bims-moremu 2024-08-18 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2024–08–18
29 papers selected by
Anna Vainshtein, Craft Science Inc.

Alterations of the skeletal muscle nuclear proteome after acute exercise reveals a post-transcriptional influence.
microRNA-1 Regulates Metabolic Flexibility in Skeletal Muscle via Pyruvate Metabolism.
Autophagy in Skeletal Muscle.
Genetic Deletion of Skeletal Muscle Inositol Polyphosphate Multikinase Disrupts Glucose Homeostasis and Impairs Exercise Tolerance.
FUS-Mediated Inhibition of Myogenesis Elicited by Suppressing TNNT1 Production.
Zfp697 is an RNA-binding protein that regulates skeletal muscle inflammation and remodeling.
Satellite cell-derived TRIM28 is pivotal for mechanical load- and injury-induced myogenesis.
Intrinsic Skeletal Muscle Function and Contraction-stimulated Glucose Uptake Do Not Vary by Time-of-day in Mice.
Exercise-specific adaptations in human skeletal muscle: Molecular mechanisms of making muscles fit and mighty.
Conditioned medium of human mesenchymal stromal/stem cells cultured on decellularized extracellular matrix promotes murine skeletal muscle repair after acute injury.
Decoding the decline: unveiling drivers of sarcopenia.
Secondary mitochondrial dysfunction across the spectrum of hereditary and acquired muscle disorders.
TAM-associated CASQ1 mutants diminish intracellular Ca2+ content and interfere with regulation of SOCE.
Mouse sarcopenia model reveals sex- and age-specific differences in phenotypic and molecular characteristics.
The Diversity of Skeletal Muscle Fiber Types.
"Unlocking Athletic Potential: Exploring Exercise Physiology from Mechanisms to Performance". Acute antioxidant supplementation and performance - should this be considered.
Loss of NAMPT and SIRT2 but not SIRT1 attenuate GLO1 expression and activity in human skeletal muscle.
Remodeling p38 signaling in muscle controls locomotor activity via IL-15.
GLUD1 determines murine muscle stem cell fate by controlling mitochondrial glutamate levels.
Mild cold stress at ambient temperature elevates muscle calcium cycling and exercise adaptations in obese female mice.
Myostatin's marvels: From muscle regulator to diverse implications in health and disease.
Epigenetics of Skeletal Muscle Atrophy.
BK channels promote action potential repolarization in skeletal muscle but contribute little to myotonia.
Calorie restriction and rapamycin distinctly mitigate aging-associated protein phosphorylation changes in mouse muscles.
JAK inhibition with tofacitinib rapidly increases contractile force in human skeletal muscle.
The Myotendinous Junction-Form and Function.
Applying technologies to simplify strategies for exercise in type 1 diabetes.
Physiological mechanisms contributing to human exercise performance.
Whole body resistance training on functional outcomes of patients with Stage 4 or 5 chronic kidney disease: A systematic review.

bioRxiv. 2024 Aug 09. pii: 2024.08.08.607176. [Epub ahead of print]

Alterations of the skeletal muscle nuclear proteome after acute exercise reveals a post-transcriptional influence.

Ryan A Martin, Mark R Viggars, James A Sanford, Zane W Taylor, Joshua R Hansen, Geremy C Clair, Joshua N Adkins, Collin M Douglas, Karyn A Esser.

Exercise is firmly established as a key contributor to overall well-being and is frequently employed as a therapeutic approach to mitigate various health conditions. One pivotal aspect of the impact of exercise lies in the systemic transcriptional response, which underpins its beneficial adaptations. While extensive research has been devoted to understanding the transcriptional response to exercise, our knowledge of the protein constituents of nuclear processes that accompany gene expression in skeletal muscle remains largely elusive. We hypothesize that alterations in the nuclear proteome following exercise hold vital clues for comprehending the transcriptional regulation and other related nuclear functions. We isolated skeletal muscle nuclei from C57BL/6 mice both sedentary control and one-hour post 30-minute treadmill running, to gain insights into the nuclear proteome after exercise. A substantial number of the 2,323 proteins identified, were related to nuclear functions. For instance, we found 59 proteins linked to nucleocytoplasmic transport were higher in sedentary mice compared to exercise, hinting at an exercise-induced modulation to nuclear trafficking. Furthermore, 135 proteins exhibited increased abundance after exercise (FDR < 0.1) while 89 proteins decreased, with the most prominent changes in proteins linked to mRNA processing and splicing. Super resolution microscopy further highlights potential localization change in mRNA processing proteins post-exercise, further suggesting changes in nuclear transport dynamics. Nonetheless, our data provide important considerations for the study of the nuclear proteome and supports a paradigm through which exercise downregulated mRNA processing and splicing, offering valuable insights into the broader landscape of the impact from acute exercise.
New & Noteworthy: Exercise plays a crucial role in promoting muscle health, but our understanding of nuclear proteins orchestrating exercise responses is limited. Isolation of skeletal muscle nuclei coupled with mass spectrometry enhanced the identification of nuclear proteins. This approach was used to investigate the effects of acute exercise, revealing changes in the muscle nuclear proteome 1-hour post-exercise, including proteins linked to post-transcriptional processing and splicing. Our findings offer insights into the exercise-induced changes within muscle nuclear proteins.

DOI: https://doi.org/10.1101/2024.08.08.607176
bioRxiv. 2024 Aug 10. pii: 2024.08.09.607377. [Epub ahead of print]

microRNA-1 Regulates Metabolic Flexibility in Skeletal Muscle via Pyruvate Metabolism.

Ahmed Ismaeel, Bailey D Peck, McLane M Montgomery, Benjamin I Burke, Jensen Goh, Gyumin Kang, Abigail B Franco, Qin Xia, Katarzyna Goljanek-Whysall, Brian McDonagh, Jared M McLendon, Pieter J Koopmans, Daniel Jacko, Kirill Schaaf, Wilhelm Bloch, Sebastian Gehlert, Yuan Wen, Kevin A Murach, Charlotte A Peterson, Ryan L Boudreau, Kelsey H Fisher-Wellman, John J McCarthy.

MicroRNA-1 (miR-1) is the most abundant miRNA in adult skeletal muscle. To determine the function of miR-1 in adult skeletal muscle, we generated an inducible, skeletal muscle-specific miR-1 knockout (KO) mouse. Integration of RNA-sequencing (RNA-seq) data from miR-1 KO muscle with Argonaute 2 enhanced crosslinking and immunoprecipitation sequencing (AGO2 eCLIP-seq) from human skeletal muscle identified miR-1 target genes involved with glycolysis and pyruvate metabolism. The loss of miR-1 in skeletal muscle induced cancer-like metabolic reprogramming, as shown by higher pyruvate kinase muscle isozyme M2 (PKM2) protein levels, which promoted glycolysis. Comprehensive bioenergetic and metabolic phenotyping combined with skeletal muscle proteomics and metabolomics further demonstrated that miR-1 KO induced metabolic inflexibility as a result of pyruvate oxidation resistance. While the genetic loss of miR-1 reduced endurance exercise performance in mice and in C. elegans, the physiological down-regulation of miR-1 expression in response to a hypertrophic stimulus in both humans and mice causes a similar metabolic reprogramming that supports muscle cell growth. Taken together, these data identify a novel post-translational mechanism of adult skeletal muscle metabolism regulation mediated by miR-1.

DOI: https://doi.org/10.1101/2024.08.09.607377
Cold Spring Harb Perspect Biol. 2024 Aug 12. pii: a041565. [Epub ahead of print]

Autophagy in Skeletal Muscle.

Anais Franco-Romero, Marco Sandri, Stefano Schiaffino.

Skeletal muscle fibers possess, like all cells of our body, an evolutionary conserved autophagy machinery, which allows them to segregate unfolded proteins and damaged organelles within autophagosomes, and to induce fusion of autophagosomes with lysosomes, leading to degradation of those altered cell constituents. This process may be selective for specific cell components, as in the case of glycogen (glycophagy) or organelles, as with mitochondria (mitophagy). The autophagic flux is activated by fasting, and contributes with the proteasome to provide the organism with amino acids required for survival. Autophagy is also essential for the normal turnover of muscle proteins and organelles, as shown by the degenerative changes induced by genetic block of the autophagic mechanism, and in several myopathies. Autophagy is enhanced in muscle by exercise and impaired during aging, suggesting that aging-dependent muscle dysfunction could be delayed by boosting autophagy.

DOI: https://doi.org/10.1101/cshperspect.a041565
bioRxiv. 2024 Aug 05. pii: 2024.07.28.605526. [Epub ahead of print]

Genetic Deletion of Skeletal Muscle Inositol Polyphosphate Multikinase Disrupts Glucose Homeostasis and Impairs Exercise Tolerance.

Ji-Hyun Lee, Ik-Rak Jung, Becky Tu-Sekine, Sunghee Jin, Frederick Anokye-Danso, Rexford S Ahima, Sangwon F Kim.

  Inositol phosphates are critical signaling messengers involved in a wide range of biological pathways in which inositol polyphosphate multikinase (IPMK) functions as a rate-limiting enzyme for inositol polyphosphate metabolism. IPMK has been implicated in cellular metabolism, but its function at the systemic level is still poorly understood. Since skeletal muscle is a major contributor to energy homeostasis, we have developed a mouse model in which skeletal muscle IPMK is specifically deleted and examined how a loss of IPMK affects whole-body metabolism. Here, we report that mice in which IPMK knockout is deleted, specifically in the skeletal muscle, displayed an increased body weight, disrupted glucose tolerance, and reduced exercise tolerance under the normal diet. Moreover, these changes were associated with an increased accumulation of triglyceride in skeletal muscle. Furthermore, we have confirmed that a loss of IPMK led to reduced beta-oxidation, increased triglyceride accumulation, and impaired insulin response in IPMK-deficient muscle cells. Thus, our results suggest that IPMK mediates the whole-body metabolism via regulating muscle metabolism and may be potentially targeted for the treatment of metabolic syndromes.

Keywords:  IPMK; Inositol polyphosphate; exercise; insulin; skeletal muscle

DOI:  https://doi.org/10.1101/2024.07.28.605526
Mol Cell Biol. 2024 Aug 12. 1-19

FUS-Mediated Inhibition of Myogenesis Elicited by Suppressing TNNT1 Production.

Eunbyul Ji, Poonam R Pandey, Jennifer L Martindale, Xiaoling Yang, Jen-Hao Yang, Dimitrios Tsitsipatis, Chang Hoon Shin, Yulan Piao, Jinshui Fan, Krystyna Mazan-Mamczarz, Nirad Banskota, Supriyo De, Myriam Gorospe.

  Myogenesis is a highly orchestrated process whereby muscle precursor cells, myoblasts, develop into muscle fibers to form skeletal muscle during embryogenesis and regenerate adult muscle. Here, we studied the RNA-binding protein FUS (fused in sarcoma), which has been implicated in muscular and neuromuscular pathologies but is poorly characterized in myogenesis. Given that FUS levels declined in human and mouse models of skeletal myogenesis, and that silencing FUS enhanced myogenesis, we hypothesized that FUS might be a repressor of myogenic differentiation. Interestingly, overexpression of FUS delayed myogenesis, accompanied by slower production of muscle differentiation markers. To identify the mechanisms through which FUS inhibits myogenesis, we uncovered RNA targets of FUS by ribonucleoprotein immunoprecipitation (RIP) followed by RNA-sequencing (RNA-seq) analysis. Stringent selection of the bound transcripts uncovered Tnnt1 mRNA, encoding troponin T1 (TNNT1), as a major effector of FUS influence on myogenesis. We found that in myoblasts, FUS retained Tnnt1 mRNA in the nucleus, preventing TNNT1 expression; however, reduction of FUS during myogenesis or by silencing FUS released Tnnt1 mRNA for export to the cytoplasm, enabling TNNT1 translation and promoting myogenesis. We propose that FUS inhibits myogenesis by suppressing TNNT1 expression through a mechanism of nuclear Tnnt1 mRNA retention.

Keywords:  Myogenesis; TNNT1; ribonucleoprotein complex; translation

DOI:  https://doi.org/10.1080/10985549.2024.2383296
Proc Natl Acad Sci U S A. 2024 Aug 20. 121(34): e2319724121

Zfp697 is an RNA-binding protein that regulates skeletal muscle inflammation and remodeling.

Jorge C Correia, Paulo R Jannig, Maya L Gosztyla, Igor Cervenka, Serge Ducommun, Stine M Præstholm, José M Dias, Kyle D Dumont, Zhengye Liu, Qishan Liang, Daniel Edsgärd, Olof Emanuelsson, Paul Gregorevic, Håkan Westerblad, Tomas Venckunas, Marius Brazaitis, Sigitas Kamandulis, Johanna T Lanner, Ana I Teixeira, Gene W Yeo, Jorge L Ruas.

  Skeletal muscle atrophy is a morbidity and mortality risk factor that happens with disuse, chronic disease, and aging. The tissue remodeling that happens during recovery from atrophy or injury involves changes in different cell types such as muscle fibers, and satellite and immune cells. Here, we show that the previously uncharacterized gene and protein Zfp697 is a damage-induced regulator of muscle remodeling. Zfp697/ZNF697 expression is transiently elevated during recovery from muscle atrophy or injury in mice and humans. Sustained Zfp697 expression in mouse muscle leads to a gene expression signature of chemokine secretion, immune cell recruitment, and extracellular matrix remodeling. Notably, although Zfp697 is expressed in several cell types in skeletal muscle, myofiber-specific Zfp697 genetic ablation in mice is sufficient to hinder the inflammatory and regenerative response to muscle injury, compromising functional recovery. We show that Zfp697 is an essential mediator of the interferon gamma response in muscle cells and that it functions primarily as an RNA-interacting protein, with a very high number of miRNA targets. This work identifies Zfp697 as an integrator of cell-cell communication necessary for tissue remodeling and regeneration.

Keywords:  RNA-binding protein; Zfp697; inflammation; muscle atrophy; skeletal muscle

DOI:  https://doi.org/10.1073/pnas.2319724121
EMBO Rep. 2024 Aug 14.

Satellite cell-derived TRIM28 is pivotal for mechanical load- and injury-induced myogenesis.

Kuan-Hung Lin, Jamie E Hibbert, Corey Gk Flynn, Jake L Lemens, Melissa M Torbey, Nathaniel D Steinert, Philip M Flejsierowicz, Kiley M Melka, Garrison T Lindley, Marcos Lares, Vijayasaradhi Setaluri, Amy J Wagers, Troy A Hornberger.

  Satellite cells are skeletal muscle stem cells that contribute to postnatal muscle growth, and they endow skeletal muscle with the ability to regenerate after a severe injury. Here we discover that this myogenic potential of satellite cells requires a protein called tripartite motif-containing 28 (TRIM28). Interestingly, different from the role reported in a previous study based on C2C12 myoblasts, multiple lines of both in vitro and in vivo evidence reveal that the myogenic function of TRIM28 is not dependent on changes in the phosphorylation of its serine 473 residue. Moreover, the functions of TRIM28 are not mediated through the regulation of satellite cell proliferation or differentiation. Instead, our findings indicate that TRIM28 regulates the ability of satellite cells to progress through the process of fusion. Specifically, we discover that TRIM28 controls the expression of a fusogenic protein called myomixer and concomitant fusion pore formation. Collectively, the outcomes of this study expose the framework of a novel regulatory pathway that is essential for myogenesis.

Keywords:  Cell Fusion; Hypertrophy; Regeneration; Skeletal Muscle

DOI:  https://doi.org/10.1038/s44319-024-00227-1
Function (Oxf). 2024 Aug 12. pii: zqae035. [Epub ahead of print]

Intrinsic Skeletal Muscle Function and Contraction-stimulated Glucose Uptake Do Not Vary by Time-of-day in Mice.

Liam S Fitzgerald, Shannon N Bremner, Samuel R Ward, Yoshitake Cho, Simon Schenk.

  A growing body of data suggests that skeletal muscle contractile function and glucose metabolism vary by time-of-day, with chronobiological effects on intrinsic skeletal muscle properties being proposed as the underlying mediator. However, no studies have directly investigated intrinsic contractile function or glucose metabolism in skeletal muscle over a 24 h circadian cycle. To address this, we assessed intrinsic contractile function and endurance, as well as contraction-stimulated glucose uptake, in isolated extensor digitorum longus and soleus from mice at four times-of-day (zeitgeber times 1, 7, 13, 19). Significantly, though both muscles demonstrated circadian-related changes in gene expression, there were no differences between the four time points in intrinsic contractile function, endurance, and contraction-stimulated glucose uptake, regardless of sex. Overall, these results suggest that time-of-day variation in exercise performance and the glycemia-reducing benefits of exercise are not due to chronobiological effects on intrinsic muscle function or contraction-stimulated glucose uptake.

Keywords:  2-deoxyglucose; chronobiology; circadian; extensor digitorum longus; fatigue; mechanics; metabolism; physiology; soleus; zeitgeber

DOI:  https://doi.org/10.1093/function/zqae035
Free Radic Biol Med. 2024 Aug 13. pii: S0891-5849(24)00600-2. [Epub ahead of print]223 341-356

Exercise-specific adaptations in human skeletal muscle: Molecular mechanisms of making muscles fit and mighty.

Aaron C Q Thomas, Connor A Stead, Jatin G Burniston, Stuart M Phillips.

  The mechanisms leading to a predominantly hypertrophied phenotype versus a predominantly oxidative phenotype, the hallmarks of resistance training (RT) or aerobic training (AT), respectively, are being unraveled. In humans, exposure of naïve persons to either AT or RT results in their skeletal muscle exhibiting generic 'exercise stress-related' signaling, transcription, and translation responses. However, with increasing engagement in AT or RT, the responses become refined, and the phenotype typically associated with each form of exercise emerges. Here, we review some of the mechanisms underpinning the adaptations of how muscles become, through AT, 'fit' and RT, 'mighty.' Much of our understanding of molecular exercise physiology has arisen from targeted analysis of post-translational modifications and measures of protein synthesis. Phosphorylation of specific residue sites has been a dominant focus, with canonical signaling pathways (AMPK and mTOR) studied extensively in the context of AT and RT, respectively. These alone, along with protein synthesis, have only begun to elucidate key differences in AT and RT signaling. Still, key yet uncharacterized differences exist in signaling and regulation of protein synthesis that drive unique adaptation to AT and RT. Omic studies are required to better understand the divergent relationship between exercise and phenotypic outcomes of training.

Keywords:  Human; Hypertrophy; Mitochondria; Protein signaling; Protein turnover

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.08.010
Biochem Biophys Res Commun. 2024 Aug 06. pii: S0006-291X(24)01047-7. [Epub ahead of print]736 150511

Conditioned medium of human mesenchymal stromal/stem cells cultured on decellularized extracellular matrix promotes murine skeletal muscle repair after acute injury.

Roman E Ushakov, Elena B Burova.

  Mesenchymal stromal/stem cells (MSCs) and their secretome are known to exert beneficial effects in many pathological states. However, MSCs therapeutic properties can be reduced due to unsuitable in vitro maintenance conditions. Standard culture protocols neglect the fact that MSCs exist in vivo in the closest connection with the extracellular matrix (ECM), the complex protein network providing an instructive microenvironment. We found recently that conditioned medium from human endometrial MSCs cultured on cell-derived decellularized extracellular matrix (CM-dECM) is dramatically enriched in a number of paracrine factors such as GM-CSF, FGF-2, HGF, MMP-1, MCP-1, IL-6, IL-8, CXCL-1, -2, -5, -6 (Ushakov et al., 2024). Given that several upregulated molecules belong to myokines that are known to participate in skeletal muscle regeneration, we hypothesized that CM-dECM may promote restoration of damaged muscle tissue. Here, we found that CM-dECM injections into barium chloride-injured murine m. tibialis anterior caused myofiber hypertrophy and promoted angiogenesis. Besides, CM-dECM significantly contributed to progression of murine C2C12 myoblasts cell cycle suggesting that muscle repair in vivo may be connected with stimulation of resident myoblasts proliferation. In this study, a role for secretome of endometrial MSCs cultured on dECM in injured murine skeletal muscle regeneration was outlined first. Our findings demonstrate that culture on dECM may be considered as a novel preconditioning approach enhancing MSCs therapeutic potential.

Keywords:  Decellularized extracellular matrix; Mesenchymal stromal/stem cells; Muscle repair; Secretome

DOI:  https://doi.org/10.1016/j.bbrc.2024.150511
J Clin Invest. 2024 Aug 15. pii: e183302. [Epub ahead of print]134(16):

Decoding the decline: unveiling drivers of sarcopenia.

Allison M Owen, Christopher S Fry.

There remains a critical need to define molecular pathways underlying sarcopenia to identify putative therapeutic targets. Research in the mechanisms of aging and sarcopenia relies heavily on preclinical rodent models. In this issue of the JCI, Kerr et al. implemented a clinically-relevant sarcopenia classification system of aged C57BL/6J mice, capturing sarcopenia prevalence across both sexes. The authors performed detailed physiological, molecular, and energetic analyses and demonstrated that mitochondrial biogenesis, oxidative capacity, and AMPK-autophagy signaling decreased as sarcopenia progressed in male mice. Sarcopenia was less prevalent in female mice with fewer alterations compared with the male-affected processes. The findings highlight factors beyond age as necessary for classifying the sarcopenic phenotype in rodent models, reveal sexual dimorphism across the trajectory of age-related declines in muscle mass and function in a commonly used rodent model, and provide insight into sex-dependent molecular alterations associated with sarcopenia progression.

DOI: https://doi.org/10.1172/JCI183302
Mitochondrion. 2024 Aug 10. pii: S1567-7249(24)00103-X. [Epub ahead of print] 101945

Secondary mitochondrial dysfunction across the spectrum of hereditary and acquired muscle disorders.

Gloria Mak, Mark Tarnopolsky, Jian-Qiang Lu.

  Mitochondria form a dynamic network within skeletal muscle. This network is not only responsible for producing adenine triphosphate through oxidative phosphorylation, but also responds through fission, fusion and mitophagy to various factors, such as increased energy demands, oxidative stress, inflammation, and calcium dysregulation. Mitochondrial dysfunction in skeletal muscle not only occurs in primary mitochondrial myopathies, but also other hereditary and acquired myopathies. As such, this review attempts to highlight the clinical and histopathologic aspects of mitochondrial dysfunction seen in hereditary and acquired myopathies, as well as discuss potential mechanisms leading to mitochondrial dysfunction and therapies to restore mitochondrial function.

Keywords:  Congenital myopathies; Inflammatory myopathies; Mitochondrial dysfunction; Muscular dystrophies

DOI:  https://doi.org/10.1016/j.mito.2024.101945
J Muscle Res Cell Motil. 2024 Aug 10.

TAM-associated CASQ1 mutants diminish intracellular Ca2+ content and interfere with regulation of SOCE.

Alessandra Gamberucci, Claudio Nanni, Enrico Pierantozzi, Matteo Serano, Feliciano Protasi, Daniela Rossi, Vincenzo Sorrentino.

  Tubular aggregate myopathy (TAM) is a rare myopathy characterized by muscle weakness and myalgia. Muscle fibers from TAM patients show characteristic accumulation of membrane tubules that contain proteins from the sarcoplasmic reticulum (SR). Gain-of-function mutations in STIM1 and ORAI1, the key proteins participating in the Store-Operated Ca2+ Entry (SOCE) mechanism, were identified in patients with TAM. Recently, the CASQ1 gene was also found to be mutated in patients with TAM. CASQ1 is the main Ca2+ buffer of the SR and a negative regulator of SOCE. Previous characterization of CASQ1 mutants in non-muscle cells revealed that they display altered Ca2+dependent polymerization, reduced Ca2+storage capacity and alteration in SOCE inhibition. We thus aimed to assess how mutations in CASQ1 affect calcium regulation in skeletal muscles, where CASQ1 is naturally expressed. We thus expressed CASQ1 mutants in muscle fibers from Casq1 knockout mice, which provide a valuable model for studying the Ca2+ storage capacity of TAM-associated mutants. Moreover, since Casq1 knockout mice display a constitutively active SOCE, the effect of CASQ1 mutants on SOCE inhibition can be also properly examined in fibers from these mice. Analysis of intracellular Ca2+ confirmed that CASQ1 mutants have impaired ability to store Ca2+and lose their ability to inhibit skeletal muscle SOCE; this is in agreement with the evidence that alterations in Ca2+entry due to mutations in either STIM1, ORAI1 or CASQ1 represents a hallmark of TAM.

Keywords:  Calcium; Myopathy; Sarcoplasmic reticulum; Skeletal muscle; Store operated calcium entry

DOI:  https://doi.org/10.1007/s10974-024-09681-9
J Clin Invest. 2024 Jun 11. pii: e172890. [Epub ahead of print]134(16):

Mouse sarcopenia model reveals sex- and age-specific differences in phenotypic and molecular characteristics.

Haiming L Kerr, Kora Krumm, Barbara Anderson, Anthony Christiani, Lena Strait, Theresa Li, Brynn Irwin, Siyi Jiang, Artur Rybachok, Amanda Chen, Elizabeth Dacek, Lucas Caeiro, Gennifer E Merrihew, James W MacDonald, Theo K Bammler, Michael J MacCoss, Jose M Garcia.

  Our study was to characterize sarcopenia in C57BL/6J mice using a clinically relevant definition to investigate the underlying molecular mechanisms. Aged male (23-32 months old) and female (27-28 months old) C57BL/6J mice were classified as non-, probable-, or sarcopenic based on assessments of grip strength, muscle mass, and treadmill running time, using 2 SDs below the mean of their young counterparts as cutoff points. A 9%-22% prevalence of sarcopenia was identified in 23-26 month-old male mice, with more severe age-related declines in muscle function than mass. Females aged 27-28 months showed fewer sarcopenic but more probable cases compared with the males. As sarcopenia progressed, a decrease in muscle contractility and a trend toward lower type IIB fiber size were observed in males. Mitochondrial biogenesis, oxidative capacity, and AMPK-autophagy signaling decreased as sarcopenia progressed in males, with pathways linked to mitochondrial metabolism positively correlated with muscle mass. No age- or sarcopenia-related changes were observed in mitochondrial biogenesis, OXPHOS complexes, AMPK signaling, mitophagy, or atrogenes in females. Our results highlight the different trajectories of age-related declines in muscle mass and function, providing insights into sex-dependent molecular changes associated with sarcopenia progression, which may inform the future development of novel therapeutic interventions.

Keywords:  Aging; Mitochondria; Mouse models; Muscle biology; Skeletal muscle

DOI:  https://doi.org/10.1172/JCI172890
Cold Spring Harb Perspect Biol. 2024 Aug 12. pii: a041477. [Epub ahead of print]

The Diversity of Skeletal Muscle Fiber Types.

Stefano Schiaffino, Francesco Chemello, Carlo Reggiani.

The widespread presence of slow-red and fast-white muscles in all vertebrates supports the evolutionary advantage of having two types of motors available for animal movement-a slow economical motor used for most activities, and a fast energetically costly motor used for rapid movements and emergency actions, and actions that require a lot of force. Skeletal muscles are composed of multiple fiber types whose structural and functional properties have only in part been characterized. Further progress in this field is mainly occurring along two directions: Multiomics approaches are providing a global picture of the molecular composition of muscle fibers up to the single fiber and single nucleus level. Signaling studies are identifying many transcription factors and pathways controlling fiber-type specification. These new data should now be integrated into a wider whole-body context by defining the matching between muscle fiber and motor neuron heterogeneity in the neuromuscular system, as well as the relevance of muscle fiber types in systemic homeostatic functions, including metabolism and thermogenesis.

DOI: https://doi.org/10.1101/cshperspect.a041477
Free Radic Biol Med. 2024 Aug 13. pii: S0891-5849(24)00599-9. [Epub ahead of print]

"Unlocking Athletic Potential: Exploring Exercise Physiology from Mechanisms to Performance". Acute antioxidant supplementation and performance - should this be considered.

Steen Larsen.

  It is well known that a training intervention leads to mitochondrial adaptations with increased skeletal muscle mitochondrial biogenesis and function. Studies have recently indicated that skeletal muscle mitochondrial function is important for athletic performance. During exercise reactive oxygen species are released from skeletal muscle potentially leading to adaptations but maybe also to fatigue. Focus has been on how chronic antioxidant supplementation affects a training adaptation, where some studies are reporting an abolished adaptation. Whether acute antioxidant supplementation could have a positive effect on fatigue and performance is interesting and highly relevant in sports where athletes are competing over several consecutive days or on the same day, with preliminary competitions in the morning and finals in the afternoon, where it is important for the athletes to recover fast. This review provides an overview of the effects of acute antioxidant supplementation and whether it leads to improved performance and/or faster recovery in humans.

Keywords:  Antioxidant supplementation; Mitochondria; Performance

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.08.013
Redox Biol. 2024 Aug 10. pii: S2213-2317(24)00278-7. [Epub ahead of print]75 103300

Loss of NAMPT and SIRT2 but not SIRT1 attenuate GLO1 expression and activity in human skeletal muscle.

Edwin R Miranda, Pallavi Varshney, Corey E Mazo, James Shadiow, Andrew T Ludlow, Jacob M Haus.

  Glyoxalase I (GLO1) is the primary enzyme for detoxification of the reactive dicarbonyl methylglyoxal (MG). Loss of GLO1 promotes accumulation of MG resulting in a recapitulation of diabetic phenotypes. We previously demonstrated attenuated GLO1 protein in skeletal muscle from individuals with type 2 diabetes (T2D). However, whether GLO1 attenuation occurs prior to T2D and the mechanisms regulating GLO1 abundance in skeletal muscle are unknown. GLO1 expression and activity were determined in skeletal muscle tissue biopsies from 15 lean healthy individuals (LH, BMI: 22.4 ± 0.7) and 5 individuals with obesity (OB, BMI: 32.4 ± 1.3). GLO1 protein was attenuated by 26 ± 0.3 % in OB compared to LH skeletal muscle (p = 0.019). Similar reductions for GLO1 activity were observed (p = 0.102). NRF2 and Keap1 expression were equivocal between groups despite a 2-fold elevation in GLO1 transcripts in OB skeletal muscle (p = 0.008). GLO1 knock-down (KD) in human immortalized myotubes promoted downregulation of muscle contraction and organization proteins indicating the importance of GLO1 expression for skeletal muscle function. SIRT1 KD had no effect on GLO1 protein or activity whereas, SIRT2 KD attenuated GLO1 protein by 28 ± 0.29 % (p < 0.0001) and GLO1 activity by 42 ± 0.12 % (p = 0.0150). KD of NAMPT also resulted in attenuation of GLO1 protein (28 ± 0.069 %, p = 0.003), activity (67 ± 0.09 %, p = 0.011) and transcripts (50 ± 0.13 %, p = 0.049). Neither the provision of the NAD+ precursors NR nor NMN were able to prevent this attenuation in GLO1 protein. However, NR did augment GLO1 specific activity (p = 0.022 vs NAMPT KD). These perturbations did not alter GLO1 acetylation status. SIRT1, SIRT2 and NAMPT protein levels were all equivocal in skeletal muscle tissue biopsies from individuals with obesity and lean individuals. These data implicate NAD+-dependent regulation of GLO1 in skeletal muscle independent of altered GLO1 acetylation and provide rationale for exploring NR supplementation to rescue attenuated GLO1 abundance and activity in conditions such as obesity.

Keywords:  Dicarbonyl stress; Methylglyoxal; NAD(+); Nicotinamide riboside

DOI:  https://doi.org/10.1016/j.redox.2024.103300
Sci Adv. 2024 Aug 16. 10(33): eadn5993

Remodeling p38 signaling in muscle controls locomotor activity via IL-15.

Cintia Folgueira, Leticia Herrera-Melle, Juan Antonio López, Victor Galvan-Alvarez, Marcos Martin-Rincon, María Isabel Cuartero, Alicia García-Culebras, Phillip A Dumesic, Elena Rodríguez, Luis Leiva-Vega, Marta León, Begoña Porteiro, Cristina Iglesias, Jorge L Torres, Lourdes Hernández-Cosido, Clara Bonacasa, Miguel Marcos, María Ángeles Moro, Jesús Vázquez, Jose A L Calbet, Bruce M Spiegelman, Alfonso Mora, Guadalupe Sabio.

Skeletal muscle has gained recognition as an endocrine organ releasing myokines upon contraction during physical exercise. These myokines exert both local and pleiotropic health benefits, underscoring the crucial role of muscle function in countering obesity and contributing to the overall positive effects of exercise on health. Here, we found that exercise activates muscle p38γ, increasing locomotor activity through the secretion of interleukin-15 (IL-15). IL-15 signals in the motor cortex, stimulating locomotor activity. This activation of muscle p38γ, leading to an increase locomotor activity, plays a crucial role in reducing the risk of diabetes and liver steatosis, unveiling a vital muscle-brain communication pathway with profound clinical implications. The correlation between p38γ activation in human muscle during acute exercise and increased blood IL-15 levels highlights the potential therapeutic relevance of this pathway in treating obesity and metabolic diseases. These findings provide valuable insights into the molecular basis of exercise-induced myokine responses promoting physical activity.

DOI: https://doi.org/10.1126/sciadv.adn5993
Dev Cell. 2024 Aug 02. pii: S1534-5807(24)00455-6. [Epub ahead of print]

GLUD1 determines murine muscle stem cell fate by controlling mitochondrial glutamate levels.

Inés Soro-Arnáiz, Gillian Fitzgerald, Sarah Cherkaoui, Jing Zhang, Paola Gilardoni, Adhideb Ghosh, Ori Bar-Nur, Evi Masschelein, Pierre Maechler, Nicola Zamboni, Martin Poms, Alessio Cremonesi, Juan Carlos Garcia-Cañaveras, Katrien De Bock, Raphael Johannes Morscher.

  Muscle stem cells (MuSCs) enable muscle growth and regeneration after exercise or injury, but how metabolism controls their regenerative potential is poorly understood. We describe that primary metabolic changes can determine murine MuSC fate decisions. We found that glutamine anaplerosis into the tricarboxylic acid (TCA) cycle decreases during MuSC differentiation and coincides with decreased expression of the mitochondrial glutamate deaminase GLUD1. Deletion of Glud1 in proliferating MuSCs resulted in precocious differentiation and fusion, combined with loss of self-renewal in vitro and in vivo. Mechanistically, deleting Glud1 caused mitochondrial glutamate accumulation and inhibited the malate-aspartate shuttle (MAS). The resulting defect in transporting NADH-reducing equivalents into the mitochondria induced compartment-specific NAD+/NADH ratio shifts. MAS activity restoration or directly altering NAD+/NADH ratios normalized myogenesis. In conclusion, GLUD1 prevents deleterious mitochondrial glutamate accumulation and inactivation of the MAS in proliferating MuSCs. It thereby acts as a compartment-specific metabolic brake on MuSC differentiation.

Keywords:  GLUD1; glutamine metabolism; malate aspartate shuttle; metabolite compartmentalization; muscle stem cells; tricarboxylic acid cycle

DOI:  https://doi.org/10.1016/j.devcel.2024.07.015
Endocrinology. 2024 Aug 13. pii: bqae102. [Epub ahead of print]

Mild cold stress at ambient temperature elevates muscle calcium cycling and exercise adaptations in obese female mice.

Steffen H Raun, Jessica L Braun, Iuliia Karavaeva, Carlos Henriquez-Olguín, Mona S Ali, Lisbeth L V Møller, Zachary Gerhart-Hines, Val A Fajardo, Erik A Richter, Lykke Sylow.

OBJECTIVE: Housing temperature is a critical regulator of mouse metabolism and thermoneutral housing can improve human translation. However, the impact of housing temperature on the ability of wheel running to rescue the detrimental effect of diet-induced obese mice is currently not fully understood.
METHODS: Lean or obese female mice were housed at standard ambient temperature (22℃) or thermoneutrality (30℃) with/without access to running wheels. The metabolic phenotype was investigated using glucose tolerance tests, indirect calorimetry, and body composition. Molecular muscle adaptations were measured using immunoblotting, qPCR, and spectrophotometric/fluorescent assays.
RESULTS: Obese female mice housed at 22°C showed lower adiposity, lower circulating insulin levels, improved glucose tolerance, and elevated basal metabolic rate compared to 30°C housing. Mice exposed to voluntary wheel running exhibited a larger fat loss and higher metabolic rate at 22°C housing compared to thermoneutrality. In obese female mice, glucose tolerance improved after exercise training independent of housing temperature. Independent of diet and training, 22°C housing increased skeletal muscle sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) activity. Additionally, 22°C-housing elevated the induction of training-responsive muscle proteins in obese mice.
CONCLUSION: Our findings highlight that housing temperature significantly influences adiposity, insulin sensitivity, muscle physiology, and exercise adaptations in diet-induced obese female mice.

DOI: https://doi.org/10.1210/endocr/bqae102
Cell Biochem Funct. 2024 Aug;42(6): e4106

Myostatin's marvels: From muscle regulator to diverse implications in health and disease.

Sonakshi Sharma, Amol S Patil.

  Myostatin, a member of the transforming growth factor-β superfamily, is a pivotal regulator of skeletal muscle growth in mammals. Its discovery has sparked significant interest due to its multifaceted roles in various physiological processes and its potential therapeutic implications. This review explores the diverse functions of myostatin in skeletal muscle development, maintenance and pathology. We delve into its regulatory mechanisms, including its interaction with other signalling pathways and its modulation by various factors such as microRNAs and mechanical loading. Furthermore, we discuss the therapeutic strategies aimed at targeting myostatin for the treatment of muscle-related disorders, including cachexia, muscular dystrophy and heart failure. Additionally, we examine the impact of myostatin deficiency on craniofacial morphology and bone development, shedding light on its broader implications beyond muscle biology. Through a comprehensive analysis of the literature, this review underscores the importance of further research into myostatin's intricate roles and therapeutic potential in human health and disease.

Keywords:  cachexia; craniofacial morphology; myostatin; regulatory mechanisms; skeletal muscle growth; transforming growth factor‐β (TGF‐β)

DOI:  https://doi.org/10.1002/cbf.4106
Int J Mol Sci. 2024 Jul 31. pii: 8362. [Epub ahead of print]25(15):

Epigenetics of Skeletal Muscle Atrophy.

Jiacheng Du, Qian Wu, Eun Ju Bae.

  Skeletal muscle atrophy, characterized by diminished muscle strength and mass, arises from various causes, including malnutrition, aging, nerve damage, and disease-related secondary atrophy. Aging markedly escalates the prevalence of sarcopenia. Concurrently, the incidence of muscle atrophy significantly rises among patients with chronic ailments such as heart failure, diabetes, and chronic obstructive pulmonary disease (COPD). Epigenetics plays a pivotal role in skeletal muscle atrophy. Aging elevates methylation levels in the promoter regions of specific genes within muscle tissues. This aberrant methylation is similarly observed in conditions like diabetes, neurological disorders, and cardiovascular diseases. This study aims to explore the relationship between epigenetics and skeletal muscle atrophy, thereby enhancing the understanding of its pathogenesis and uncovering novel therapeutic strategies.

Keywords:  epigenetics; skeletal muscle atrophy

DOI:  https://doi.org/10.3390/ijms25158362
Pflugers Arch. 2024 Aug 16.

BK channels promote action potential repolarization in skeletal muscle but contribute little to myotonia.

Chris Dupont, Brianna Blake, Andrew A Voss, Mark M Rich.

  Patients with myotonia congenita suffer from slowed relaxation of muscle (myotonia), due to hyperexcitability caused by loss-of-function mutations in the ClC-1 chloride channel. A recent study suggested that block of large-conductance voltage- and Ca2+- activated K+ channels (BK) may be effective as therapy. The mechanism underlying efficacy was suggested to be lessening of the depolarizing effect of build-up of K+ in t-tubules of muscle during repetitive firing. BK channels are widely expressed in the nervous system and have been shown to play a central role in regulation of excitability, but their contribution to muscle excitability has not been determined. We performed intracellular recordings as well as force measurements in both wild type and BK-/- mouse extensor digitorum longus muscles. Action potential width was increased in BK-/- muscle due to slowing of repolarization, consistent with the possibility K+ build-up in t-tubules is lessened by block of BK channels in myotonic muscle. However, there was no difference in the severity of myotonia triggered by block of muscle Cl- channels with 9-anthracenecarboxylic acid (9AC) in wild type and BK-/- muscle fibers. Further study revealed no difference in the interspike membrane potential during repetitive firing suggesting there was no reduction in K+ build-up in t-tubules of BK-/- muscle. Force recordings following block of muscle Cl- channels demonstrated little reduction in myotonia in BK-/- muscle. In contrast, the current standard of care, mexiletine, significantly reduced myotonia. Our data suggest BK channels regulate muscle excitability, but are not an attractive target for therapy of myotonia.

Keywords:  Excitation; K+ channel; Myotonia congenita; Potassium; t-tubule

DOI:  https://doi.org/10.1007/s00424-024-03005-z
Commun Biol. 2024 Aug 10. 7(1): 974

Calorie restriction and rapamycin distinctly mitigate aging-associated protein phosphorylation changes in mouse muscles.

Meric Ataman, Nitish Mittal, Lionel Tintignac, Alexander Schmidt, Daniel J Ham, Asier González, Markus A Ruegg, Mihaela Zavolan.

Calorie restriction (CR) and treatment with rapamycin (RM), an inhibitor of the mTORC1 growth-promoting signaling pathway, are known to slow aging and promote health from worms to humans. At the transcriptome and proteome levels, long-term CR and RM treatments have partially overlapping effects, while their impact on protein phosphorylation within cellular signaling pathways have not been compared. Here we measured the phosphoproteomes of soleus, tibialis anterior, triceps brachii and gastrocnemius muscles from adult (10 months) and 30-month-old (aged) mice receiving either a control, a calorie restricted or an RM containing diet from 15 months of age. We reproducibly detected and extensively analyzed a total of 6960 phosphosites, 1415 of which are not represented in standard repositories. We reveal the effect of these interventions on known mTORC1 pathway substrates, with CR displaying greater between-muscle variation than RM. Overall, CR and RM have largely consistent, but quantitatively distinct long-term effects on the phosphoproteome, mitigating age-related changes to different degrees. Our data expands the catalog of protein phosphorylation sites in the mouse, providing important information regarding their tissue-specificity, and revealing the impact of long-term nutrient-sensing pathway inhibition on mouse skeletal muscle.

DOI: https://doi.org/10.1038/s42003-024-06679-4
Life Sci Alliance. 2024 Nov;pii: e202402885. [Epub ahead of print]7(11):

JAK inhibition with tofacitinib rapidly increases contractile force in human skeletal muscle.

Joseph B Shrager, Ryan Randle, Myung Lee, Syed Saadan Ahmed, Winston Trope, Natalie Lui, George Poultsides, Doug Liou, Brendan Visser, Jeffrey A Norton, Shannon M Nesbit, Hao He, Ntemena Kapula, Bailey Wallen, Emmanuel Fatodu, Cheyenne A Sadeghi, Harrison B Konsker, Irmina Elliott, Brandon Guenthart, Leah Backhus, Roger Cooke, Mark Berry, Huibin Tang.

Reduction in muscle contractile force associated with many clinical conditions incurs serious morbidity and increased mortality. Here, we report the first evidence that JAK inhibition impacts contractile force in normal human muscle. Muscle biopsies were taken from patients who were randomized to receive tofacitinib (n = 16) or placebo (n = 17) for 48 h. Single-fiber contractile force and molecular studies were carried out. The contractile force of individual diaphragm myofibers pooled from the tofacitinib group (n = 248 fibers) was significantly higher than those from the placebo group (n = 238 fibers), with a 15.7% greater mean maximum specific force (P = 0.0016). Tofacitinib treatment similarly increased fiber force in the serratus anterior muscle. The increased force was associated with reduced muscle protein oxidation and FoxO-ubiquitination-proteasome signaling, and increased levels of smooth muscle MYLK. Inhibition of MYLK attenuated the tofacitinib-dependent increase in fiber force. These data demonstrate that tofacitinib increases the contractile force of skeletal muscle and offers several underlying mechanisms. Inhibition of the JAK-STAT pathway is thus a potential new therapy for the muscle dysfunction that occurs in many clinical conditions.

DOI: https://doi.org/10.26508/lsa.202402885
Cold Spring Harb Perspect Biol. 2024 Aug 12. pii: a041500. [Epub ahead of print]

The Myotendinous Junction-Form and Function.

Abigail L Mackey.

A critical link in the chain of force transmission from muscle fiber cross-bridge to bone is the interface between muscle and tendon-the myotendinous junction (MTJ). To meet the challenge of connecting these two tissues, the MTJ is specialized molecularly and morphologically. Distinct transcriptional profiles are evident for the myonuclei at the myofiber tips and a population of mononuclear tendon cells at the MTJ, demonstrating support from both sides in MTJ maintenance. Paradoxically, despite this high degree of specialization, the MTJ remains susceptible to strain (rupture) injury and is often associated with failed tissue healing. Incomplete understanding of the nature of the MTJ and the elements contributing to its plasticity hinder tackling this unsolved clinical challenge. The goal of this review is to summarize key structural and molecular features of the MTJ, discuss MTJ adaptation in response to mechanical (un)loading, aging, and injury, and highlight the major unanswered questions surrounding the MTJ.

DOI: https://doi.org/10.1101/cshperspect.a041500
Diabetologia. 2024 Aug 15.

Applying technologies to simplify strategies for exercise in type 1 diabetes.

Bruce A Perkins, Lauren V Turner, Michael C Riddell.

  Challenges and fears related to managing glucose levels around planned and spontaneous exercise affect outcomes and quality of life in people living with type 1 diabetes. Advances in technology, including continuous glucose monitoring, open-loop insulin pump therapy and hybrid closed-loop (HCL) systems for exercise management in type 1 diabetes, address some of these challenges. In this review, three research or clinical experts, each living with type 1 diabetes, leverage published literature and clinical and personal experiences to translate research findings into simplified, patient-centred strategies. With an understanding of limitations in insulin pharmacokinetics, variable intra-individual responses to aerobic and anaerobic exercise, and the features of the technologies, six steps are proposed to guide clinicians in efficiently communicating simplified actions more effectively to individuals with type 1 diabetes. Fundamentally, the six steps centre on two aspects. First, regardless of insulin therapy type, and especially needed for spontaneous exercise, we provide an estimate of glucose disposal into active muscle meant to be consumed as extra carbohydrates for exercise ('ExCarbs'; a common example is 0.5 g/kg body mass per hour for adults and 1.0 g/kg body mass per hour for youth). Second, for planned exercise using open-loop pump therapy or HCL systems, we additionally recommend pre-emptive basal insulin reduction or using HCL exercise modes initiated 90 min (1-2 h) before the start of exercise until the end of exercise. Modifications for aerobic- and anaerobic-type exercise are discussed. The burden of pre-emptive basal insulin reductions and consumption of ExCarbs are the limitations of HCL systems, which may be overcome by future innovations but are unquestionably required for currently available systems.

Keywords:  Automated insulin delivery; Diabetes technology; Exercise; Hybrid closed loop; Review; Type 1 diabetes

DOI:  https://doi.org/10.1007/s00125-024-06229-x
J Physiol. 2024 Aug 12.

Physiological mechanisms contributing to human exercise performance.

Scott K Powers.

DOI: https://doi.org/10.1113/JP287382
Physiol Rep. 2024 Aug;12(15): e16151

Whole body resistance training on functional outcomes of patients with Stage 4 or 5 chronic kidney disease: A systematic review.

Salma Abrahim, Alexandra P Steele, Jennifer Voth, Joan C Krepinsky, Matthew B Lanktree, Thomas J Hawke.

  Chronic kidney disease (CKD) causes skeletal muscle wasting, resulting in reduced function and inability to live independently. This systematic review critically appraised the scientific literature regarding the effects of full-body resistance training on clinically-relevant functional capacity measures in CKD. The study population included studies of people with Stage 4 or 5 CKD and a mean age of 40+ years old. Eight databases were searched for eligible studies: Pubmed, Embase, Cochrane, CINAHL, Scopus, Web of Science, MEDLINE, and AGELINE. MeSH terms and keyword combinations were used for screening following the PRISMA conduct. Inclusion criteria were based on PICO principles and no date of publication filter was applied. The intervention was training 2 days/week of structured resistance exercises using major upper and lower muscle groups. Minimum intervention period was 7 weeks. Comparison groups maintained their habitual activity without structured exercise training. Outcome measures of interest were: 6-min walk test, grip strength, timed up-and-go test, and sit-to-stand. Eight randomized controlled trials and one nonequivalent comparison-group study fulfilled the inclusion criteria and underwent data extraction. All studies were of hemodialysis patients. The evidence indicates that full-body resistance exercise significantly improved grip strength, timed up and go and sit to stand tests; metrics associated with enhanced quality and quantity of life.

Keywords:  exercise training; kidney disease, chronic; physical fitness; resistance exercise; systematic reviews; weight‐lifting exercise

DOI:  https://doi.org/10.14814/phy2.16151