mass, resulting in a dramatic decrease in life quality and reported mortality in more than 30% of patients with advanced cancers. The lack of directed treatments to prevent or relieve muscle loss indicates our inadequate knowledge of molecular mechanisms involved in muscle cell organization and the molecular etiology of cancer-induced cachexia (CIC). This review highlights the latest knowledge of regulatory mechanisms involved in maintaining muscle function and their deregulation in wasting syndromes, particularly in cachexia. Recently, protein posttranslational modification by the small ubiquitin-like modifier (SUMO) has emerged as a key regulatory mechanism of protein function with implications for different aspects of cell physiology and diseases. We also review an atypical association of SUMO-mediated pathways in this context and deliberate on potential treatment strategies to alleviate muscle atrophy.

Keywords:  SUMO-specific isopeptidase; cachexia; chromatin signaling; muscle atrophy; muscle metabolism; sarcomere; ubiquitin-like modifiers; ubiquitination

DOI:  https://doi.org/10.3390/cells12040644
Appl Physiol Nutr Metab. 2023 Feb 21.

Does initial skeletal muscle size or sex affect the magnitude of muscle loss in response to 14 days immobilization?

Vernon G Coffey, Chris McGlory, Stuart M Phillips, Thomas M Doering.

We aimed to determine if there was a relationship between pre-immobilization skeletal muscle size and the magnitude of muscle atrophy following 14 d of unilateral lower limb immobilization. Our findings (n=30) show that pre-immobilization leg fat-free mass and quadriceps cross-sectional area (CSA) were unrelated to the magnitude of muscle atrophy. However, sex-based differences may be present, but confirmatory work is required. In women, pre-immobilization leg fat-free mass and CSA were associated with changes in quadriceps CSA after immobilization (n=9, r2=0.54-0.68; P<0.05). The extent of muscle atrophy is not affected by initial muscle mass, but there is potential for sex-based differences.

DOI: https://doi.org/10.1139/apnm-2022-0458
Mol Ther Methods Clin Dev. 2023 Mar 09. 28 284-299

Systemic γ-sarcoglycan AAV gene transfer results in dose-dependent correction of muscle deficits in the LGMD 2C/R5 mouse model.

Young-Eun Seo, Stephen H Baine, Amber N Kempton, Oliver C Rogers, Sarah Lewis, Kaitlin Adegboye, Alex Haile, Danielle A Griffin, Ellyn L Peterson, Eric R Pozsgai, Rachael A Potter, Louise R Rodino-Klapac.

  Limb-girdle muscular dystrophy (LGMD) type 2C/R5 results from mutations in the γ-sarcoglycan (SGCG) gene and is characterized by muscle weakness and progressive wasting. Loss of functional γ-sarcoglycan protein in the dystrophin-associated protein complex destabilizes the sarcolemma, leading to eventual myofiber death. The SGCG knockout mouse (SGCG -/-) has clinical-pathological features that replicate the human disease, making it an ideal model for translational studies. We designed a self-complementary rAAVrh74 vector containing a codon-optimized human SGCG transgene driven by the muscle-specific MHCK7 promoter (SRP-9005) to investigate adeno-associated virus (AAV)-mediated SGCG gene transfer in SGCG -/- mice as proof of principle for LGMD 2C/R5. Gene transfer therapy resulted in widespread transgene expression in skeletal muscle and heart, improvements in muscle histopathology characterized by decreased central nuclei and fibrosis, and normalized fiber size. Histopathologic improvements were accompanied by functional improvements, including increased ambulation and force production and resistance to injury of the tibialis anterior and diaphragm muscles. This study demonstrates successful systemic delivery of the hSGCG transgene in SGCG -/- mice, with functional protein expression, reconstitution of the sarcoglycan complex, and corresponding physiological and functional improvements, which will help establish a minimal effective dose for translation of SRP-9005 gene transfer therapy in patients with LGMD 2C/R5.

Keywords:  SGCG gene; SRP-9005; adeno-associated virus; dystrophin-associated protein complex; gene therapy; gene transfer; histopathology; limb-girdle muscular dystrophy; rAAVrh74 vector; γ-sarcoglycan

DOI:  https://doi.org/10.1016/j.omtm.2023.01.004
Development. 2023 Feb 20. pii: dev.201194. [Epub ahead of print]

Drosophila Tropomodulin is required for multiple actin-dependent processes within developing myofibers.

Carolina Zapater I Morales, Peter J Carman, David B Soffar, Stefanie E Windner, Roberto Dominguez, Mary K Baylies.

  Proper muscle contraction requires the assembly and maintenance of sarcomeres and myofibrils. While the protein components of myofibrils are generally known, less is known about the mechanisms by which they individually function and together synergize for myofibril assembly and maintenance. For example, it is unclear how the disruption of actin filament (F-actin) regulatory proteins leads to the muscle weakness observed in myopathies. Here, we show that knockdown of Drosophila Tropomodulin (Tmod), results in several myopathy-related phenotypes, including reduction of muscle cell (myofiber) size, increased sarcomere length, disorganization and misorientation of myofibrils, ectopic F-actin accumulation, loss of tension-mediating proteins at the myotendinous junction, and misshaped and internalized nuclei. Our findings support and extend the tension-driven self-organization myofibrillogenesis model. We show that, like its mammalian counterpart, Drosophila Tmod caps F-actin pointed-ends, and we propose that this activity is critical for cellular processes in different locations within the myofiber that directly and indirectly contribute to the maintenance of muscle function. Our findings provide significant insights to the role of Tmod in muscle development, maintenance, and disease.

Keywords:   Drosophila ; Misshapen nuclei; Myofibril orientation; Sarcomere length; Skeletal muscle; Tension-mediating proteins; Tropomodulin (Tmod)

DOI:  https://doi.org/10.1242/dev.201194
J Cachexia Sarcopenia Muscle. 2023 Feb 21.

Cellular interplay in skeletal muscle regeneration and wasting: insights from animal models.

Pauline Henrot, Léo Blervaque, Isabelle Dupin, Maéva Zysman, Pauline Esteves, Fares Gouzi, Maurice Hayot, Pascal Pomiès, Patrick Berger.

  Skeletal muscle wasting, whether related to physiological ageing, muscle disuse or to an underlying chronic disease, is a key determinant to quality of life and mortality. However, cellular basis responsible for increased catabolism in myocytes often remains unclear. Although myocytes represent the vast majority of skeletal muscle cellular population, they are surrounded by numerous cells with various functions. Animal models, mostly rodents, can help to decipher the mechanisms behind this highly dynamic process, by allowing access to every muscle as well as time-course studies. Satellite cells (SCs) play a crucial role in muscle regeneration, within a niche also composed of fibroblasts and vascular and immune cells. Their proliferation and differentiation is altered in several models of muscle wasting such as cancer, chronic kidney disease or chronic obstructive pulmonary disease (COPD). Fibro-adipogenic progenitor cells are also responsible for functional muscle growth and repair and are associated in disease to muscle fibrosis such as in chronic kidney disease. Other cells have recently proven to have direct myogenic potential, such as pericytes. Outside their role in angiogenesis, endothelial cells and pericytes also participate to healthy muscle homoeostasis by promoting SC pool maintenance (so-called myogenesis-angiogenesis coupling). Their role in chronic diseases muscle wasting has been less studied. Immune cells are pivotal for muscle repair after injury: Macrophages undergo a transition from the M1 to the M2 state along with the transition between the inflammatory and resolutive phase of muscle repair. T regulatory lymphocytes promote and regulate this transition and are also able to activate SC proliferation and differentiation. Neural cells such as terminal Schwann cells, motor neurons and kranocytes are notably implicated in age-related sarcopenia. Last, newly identified cells in skeletal muscle, such as telocytes or interstitial tenocytes could play a role in tissular homoeostasis. We also put a special focus on cellular alterations occurring in COPD, a chronic and highly prevalent respiratory disease mainly linked to tobacco smoke exposure, where muscle wasting is strongly associated with increased mortality, and discuss the pros and cons of animal models versus human studies in this context. Finally, we discuss resident cells metabolism and present future promising leads for research, including the use of muscle organoids.

Keywords:  Cachexia; Fibrocytes; Myofibres; Neutrophils; Sarcopenia

DOI:  https://doi.org/10.1002/jcsm.13103
Development. 2023 Feb 15. pii: dev201026. [Epub ahead of print]150(4):

Hox11-expressing interstitial cells contribute to adult skeletal muscle at homeostasis.

Corey G K Flynn, Paul R Van Ginkel, Katharine A Hubert, Qingyuan Guo, Steven M Hrycaj, Aubrey E McDermott, Angelo Madruga, Anna P Miller, Deneen M Wellik.

  Interstitial stromal cells play critical roles in muscle development, regeneration and repair and we have previously reported that Hoxa11 and Hoxd11 are expressed in the interstitial cells of muscles attached to the zeugopod, and are crucial for the proper embryonic patterning of these muscles. Hoxa11eGFP expression continues in a subset of muscle interstitial cells through adult stages. The induction of Hoxa11-CreERT2-mediated lineage reporting (Hoxa11iTom) at adult stages in mouse results in lineage induction only in the interstitial cells. However, Hoxa11iTom+ cells progressively contribute to muscle fibers at subsequent stages. The contribution to myofibers exceeds parallel Pax7-CreERT2-mediated lineage labeling. Nuclear-specific lineage labeling demonstrates that Hoxa11-expressing interstitial cells contribute nuclear contents to myofibers. Crucially, at no point after Hoxa11iTom induction are satellite cells lineage labeled. When examined in vitro, isolated Hoxa11iTom+ interstitial cells are not capable of forming myotubes, but Hoxa11iTom+ cells can contribute to differentiating myotubes, supporting Hox-expressing interstitial cells as a new population of muscle progenitors, but not stem cells. This work adds to a small but growing body of evidence that supports a satellite cell-independent source of muscle tissue in vivo.

Keywords:  Hox genes; Muscle interstitial cells; Skeletal muscle

DOI:  https://doi.org/10.1242/dev.201026
Cell Metab. 2023 Feb 14. pii: S1550-4131(23)00011-6. [Epub ahead of print]

Exercise-activated hepatic autophagy via the FN1-α5β1 integrin pathway drives metabolic benefits of exercise.

Kenta Kuramoto, Huijia Liang, Jung-Hwa Hong, Congcong He.

  How exercise elicits systemic metabolic benefits in both muscles and non-contractile tissues is unclear. Autophagy is a stress-induced lysosomal degradation pathway that mediates protein and organelle turnover and metabolic adaptation. Exercise activates autophagy in not only contracting muscles but also non-contractile tissues including the liver. However, the role and mechanism of exercise-activated autophagy in non-contractile tissues remain mysterious. Here, we show that hepatic autophagy activation is essential for exercise-induced metabolic benefits. Plasma or serum from exercised mice is sufficient to activate autophagy in cells. By proteomic studies, we identify fibronectin (FN1), which was previously considered as an extracellular matrix protein, as an exercise-induced, muscle-secreted, autophagy-inducing circulating factor. Muscle-secreted FN1 mediates exercise-induced hepatic autophagy and systemic insulin sensitization via the hepatic receptor α5β1 integrin and the downstream IKKα/β-JNK1-BECN1 pathway. Thus, we demonstrate that hepatic autophagy activation drives exercise-induced metabolic benefits against diabetes via muscle-secreted soluble FN1 and hepatic α5β1 integrin signaling.

Keywords:  ATG7; BECN1; autophagy; exercise; fibronectin; insulin sensitivity; integrin; liver; muscle

DOI:  https://doi.org/10.1016/j.cmet.2023.01.011
eNeuro. 2023 Feb 21. pii: ENEURO.0086-22.2023. [Epub ahead of print]

Deletion of Sod1 in motor neurons exacerbates age-related changes in axons and neuromuscular junctions in mice.

N Pollock, P C Macpherson, C A Staunton, K Hemmings, C S Davis, E D Owen, A Vasilaki, H Van Remmen, A Richardson, A McArdle, S V Brooks, M J Jackson.

  Whole body knock out of Cu,Zn superoxide dismutase (Sod1KO) results in accelerated, age-related loss of muscle mass and function associated with neuromuscular junction (NMJ) breakdown similar to sarcopenia. In order to determine whether altered redox in motor neurons underlies this phenotype, an inducible neuron-specific deletion of Sod1 (i-mnSod1KO) was compared with wild type (WT) mice of different ages (adult, mid-age and old) and whole body Sod1KO mice. Nerve oxidative damage, motor neuron numbers and structural changes to neurons and NMJ were examined.Tamoxifen-induced deletion of neuronal Sod1 from 2 months of age. No specific effect of a lack of neuronal Sod1 was seen on markers of nerve oxidation (electron paramagnetic resonance of an in vivo spin probe, protein carbonyl or protein 3-nitrotyrosine contents). i-mnSod1KO mice showed increased denervated NMJ, reduced numbers of large axons and increased number of small axons compared with old WT mice. A large proportion of the innervated NMJs in old i-mnSod1KO mice displayed a simpler structure than that seen in adult or old WT mice.Thus, previous work showed that neuronal deletion of Sod1 induced exaggerated loss of muscle in old mice and we report that this deletion leads to a specific nerve phenotype including reduced axonal area, increased proportion of denervated NMJ and reduced acetyl choline receptor complexity. Other changes in nerve and NMJ structure seen in the old i-mnSod1KO mice reflect ageing of the mice.Significance statementSarcopenia is the age-related loss of muscle mass and function. It is a significant contributor to frailty and to increased falls in the elderly. While multifactorial, changes in redox status have been shown to have significant influence over neuromuscular aging, recent work suggests that changes in motor neurons may be the driving factor in muscle atrophy. The current study confirmed that a specific lack of Sod1 in the motor neuron causes significant alteration in axonal architecture and the neuromuscular junctions which can drive reduced muscle mass and function. Pinpointing early changes in motor neurons may provide therapeutic targets critical for maintaining muscle in the elderly.

Keywords:  axon; motor unit; oxidative stress; skeletal muscle

DOI:  https://doi.org/10.1523/ENEURO.0086-22.2023
Med Sci (Basel). 2023 02 10. pii: 19. [Epub ahead of print]11(1):

Chronic Stress Induces Type 2b Skeletal Muscle Atrophy via the Inhibition of mTORC1 Signaling in Mice.

Shigeko Fushimi, Tsutomu Nohno, Hironobu Katsuyama.

  Chronic stress induces psychological and physiological changes that may have negative sequelae for health and well-being. In this study, the skeletal muscles of male C57BL/6 mice subjected to repetitive water-immersion restraint stress to model chronic stress were examined. In chronically stressed mice, serum corticosterone levels significantly increased, whereas thymus volume and bone mineral density decreased. Further, body weight, skeletal muscle mass, and grip strength were significantly decreased. Histochemical analysis of the soleus muscles revealed a significant decrease in the cross-sectional area of type 2b muscle fibers. Although type 2a fibers also tended to decrease, chronic stress had no impact on type 1 muscle fibers. Chronic stress increased the expression of REDD1, FoxO1, FoxO3, KLF15, Atrogin1, and FKBP5, but did not affect the expression of myostatin or myogenin. In contrast, chronic stress resulted in a decrease in p-S6 and p-4E-BP1 levels in the soleus muscle. Taken together, these results indicate that chronic stress promotes muscle atrophy by inhibiting mammalian targets of rapamycin complex 1 activity due to the upregulation of its inhibitor, REDD1.

Keywords:  REDD1 inhibition; chronic stress; mTORC1 signaling; soleus muscle; type 2b muscle fiber

DOI:  https://doi.org/10.3390/medsci11010019
Proc Natl Acad Sci U S A. 2023 Feb 28. 120(9): e2219346120

Titin activates myosin filaments in skeletal muscle by switching from an extensible spring to a mechanical rectifier.

Caterina Squarci, Pasquale Bianco, Massimo Reconditi, Irene Pertici, Marco Caremani, Theyencheri Narayanan, Ádám I Horváth, András Málnási-Csizmadia, Marco Linari, Vincenzo Lombardi, Gabriella Piazzesi.

  Titin is a molecular spring in parallel with myosin motors in each muscle half-sarcomere, responsible for passive force development at sarcomere length (SL) above the physiological range (>2.7 μm). The role of titin at physiological SL is unclear and is investigated here in single intact muscle cells of the frog (Rana esculenta), by combining half-sarcomere mechanics and synchrotron X-ray diffraction in the presence of 20 μM para-nitro-blebbistatin, which abolishes the activity of myosin motors and maintains them in the resting state even during activation of the cell by electrical stimulation. We show that, during cell activation at physiological SL, titin in the I-band switches from an SL-dependent extensible spring (OFF-state) to an SL-independent rectifier (ON-state) that allows free shortening while resisting stretch with an effective stiffness of ~3 pN nm-1 per half-thick filament. In this way, I-band titin efficiently transmits any load increase to the myosin filament in the A-band. Small-angle X-ray diffraction signals reveal that, with I-band titin ON, the periodic interactions of A-band titin with myosin motors alter their resting disposition in a load-dependent manner, biasing the azimuthal orientation of the motors toward actin. This work sets the stage for future investigations on scaffold and mechanosensing-based signaling functions of titin in health and disease.

Keywords:  muscle regulation; myosin filament activation; skeletal muscle; striated muscle; titin

DOI:  https://doi.org/10.1073/pnas.2219346120
Geroscience. 2023 Feb 23.

Sex differences in skeletal muscle-aging trajectory: same processes, but with a different ranking.

Jelle C B C de Jong, Brecht J Attema, Marjanne D van der Hoek, Lars Verschuren, Martien P M Caspers, Robert Kleemann, Feike R van der Leij, Anita M van den Hoek, Arie G Nieuwenhuizen, Jaap Keijer.

  Sex differences in muscle aging are poorly understood, but could be crucial for the optimization of sarcopenia-related interventions. To gain insight into potential sex differences in muscle aging, we recruited young (23 ± 2 years, 13 males and 13 females) and old (80 ± 3.5 years, 28 males and 26 females) participants. Males and females in both groups were highly matched, and vastus lateralis muscle parameters of old versus young participants were compared for each sex separately, focusing on gene expression. The overall gene expression profiles separated the sexes, but similar gene expression patterns separated old from young participants in males and females. Genes were indeed regulated in the same direction in both sexes during aging; however, the magnitude of differential expression was sex specific. In males, oxidative phosphorylation was the top-ranked differentially expressed process, and in females, this was cell growth mediated by AKT signaling. Findings from RNA-seq data were studied in greater detail using alternative approaches. In addition, we confirmed our data using publicly available data from three independent human studies. In conclusion, top-ranked pathways differ between males and females, but were present and altered in the same direction in both sexes. We conclude that the same processes are associated with skeletal muscle aging in males and females, but the differential expression of those processes in old vs. young participants is sex specific.

Keywords:  AKT signaling; Frailty; Gender; Mitochondria; Myofiber type; Oxidative phosphorylation

DOI:  https://doi.org/10.1007/s11357-023-00750-4
J Physiol. 2023 Feb 22.

The PoWeR of exercise: exploring the anti-ageing effects of exercise through epigenetic modifications to skeletal muscle.

Annabel J Critchlow, Ross M Williams, Sarah E Alexander.

DOI: https://doi.org/10.1113/JP284288
Sci Rep. 2023 Feb 17. 13(1): 2830

The association between muscle architecture and muscle spindle abundance.

Roger W P Kissane, James P Charles, Robert W Banks, Karl T Bates.

Across the human body, skeletal muscles have a broad range of biomechanical roles that employ complex proprioceptive control strategies to successfully execute a desired movement. This information is derived from peripherally located sensory apparatus, the muscle spindle and Golgi tendon organs. The abundance of these sensory organs, particularly muscle spindles, is known to differ considerably across individual muscles. Here we present a comprehensive data set of 119 muscles across the human body including architectural properties (muscle fibre length, mass, pennation angle and physiological cross-sectional area) and statistically test their relationships with absolute spindle number and relative spindle abundance (the residual value of the linear regression of the log-transformed spindle number and muscle mass). These data highlight a significant positive relationship between muscle spindle number and fibre length, emphasising the importance of fibre length as an input into the central nervous system. However, there appears to be no relationship between muscles architecturally optimised to function as displacement specialists and their provision of muscle spindles. Additionally, while there appears to be regional differences in muscle spindle abundance, independent of muscle mass and fibre length, our data provide no support for the hypothesis that muscle spindle abundance is related to anatomical specialisation.

DOI: https://doi.org/10.1038/s41598-023-30044-w
J Gen Physiol. 2023 Apr 03. pii: e202213203. [Epub ahead of print]155(4):

Probenecid affects muscle Ca2+ homeostasis and contraction independently from pannexin channel block.

Francisco Jaque-Fernandez, Bruno Allard, Laloé Monteiro, Aude Lafoux, Corinne Huchet, Enrique Jaimovich, Christine Berthier, Vincent Jacquemond.

Tight control of skeletal muscle contractile activation is secured by the excitation-contraction (EC) coupling protein complex, a molecular machinery allowing the plasma membrane voltage to control the activity of the ryanodine receptor Ca2+ release channel in the sarcoplasmic reticulum (SR) membrane. This machinery has been shown to be intimately linked to the plasma membrane protein pannexin-1 (Panx1). We investigated whether the prescription drug probenecid, a widely used Panx1 blocker, affects Ca2+ signaling, EC coupling, and muscle force. The effect of probenecid was tested on membrane current, resting Ca2+, and SR Ca2+ release in isolated mouse muscle fibers, using a combination of whole-cell voltage-clamp and Ca2+ imaging, and on electrically triggered contraction of isolated muscles. Probenecid (1 mM) induces SR Ca2+ leak at rest and reduces peak voltage-activated SR Ca2+ release and contractile force by 40%. Carbenoxolone, another Panx1 blocker, also reduces Ca2+ release, but neither a Panx1 channel inhibitory peptide nor a purinergic antagonist affected Ca2+ release, suggesting that probenecid and carbenoxolone do not act through inhibition of Panx1-mediated ATP release and consequently altered purinergic signaling. Probenecid may act by altering Panx1 interaction with the EC coupling machinery, yet the implication of another molecular target cannot be excluded. Since probenecid has been used both in the clinic and as a masking agent for doping in sports, these results should encourage evaluation of possible effects on muscle function in treated individuals. In addition, they also raise the question of whether probenecid-induced altered Ca2+ homeostasis may be shared by other tissues.

DOI: https://doi.org/10.1085/jgp.202213203
Aging Dis. 2023 Feb 01. 14(1): 25-32

The Role of Sirtuins in Sarcopenia and Frailty.

Masroor Anwar, Rashmita Pradhan, Sharmistha Dey, Rahul Kumar.

  The population of older individuals is increasing rapidly, but only a small fraction among them is able to experiences a healthy life. Due to lack of physical exercise and oxidative stress, aging leads to sarcopenia and finally end up with frailty. Sarcopenia is a component of the frailty and described as age related degenerative changes in the skeletal muscle mass, strength and quality. Though the loss of muscle strength and mass gradually seem inevitable during aging, it can be partially prevented or overcome by a deeper insight into the pathogenesis. Sirtuin protein leads to longevity across different organisms ranging from worms to mammals. Expression of sirtuin protein increases during physical exercise and thus strengthens muscle mass. Satellite cells leads to muscle repair in a SIRT1 dependent manner. In addition, SIRT1 improves insulin sensitivity and induces autophagy in the aged mice. The current paper discussed the putative role of sirtuins in sarcopenia and frailty. Moreover, it highlighted the pathways by which sirtuins can inhibit ROS production, inflammation and mitochondrial dysfunctions and therefore confers a protective role against frailty and sarcopenia. The critical role of sirtuins in the sarcopenia and frailty pathogenesis can eventually fuel the development of novel interventions by targeting sirtuins.

Keywords:  Aging; Frailty; Oxidative stress; Sarcopenia; Sirtuins

DOI:  https://doi.org/10.14336/AD.2022.0622
Am J Physiol Lung Cell Mol Physiol. 2023 Feb 21.

11β-HSD1 determines the extent of muscle atrophy in a model of acute exacerbation of COPD.

Justine M Webster, Kelsy Waaijenberg, Wouter R P H van de Worp, Marco C J M Kelders, Sara Lambrichts, Claire Martin, Frank Verhaegen, Brent van der Heyden, Charlotte Smith, Gareth G Lavery, Annemie M W J Schols, Rowan S Hardy, Ramon C J Langen.

  Muscle atrophy is an extra-pulmonary complication of acute exacerbations (AE) in chronic obstructive pulmonary disease (COPD). The endogenous production and therapeutic application of glucocorticoids (GCs) have been implicated as drivers of muscle loss in AE-COPD. The enzyme 11 beta-hydroxysteroid dehydrogenase 1 (11β-HSD1) activates GCs and contributes towards GC-induced muscle wasting. To explore the potential of 11βHSD1 inhibition to prevent muscle wasting here, the objective of this study was to ascertain the contribution of endogenous GC activation and amplification by 11βHSD1 in skeletal muscle wasting during AE-COPD. Emphysema was induced by intra-tracheal (IT) instillation of elastase to model COPD in WT and 11βHSD1/KO mice, followed by vehicle or IT-LPS administration to mimic AE. µCT scans were obtained prior and at study endpoint 48h following IT-LPS, to assess emphysema development and muscle mass changes, respectively. Plasma cytokine and GC profiles were determined by ELISA. In vitro myonuclear accretion and cellular response to plasma and GCs were determined in C2C12 and human primary myotubes. Muscle wasting was exacerbated in LPS-11βHSD1/KO animals compared to WT controls. RT-qPCR and western blot analysis showed elevated catabolic and suppressed anabolic pathways in muscle of LPS-11βHSD1/KO animals relative to WTs. Plasma corticosterone levels were higher in LPS-11βHSD1/KO animals, whilst C2C12 myotubes treated with LPS-11βHSD1/KO plasma or exogenous GCs displayed reduced myonuclear accretion relative to WT counterparts. This study reveals that 11β-HSD1 inhibition aggravates muscle wasting in a model of AE-COPD, suggesting that therapeutic inhibition of 11β-HSD1 may not be appropriate to prevent muscle wasting in this setting.

Keywords:  11beta hydroxysteroid dehydrogenase type 1; COPD; Muscle atrophy; glucocorticoids; inflammation

DOI:  https://doi.org/10.1152/ajplung.00009.2022
Antioxidants (Basel). 2023 Feb 16. pii: 501. [Epub ahead of print]12(2):

Endogenous and Exogenous Antioxidants in Skeletal Muscle Fatigue Development during Exercise.

Elżbieta Supruniuk, Jan Górski, Adrian Chabowski.

  Muscle fatigue is defined as a decrease in maximal force or power generated in response to contractile activity, and it is a risk factor for the development of musculoskeletal injuries. One of the many stressors imposed on skeletal muscle through exercise is the increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which intensifies as a function of exercise intensity and duration. Exposure to ROS/RNS can affect Na+/K+-ATPase activity, intramyofibrillar calcium turnover and sensitivity, and actin-myosin kinetics to reduce muscle force production. On the other hand, low ROS/RNS concentrations can likely upregulate an array of cellular adaptative responses related to mitochondrial biogenesis, glucose transport and muscle hypertrophy. Consequently, growing evidence suggests that exogenous antioxidant supplementation might hamper exercise-engendering upregulation in the signaling pathways of mitogen-activated protein kinases (MAPKs), peroxisome-proliferator activated co-activator 1α (PGC-1α), or mammalian target of rapamycin (mTOR). Ultimately, both high (exercise-induced) and low (antioxidant intervention) ROS concentrations can trigger beneficial responses as long as they do not override the threshold range for redox balance. The mechanisms underlying the two faces of ROS/RNS in exercise, as well as the role of antioxidants in muscle fatigue, are presented in detail in this review.

Keywords:  antioxidants; exercise; muscle fatigue; oxidative stress

DOI:  https://doi.org/10.3390/antiox12020501
Sci Signal. 2023 Feb 21. 16(773): eabn0782

Optogenetic decoding of Akt2-regulated metabolic signaling pathways in skeletal muscle cells using transomics analysis.

Genki Kawamura, Toshiya Kokaji, Kentaro Kawata, Yuka Sekine, Yutaka Suzuki, Tomoyoshi Soga, Yoshibumi Ueda, Mizuki Endo, Shinya Kuroda, Takeaki Ozawa.

Insulin regulates various cellular metabolic processes by activating specific isoforms of the Akt family of kinases. Here, we elucidated metabolic pathways that are regulated in an Akt2-dependent manner. We constructed a transomics network by quantifying phosphorylated Akt substrates, metabolites, and transcripts in C2C12 skeletal muscle cells with acute, optogenetically induced activation of Akt2. We found that Akt2-specific activation predominantly affected Akt substrate phosphorylation and metabolite regulation rather than transcript regulation. The transomics network revealed that Akt2 regulated the lower glycolysis pathway and nucleotide metabolism and cooperated with Akt2-independent signaling to promote the rate-limiting steps in these processes, such as the first step of glycolysis, glucose uptake, and the activation of the pyrimidine metabolic enzyme CAD. Together, our findings reveal the mechanism of Akt2-dependent metabolic pathway regulation, paving the way for Akt2-targeting therapeutics in diabetes and metabolic disorders.

DOI: https://doi.org/10.1126/scisignal.abn0782
Biology (Basel). 2023 Feb 17. pii: 325. [Epub ahead of print]12(2):

Effect of Zbed6 Single-Allele Knockout on the Growth and Development of Skeletal Muscle in Mice.

Ling Liu, Shengnan Wang, Wenjie Tian, Cheng Xu, Chengjie Wei, Kai Cui, Lin Jiang, Dandan Wang.

  ZBED6, a key transcription factor, plays an important role in skeletal muscle and organ growth. ZBED6 knockout (ZBED6-/-) leads to the upregulation of IGF2 in pig and mice muscle, thereby increasing muscle mass. However, the effects and mechanism of Zbed6 single-allele knockout (Zbed6+/-) on mice muscle remain unknown. Here, we reported that Zbed6+/- promotes muscle growth by a new potential target gene rather than Igf2 in mice muscle. Zbed6+/- mice showed markedly higher muscle mass (25%) and a markedly higher muscle weight ratio (18%) than wild-type (WT) mice, coinciding with a larger muscle fiber area (28%). Despite a significant increase in muscle growth, Zbed6+/- mice showed similar Igf2 expression with WT mice, indicating that a ZBED6-Igf2-independent regulatory pathway exists in Zbed6+/- mice muscle. RNA-seq of muscle between the Zbed6+/- and WT mice revealed two terms related to muscle growth. Overlapping the DEGs and C2C12 Chip-seq data of ZBED6 screened out a potential ZBED6 target gene Barx2, which may regulate muscle growth in Zbed6+/- mice. These results may open new research directions leading to a better understanding of the integral functions of ZBED6 and provide evidence of Zbed6+/- promoting muscle growth by regulating Barx2 in mice.

Keywords:  BARX2; IGF2; ZBED6; mice; single-allele knockout; skeletal muscle

DOI:  https://doi.org/10.3390/biology12020325
JCI Insight. 2023 Feb 23. pii: e162835. [Epub ahead of print]

Spatiotemporal mapping of immune and stem cell dysregulation after volumetric muscle loss.

Jacqueline A Larouche, Emily C Wallace, Bonnie D Spence, Eric Buras, Carlos A Aguilar.

  Volumetric muscle loss (VML) is an acute trauma that results in persistent inflammation, supplantation of muscle tissue with fibrotic scarring, and decreased muscle function. The cell types, nature of cellular communication, and tissue locations that drive the aberrant VML response have remained elusive. Herein, we used spatial transcriptomics on a mouse model of VML and observed VML engenders a unique spatial pro-fibrotic pattern driven by crosstalk between fibrotic and inflammatory macrophages and mesenchymal derived cells. The dysregulated response impinged on muscle stem cell mediated repair, and targeting this circuit resulted in increased regeneration and reductions in inflammation and fibrosis. Collectively, these results enhance our understanding of the cellular crosstalk that drives aberrant regeneration and provides further insight into possible avenues for fibrotic therapy exploration.

Keywords:  Adult stem cells; Fibrosis; Muscle Biology; Skeletal muscle; Stem cells

DOI:  https://doi.org/10.1172/jci.insight.162835
Physiol Rep. 2023 Feb;11(4): e15536

A role for β-catenin in diet-induced skeletal muscle insulin resistance.

Stewart W C Masson, Waruni C Dissanayake, Sophie C Broome, Christopher P Hedges, Wouter M Peeters, Martin Gram, David S Rowlands, Peter R Shepherd, Troy L Merry.

  A central characteristic of insulin resistance is the impaired ability for insulin to stimulate glucose uptake into skeletal muscle. While insulin resistance can occur distal to the canonical insulin receptor-PI3k-Akt signaling pathway, the signaling intermediates involved in the dysfunction are yet to be fully elucidated. β-catenin is an emerging distal regulator of skeletal muscle and adipocyte insulin-stimulated GLUT4 trafficking. Here, we investigate its role in skeletal muscle insulin resistance. Short-term (5-week) high-fat diet (HFD) decreased skeletal muscle β-catenin protein expression 27% (p = 0.03), and perturbed insulin-stimulated β-cateninS552 phosphorylation 21% (p = 0.009) without affecting insulin-stimulated Akt phosphorylation relative to chow-fed controls. Under chow conditions, mice with muscle-specific β-catenin deletion had impaired insulin responsiveness, whereas under HFD, both mice exhibited similar levels of insulin resistance (interaction effect of genotype × diet p < 0.05). Treatment of L6-GLUT4-myc myocytes with palmitate lower β-catenin protein expression by 75% (p = 0.02), and attenuated insulin-stimulated β-catenin phosphorylationS552 and actin remodeling (interaction effect of insulin × palmitate p < 0.05). Finally, β-cateninS552 phosphorylation was 45% lower in muscle biopsies from men with type 2 diabetes while total β-catenin expression was unchanged. These findings suggest that β-catenin dysfunction is associated with the development of insulin resistance.

Keywords:  Wnt-signaling; glucose transport; insulin resistance; obesity

DOI:  https://doi.org/10.14814/phy2.15536
Antioxidants (Basel). 2023 Jan 31. pii: 331. [Epub ahead of print]12(2):

BMP-7 Attenuates Sarcopenia and Adverse Muscle Remodeling in Diabetic Mice via Alleviation of Lipids, Inflammation, HMGB1, and Pyroptosis.

Chandrakala Aluganti Narasimhulu, Dinender K Singla.

  Diabetic myopathy involves hyperglycemia, oxidative stress, and inflammation. However, the role of hypercholesterolemia-induced inflammation-mediated pathological mechanisms leading to fibrosis, sarcopenia, deterioration of muscle, and muscle dysfunction in diabetes is not well understood. In this study, we investigated the novel role of bone morphogenetic protein-7 (BMP-7) in ameliorating metabolic alterations, inflammation, pyroptosis, TGF-β/SMAD cell signaling mechanisms, and progression of diabetic myopathy. C57BL/6J mice were treated with saline, streptozotocin (STZ), or STZ+BMP-7. Diabetes was confirmed by increased fasting glucose levels and a glucose tolerance test. Gastrocnemius muscle and blood samples were collected for lipid and tissue analysis using various methods. A significant increase in hyperglycemia resulted in an increase in lipid accumulation, monocyte infiltration, and inflammation, as well as an increase in pyroptotic markers and signaling markers in diabetic muscle myocytes. A structural analysis showed significant muscle loss, and increased muscle deterioration and fibrosis leading to muscle dysfunction. BMP-7 attenuated pathological processes that resulted in significantly improved muscle function. We report, for the first time, that increased hyperlipidemia aggravates inflammation-induced pyroptosis, resulting in significant muscle loss, sarcopenia, and adverse skeletal muscle remodeling in diabetic muscle myopathy. Interventional treatment with BMP-7 attenuates hypercholesterolemia-induced inflammation-mediated sarcopenia and adverse muscle remodeling, suggesting BMP-7 could be a potential treatment option for diabetic muscle myopathy.

Keywords:  cell death; diabetic myopathy; inflammasome; inflammation; muscle atrophy

DOI:  https://doi.org/10.3390/antiox12020331
Geriatr Gerontol Int. 2023 Feb 22.

Accumulation of polyunsaturated fatty acid-derived metabolites in the sarcopenic muscle of aging mice.

Tomoyasu Kadoguchi, Kazunori Shimada, Naoshi Fukui, Nobuho Tanaka, Hirotaka Tsuno, Tomoyuki Shiozawa, Kosuke Fukao, Miho Nishitani-Yokoyama, Kikuo Isoda, Satoshi Matsushita, Norihiko Yokoyama, Hiroyuki Daida.

   AIM: Although it is known that advanced age alters skeletal muscle lipid metabolism, the role(s) of polyunsaturated fatty acid-derived metabolites (mostly eicosanoids and docosanoids) in sarcopenia are not clear. We therefore examined the changes in the metabolites of arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid in the sarcopenic muscle of aged mice.
METHODS: We used 6- and 24-month-old male C57BL/6J mice as healthy and sarcopenic muscle models, respectively. Skeletal muscles were removed from the lower limb and subjected to a liquid chromatography-tandem mass spectrometry analysis.
RESULTS: The liquid chromatography-tandem mass spectrometry analysis detected distinct changes of metabolites in the muscles of the aged mice. Of the 63 metabolites identified, nine were significantly higher in the sarcopenic muscle of aged mice compared with the healthy muscle of young mice. In particular, prostaglandin E2 , prostaglandin F2a , thromboxane B2 , 5-hydroxyeicosatetraenoic acid, and 15-oxo-eicosatetraenoic acid (arachidonic acid-derived metabolites), 12-hydroxy-eicosapentaenoic acid and 14,15-epoxy-eicosatetraenoic acid (eicosapentaenoic acid-derived metabolites) and 10-hydroxydocosa-hexaenoic acid and 14-hydroxyoctadeca-pentaenoic acid (docosahexaenoic acid-derived metabolites) were significantly higher in aged tissue compared with young tissue (all P < 0.05).
CONCLUSIONS: We observed the accumulation of metabolites in the sarcopenic muscle of aged mice. Our results may provide new insights into the pathogenesis and progression of aging- or disease-related sarcopenia. Geriatr Gerontol Int ••; ••: ••-•• Geriatr Gerontol Int 2023; ••: ••-••.

Keywords:  aging; basic science; lipid mediators; molecular biology; pathology; skeletal muscle

DOI:  https://doi.org/10.1111/ggi.14561
J Nutr. 2023 Feb 21. pii: S0022-3166(23)12680-0. [Epub ahead of print]

VEGAN AND OMNIVOROUS HIGH PROTEIN DIETS SUPPORT COMPARABLE DAILY MYOFIBRILLAR PROTEIN SYNTHESIS RATES AND SKELETAL MUSCLE HYPERTROPHY IN YOUNG ADULTS.

Alistair J Monteyne, Mariana Oc Coelho, Andrew J Murton, Doaa R Abdelrahman, Jamie R Blackwell, Christopher P Koscien, Karen M Knapp, Jonathan Fulford, Tim Ja Finnigan, Marlou L Dirks, Francis B Stephens, Benjamin T Wall.

   INTRODUCTION: It remains unclear whether non-animal-derived dietary protein sources (and therefore vegan diets) can support resistance training-induced skeletal muscle remodelling to the same extent as animal-derived protein sources METHODS: In Phase 1, 16 healthy young adults (m=8, f=8; age: 23±1 y; BMI: 23±1 kg/m2) completed a three-day dietary intervention (high protein, 1.8 g·kg bm-1·day-1) where protein was derived from omnivorous (OMNI1; n=8) or exclusively non-animal (VEG1; n=8) sources, alongside daily unilateral leg resistance exercise. Resting and exercised daily myofibrillar protein synthesis (MyoPS) rates were assessed using deuterium oxide. In Phase 2, 22 healthy young adults (m=11, f=11; age: 24±1 y; BMI: 23±0 kg/m2) completed a 10 week, high-volume (5 d/week), progressive resistance exercise programme whilst consuming an omnivorous (OMNI2; n=12) or non-animal-derived (VEG2; n=10) high-protein diet (∼2 g·kg bm-1·day-1). Muscle fiber cross sectional area (CSA), whole-body lean mass (via DXA), thigh muscle volume (via MRI), muscle strength and muscle function were determined pre, after two (W2) and five (W5) weeks, and post-intervention RESULTS: Daily myofibrillar protein synthesis rates were ∼12% higher in the exercised compared with rested leg (2.20±0.33 vs 2.46±0.27 %·d-1 and 2.36±0.53 vs 2.62±0.56 %·d-1in OMNI1 and VEG1, respectively; P<0.001) and not different between groups (P>0.05). Resistance training increased lean mass in both groups by a similar magnitude (OMNI2 2.6±1.1 kg, VEG2 3.1±2.5 kg; P>0.05). Likewise, training comparably increased thigh muscle volume (OMNI2 8.3±3.6%, VEG2 8.3±.4.1%; P>0.05), and muscle fiber CSA (OMNI2 33±24%, VEG2 32±48%; P>0.05). Both groups increased strength (1-RM) of multiple muscle groups, to comparable degrees CONCLUSION: Omnivorous and vegan diets can support comparable rested and exercised daily myofibrillar protein synthesis rates in healthy young adults consuming a high-protein diet. This translates to similar skeletal muscle adaptive responses during prolonged high-volume resistance training irrespective of dietary protein provenance.

Keywords:  Mycoprotein; hypertrophy; muscle protein synthesis; resistance exercise

DOI:  https://doi.org/10.1016/j.tjnut.2023.02.023
Nat Commun. 2023 Feb 21. 14(1): 949

Time-restricted feeding promotes muscle function through purine cycle and AMPK signaling in Drosophila obesity models.

Christopher Livelo, Yiming Guo, Farah Abou Daya, Vasanthi Rajasekaran, Shweta Varshney, Hiep D Le, Stephen Barnes, Satchidananda Panda, Girish C Melkani.

Obesity caused by genetic and environmental factors can lead to compromised skeletal muscle function. Time-restricted feeding (TRF) has been shown to prevent muscle function decline from obesogenic challenges; however, its mechanism remains unclear. Here we demonstrate that TRF upregulates genes involved in glycine production (Sardh and CG5955) and utilization (Gnmt), while Dgat2, involved in triglyceride synthesis is downregulated in Drosophila models of diet- and genetic-induced obesity. Muscle-specific knockdown of Gnmt, Sardh, and CG5955 lead to muscle dysfunction, ectopic lipid accumulation, and loss of TRF-mediated benefits, while knockdown of Dgat2 retains muscle function during aging and reduces ectopic lipid accumulation. Further analyses demonstrate that TRF upregulates the purine cycle in a diet-induced obesity model and AMPK signaling-associated pathways in a genetic-induced obesity model. Overall, our data suggest that TRF improves muscle function through modulations of common and distinct pathways under different obesogenic challenges and provides potential targets for obesity treatments.

DOI: https://doi.org/10.1038/s41467-023-36474-4
bioRxiv. 2023 Feb 15. pii: 2023.02.15.528714. [Epub ahead of print]

Gene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging.

James R Occean, Na Yang, Yan Sun, Marshall S Dawkins, Rachel Munk, Cedric Belair, Showkat Dar, Carlos Anerillas, Lin Wang, Changyou Shi, Christopher Dunn, Michel Bernier, Nathan L Price, Julie S Kim, Chang-Yi Cui, Jinshui Fan, Moitrayee Bhattacharyya, Supriyo De, Manolis Maragkakis, Rafael deCabo, Simone Sidoli, Payel Sen.

DNA hydroxymethylation (5hmC) is the most abundant oxidative derivative of DNA methylation (5mC) and is typically enriched at enhancers and gene bodies of transcriptionally active and tissue-specific genes. Although aberrant genomic 5hmC has been implicated in many age-related diseases, the functional role of the modification in aging remains largely unknown. Here, we report that 5hmC is stably enriched in multiple aged organs. Using the liver and cerebellum as model organs, we show that 5hmC accumulates in gene bodies associated with tissue-specific function and thereby restricts the magnitude of gene expression changes during aging. Mechanistically, we found that 5hmC decreases binding affinity of splicing factors compared to unmodified cytosine and 5mC, and is correlated with age-related alternative splicing events, suggesting RNA splicing as a potential mediator of 5hmCâ€™s transcriptionally restrictive function. Furthermore, we show that various age-related contexts, such as prolonged quiescence and senescence, are partially responsible for driving the accumulation of 5hmC with age. We provide evidence that this age-related function is conserved in mouse and human tissues, and further show that the modification is altered by regimens known to modulate lifespan. Our findings reveal that 5hmC is a regulator of tissue-specific function and may play a role in regulating longevity.

DOI: https://doi.org/10.1101/2023.02.15.528714
Biomedicines. 2023 Jan 17. pii: 234. [Epub ahead of print]11(2):

Sex-Specific Patterns of Diaphragm Phospholipid Content and Remodeling during Aging and in a Model of SELENON-Related Myopathy.

Rezlène Bargui, Audrey Solgadi, Florent Dumont, Bastien Prost, Nathalie Vadrot, Anne Filipe, Andrew T V Ho, Ana Ferreiro, Maryline Moulin.

  Growing evidence shows that the lipid bilayer is a key site for membrane interactions and signal transduction. Surprisingly, phospholipids have not been widely studied in skeletal muscles, although mutations in genes involved in their biosynthesis have been associated with muscular diseases. Using mass spectrometry, we performed a phospholipidomic profiling in the diaphragm of male and female, young and aged, wild type and SelenoN knock-out mice, the murine model of an early-onset inherited myopathy with severe diaphragmatic dysfunction. We identified 191 phospholipid (PL) species and revealed an important sexual dimorphism in PLs in the diaphragm, with almost 60% of them being significantly different between male and female animals. In addition, 40% of phospholipids presented significant age-related differences. Interestingly, SELENON protein absence was responsible for remodeling of 10% PL content, completely different in males and in females. Expression of genes encoding enzymes involved in PL remodeling was higher in males compared to females. These results establish the diaphragm PL map and highlight an important PL remodeling pattern depending on sex, aging and partly on genotype. These differences in PL profile may contribute to the identification of biomarkers associated with muscular diseases and muscle aging.

Keywords:  aging; cardiolipin; mass spectrometry; myopathy; phospholipid; selenoprotein N; sexual dimorphism; sphingomyelin

DOI:  https://doi.org/10.3390/biomedicines11020234
Acta Physiol (Oxf). 2023 Feb 23. e13953

When should I run - the role of exercise timing in metabolic health.

Henriette Kirchner, Leon Weisner, Britta Wilms.

  The prevalence of type 2 diabetes is reaching epidemic proportions. First line therapy approaches are lifestyle interventions including exercise. Although a vast amount of studies reports on beneficial effects of exercise on metabolism in humans per se, overall data are contradictory which makes it difficult to optimize interventions. Innovative exercise strategies and its underlying mechanism are needed to elucidate in order to close this therapeutic gap. The skeletal muscle produces and secretes myokines and microRNAs in response to exercise and both are discussed as mechanisms linking exercise and metabolic adaptation. Aspects of chronophysiology such as diurnal variation in insulin sensitivity or exercise as a signal to reset dysregulated peripheral clocks are of growing interest in the context of impaired metabolism. Deep insight of how exercise timing determines metabolic adaptations is required to optimize exercise interventions. This review aims to summarize the current state of research on the interaction between timing of exercise and metabolism in humans, providing insights into proposed mechanistic concepts focusing on myokines and microRNAs. First evidence points to an impact of timing of exercise on health outcome, although data are inconclusive. Underlying mechanisms remain elusive. It is currently unknown if the timed release of mykokines depends on time of day when exercise is performed. miRNAs have been found as an important mediator of processes associated with exercise adaptation. Further research is needed to evaluate their full relevance. In conclusion, it seems to be too early to provide concrete recommendations on timing of exercise to maximize beneficial effects.

Keywords:  chronophysiology; exercise; metabolic disease; miRNA; myokines; physical activity; timing

DOI:  https://doi.org/10.1111/apha.13953
Cells. 2023 Feb 06. pii: 527. [Epub ahead of print]12(4):

Extracellular Vesicles in Aging: An Emerging Hallmark?

Giorgia Manni, Sandra Buratta, Maria Teresa Pallotta, Davide Chiasserini, Alessandro Di Michele, Carla Emiliani, Stefano Giovagnoli, Luisa Pascucci, Rita Romani, Ilaria Bellezza, Lorena Urbanelli, Francesca Fallarino.

  Extracellular vesicles (EVs) are membrane-enclosed particles secreted by cells and circulating in body fluids. Initially considered as a tool to dispose of unnecessary material, they are now considered an additional method to transmit cell signals. Aging is characterized by a progressive impairment of the physiological functions of tissues and organs. The causes of aging are complex and interconnected, but there is consensus that genomic instability, telomere erosion, epigenetic alteration, and defective proteostasis are primary hallmarks of the aging process. Recent studies have provided evidence that many of these primary stresses are associated with an increased release of EVs in cell models, able to spread senescence signals in the recipient cell. Additional investigations on the role of EVs during aging also demonstrated the great potential of EVs for the modulation of age-related phenotypes and for pro-rejuvenation therapies, potentially beneficial for many diseases associated with aging. Here we reviewed the current literature on EV secretion in senescent cell models and in old vs. young individual body fluids, as well as recent studies addressing the potential of EVs from different sources as an anti-aging tool. Although this is a recent field, the robust consensus on the altered EV release in aging suggests that altered EV secretion could be considered an emerging hallmark of aging.

Keywords:  aging; extracellular vesicles (EVs); senescence; senescence-associated secretory phenotype (SASP)

DOI:  https://doi.org/10.3390/cells12040527
Cell Death Discov. 2023 Feb 24. 9(1): 76

TNF-α contributes to sarcopenia through caspase-8/caspase-3/GSDME-mediated pyroptosis.

Jingying Wu, Siming Lin, Weixiao Chen, Guili Lian, Weibin Wu, Ai Chen, Mohammad Ismail Hajary Sagor, Li Luo, Huajun Wang, Liangdi Xie.

Sarcopenia has become a leading cause of disability and mortality in the elderly. It has been reported that programmed cell death (PCD) is associated with the development of sarcopenia that is characterized by reduction of muscle fiber size and number. TNF-α is also validated to play a prominent role in sarcopenia through its complex signaling pathways including cell death signaling. However, it is still unclear whether TNF-α contributes to sarcopenia by mediating pyroptosis, one type of PCD. Here, we first established naturally aged mice with sarcopenia model and confirmed an inflammatory state represented by TNF-α in aged mice. Evidence of GSDME-mediated pyroptosis and activation of apoptotic caspase-8/-3 were also found in skeletal muscle cells of aged mice with sarcopenia. We demonstrated that TNF-α triggered GSDME-mediated pyroptosis in myotubes through activating caspase-8 and caspase-3 by using caspase-8 and caspase-3 inhibitors. Comparing the activation of caspase-8 and GSDME expression between TNF Complex IIa and TNF Complex IIb, TNF-α was found to be more inclined to assemble TNF Complex IIb in activating caspase-8 and triggering pyroptosis. Moreover, pyroptotic myotubes were validated to result in decreased expression of MHC1 and finally loss of myotubes by knockdown of GSDME. Our work reveals a novel mechanism that TNF-ɑ/caspase-8/caspase-3/GSDME signaling-mediated pyroptosis contributes to the development of sarcopenia. Caspase-3/GSDME signaling-mediated pyroptosis may be a promising therapeutic target for sarcopenia.

DOI: https://doi.org/10.1038/s41420-023-01365-6
Int Immunopharmacol. 2023 Feb 18. pii: S1567-5769(23)00102-9. [Epub ahead of print]117 109779

Inhibition of DDX3X alleviates persistent inflammation, immune suppression and catabolism syndrome in a septic mice model.

Yukun Liu, Yongsheng Zhang, Chuntao Wang, Qinxin Liu, Tianyu Li, Wei Wang, Fan Yang, Zhanfei Li, Xiangjun Bai, Yuchang Wang.

   OBJECTIVE: DDX3X is involved in various pathological processes such as infection, immunity and cell death. This study aimed to investigate the effect of RK-33, a specific inhibitor of DDX3X, on the progression of sepsis to persistent inflammation, immune suppression and catabolism syndrome(PICS).
METHODS: The septic mice model was established using caecal ligation and perforation (CLP). The mice were randomly divided into four groups: sham group, sham + RK-33 group (20 mg/kg, intraperitoneal injection, once a day), CLP group and CLP + RK-33 group (20 mg/kg, intraperitoneal injection, once a day). The number of inflammatory cells in the peripheral blood, spleen and bone marrow was calculated, and inflammatory cytokines were detected using an enzyme-linked immunosorbent assay. The septic mice's body weight and skeletal muscle mass were measured, and skeletal muscle tissues were examined using eosin staining. Western blotting was performed to detect the expression levels of MuRF1, atrogin1 and NLRP3 in the skeletal muscle of septic mice. Additionally, reactive oxidative species, superoxide dismutase and malondialdehyde were measured using commercial kits.
RESULTS: RK-33 reduced inflammatory cell counts and cytokine levels in CLP mice, ameliorated the decline in CD4 and CD8 T cells and prevented the loss of body weight and skeletal muscle mass in septic mice. Additionally, RX-33 reduced oxidative stress in the skeletal muscle of septic mice.
CONCLUSION: In the established sepsis mouse model, RK-33 alleviated inflammation and oxidative stress, ameliorated CLP-induced immunosuppression and skeletal muscle atrophy and improved survival. These findings suggest that RK-33 could be a novel potential therapeutic agent for preventing the progression of sepsis to PICS.

Keywords:  DDX3X; NLRP3; PICS; Sepsis; Skeletal muscle atrophy; T cells

DOI:  https://doi.org/10.1016/j.intimp.2023.109779
Dev Cell. 2023 Feb 09. pii: S1534-5807(23)00038-2. [Epub ahead of print]

Rab8a as a mitochondrial receptor for lipid droplets in skeletal muscle.

Qian Ouyang, Qiaoli Chen, Shunyuan Ke, Longfei Ding, Xinyu Yang, Ping Rong, Weikuan Feng, Ye Cao, Qi Wang, Min Li, Shu Su, Wen Wei, Minjun Liu, Jin Liu, Xu Zhang, John Zhong Li, Hong-Yu Wang, Shuai Chen.

  Dynamic interaction between lipid droplets (LDs) and mitochondria controls the mobilization of long-chain fatty acids (LCFAs) from LDs for mitochondrial β-oxidation in skeletal muscle in response to energy stress. However, little is known about the composition and regulation of the tethering complex mediating LD-mitochondrion interaction. Here, we identify Rab8a as a mitochondrial receptor for LDs forming the tethering complex with the LD-associated PLIN5 in skeletal muscle. In rat L6 skeletal muscle cells, the energy sensor AMPK increases the GTP-bound active Rab8a that promotes LD-mitochondrion interaction through binding to PLIN5 upon starvation. The assembly of the Rab8a-PLIN5 tethering complex also recruits the adipose triglyceride lipase (ATGL), which couples LCFA mobilization from LDs with its transfer into mitochondria for β-oxidation. Rab8a deficiency impairs fatty acid utilization and decreases endurance during exercise in a mouse model. These findings may help to elucidate the regulatory mechanisms underlying the beneficial effects of exercise on lipid homeostasis control.

Keywords:  AMPK; Rab8a; energy metabolism; exercise; fatty acid oxidation; lipid droplets; mitochondria; organelle interaction; skeletal muscle

DOI:  https://doi.org/10.1016/j.devcel.2023.01.007