bims-moremu 2023-02-05 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2023‒02‒05
29 papers selected by
Anna Vainshtein
Craft Science Inc.

Metabolism and exercise: the skeletal muscle clock takes centre stage.
A single dose of exercise stimulates skeletal muscle mitochondrial plasticity in myotonic dystrophy type 1.
Lipin1 plays complementary roles in myofiber stability and regeneration in dystrophic muscles.
Fusion of dysfunction muscle stem cells with myofibers induces sarcopenia in mice.
Skeletal muscle releases extracellular vesicles with distinct protein and microRNA signatures that function in the muscle microenvironment.
Circulating exosome-like vesicle and skeletal muscle microRNAs are altered with age and resistance training.
Three-dimensional chromatin re-organization during muscle stem cell aging.
Regular exercise effectively protects against the aging-associated decline in skeletal muscle NAD content.
Adult skeletal muscle PRC is involved in maintaining mitochondrial content.
Re-organization of nucleolar architecture in myogenic differentiation.
Controlling Inflammation Improves Aging Skeletal Muscle Health.
Chemical reprogramming of melanocytes to skeletal muscle cells.
Intra-cellular to inter-organ mitochondrial communication in striated muscle in health and disease.
Dexamethasone leads to Zn2+ accumulation and increased unbound Zn2+ in C2C12 muscle and 3T3-L1 adipose cells.
Exercise-induced skeletal muscle angiogenesis: impact of age, sex, angiocrines and cellular mediators.
Transcriptional reprogramming of skeletal muscle stem cells by the niche environment.
TRIM72 Alleviates Muscle Inflammation in mdx Mice via Promoting Mitophagy-Mediated NLRP3 Inflammasome Inactivation.
The mitochondrial multi-omic response to exercise training across tissues.
Local and systemic administration of AAV vectors with alphaherpesvirus latency-associated promoter 2 drives potent transgene expression in mouse liver, kidney, and skeletal muscle.
Advanced glycation end products induce skeletal muscle atrophy and insulin resistance via activating ROS-mediated ER stress PERK/FOXO1 signaling.
The m6A reader YTHDC1 regulates muscle stem cell proliferation via PI4K-Akt-mTOR signalling.
Spatial compartmentalization of signaling imparts source-specific functions on secreted factors.
Normal muscle fiber type distribution is recapitulated in aged ephrin-A3-/- mice that previously lacked most slow myofibers.
Protein quality and the food matrix: Defining optimal vs. maximal meal-based protein intakes for stimulating muscle protein synthesis.
Bicalutamide and Trehalose Ameliorate Spinal and Bulbar Muscular Atrophy Pathology in Mice.
Multiomic identification of key transcriptional regulatory programs during endurance exercise training.
Muscle FOXO-Specific Overexpression and Endurance Exercise Protect Skeletal Muscle and Heart from Defects Caused by a High-Fat Diet in Young Drosophila.
Challenges and Future Prospects of Targeting Myostatin/Activin A Signaling to Treat Diseases of Muscle Loss and Metabolic Dysfunction.
Spatial metabolomics reveals skeletal myofiber subtypes.

Nat Rev Endocrinol. 2023 Feb 01.

Metabolism and exercise: the skeletal muscle clock takes centre stage.

Ryan A Martin, Mark R Viggars, Karyn A Esser.

Circadian rhythms that influence mammalian homeostasis and overall health have received increasing interest over the past two decades. The molecular clock, which is present in almost every cell, drives circadian rhythms while being a cornerstone of physiological outcomes. The skeletal muscle clock has emerged as a primary contributor to metabolic health, as the coordinated expression of the core clock factors BMAL1 and CLOCK with the muscle-specific transcription factor MYOD1 facilitates the circadian and metabolic programme that supports skeletal muscle physiology. The phase of the skeletal muscle clock is sensitive to the time of exercise, which provides a rationale for exploring the interactions between the skeletal muscle clock, exercise and metabolic health. Here, we review the underlying mechanisms of the skeletal muscle clock that drive muscle physiology, with a particular focus on metabolic health. Additionally, we highlight the interaction between exercise and the skeletal muscle clock as a means of reinforcing metabolic health and discuss the possible implications of the time of exercise as a chronotherapeutic approach.

DOI: https://doi.org/10.1038/s41574-023-00805-8
Acta Physiol (Oxf). 2023 Feb 01. e13943

A single dose of exercise stimulates skeletal muscle mitochondrial plasticity in myotonic dystrophy type 1.

Andrew I Mikhail, Alexander Manta, Sean Y Ng, Aislin K Osborne, Stephanie R Mattina, Mark R Mackie, Vladimir Ljubicic.

  AIM: Myotonic dystrophy type 1 (DM1) is the second most common muscular dystrophy after Duchenne and is the most prevalent muscular dystrophy in adults. DM1 patients that participate in aerobic exercise training experience several physiological benefits concomitant with improved muscle mitochondrial function without alterations in typical DM1-specific disease mechanisms, which suggests that correcting organelle health is key to ameliorate the DM1 pathology. However, our understanding of the molecular mechanisms of mitochondrial turnover and dynamics in DM1 skeletal muscle is lacking.METHODS: Skeletal muscle tissue were sampled from healthy and DM1 mice under sedentary conditions and at several recovery time-points following an exhaustive treadmill run.
RESULTS: We demonstrate that DM1 patients exhibit an imbalance in the transcriptional apparatus for mitochondrial turnover and dynamics in skeletal muscle. Additionally, DM1 mice displayed elevated expression of autophagy and mitophagy regulators. A single dose of exercise successfully enhanced canonical exercise molecular pathways and skeletal muscle mitochondrial biogenesis despite failing to alter the cellular pathology in DM1 mice. However, treadmill running stimulated coordinated organelle fusion and fission signaling, as well as improved alternative splicing of Optic atrophy 1. Exercise also evoked autophagy and mitophagy pathways in DM1 skeletal muscle resulting in the normalized expression of autophagy- and lysosome-related machinery responsible for the clearance of dysfunctional organelles.
CONCLUSION: Collectively, our data indicate that mitochondrial dynamics and turnover processes in DM1 skeletal muscle are initiated with a single dose of exercise, which may underlie the adaptive benefits previously documented in DM1 mice and patients.

Keywords:  AMP-activated protein kinase; autophagy; biogenesis; dynamics; mitophagy

DOI:  https://doi.org/10.1111/apha.13943
J Physiol. 2023 Jan 30.

Lipin1 plays complementary roles in myofiber stability and regeneration in dystrophic muscles.

Abdulrahman Jama, Abdullah A Alshudukhi, Steve Burke, Lixin Dong, John Karanja Kamau, Andrew Alvin Voss, Hongmei Ren.

  Duchenne muscular dystrophy (DMD) is a severe muscle wasting disorder caused by dystrophin mutation, leading to the loss of sarcolemmal integrity and resulting in progressive myofiber necrosis and impaired muscle function. Our previous studies suggest that lipin1 is important for skeletal muscle regeneration and myofiber integrity. Additionally, we discovered that mRNA expression levels of lipin1 were significantly reduced in skeletal muscle of DMD patients and mdx mouse model. To understand the role of lipin1 in dystrophic muscle, we generated dystrophin/lipin1 double knockout (DKO) mice, and compared the limb muscle pathology and function of wild-type B10, muscle-specific lipin1 deficient (lipin1Myf5cKO ), mdx and DKO mice. We found that further knockout of lipin1 in dystrophic muscle exhibited a more severe phenotype characterized by increased necroptosis, fibrosis and exacerbated membrane damage in DKO compared to mdx mice. In BaCl2 -induced muscle injury, both lipin1Myf5cKO and DKO showed prolonged regeneration at day 14 post-injection, suggesting that lipin1 is critical for muscle regeneration. In situ contractile function assays showed that lipin1 deficiency in dystrophic muscle led to reduced specific force production. Using cell culture system, we found that lipin1 deficiency led to elevated expression levels of necroptotic markers and medium creatine kinase which could be due to sarcolemmal damage. Most importantly, restoration of lipin1 inhibited the elevation of necroptotic markers in differentiated primary lipin1-deficient myoblasts. Overall, our data suggest that lipin1 plays complementary roles in myofiber stability and muscle function in dystrophic muscles, and overexpression of lipin1 may serve as a potential therapeutic strategy for dystrophic muscles. We identified that lipin1 mRNA expression levels are significantly reduced in skeletal muscles of DMD patients and mdx mice. We found that further depletion of lipin1 in skeletal muscles of mdx mice induces more severe dystrophic phenotypes including enhanced myofiber sarcolemma damage, muscle necroptosis, inflammation, fibrosis, and reduced specific force production. Lipin1 deficiency leads to elevated expression levels of necroptotic markers while restoration of lipin1 inhibits their expression. Our results suggest that lipin1 is functionally complementary to dystrophin in muscle membrane integrity and muscle regeneration. Abstract figure legend Lipin1 plays complementary roles in myofiber stability and muscle function in dystrophic muscles. Further knockout of lipin1 in dystrophic muscle exhibited increased necroptosis, inflammation, fibrosis, sarcolemma damage, and reduced force production (Figure is created with BioRender.com). This article is protected by copyright. All rights reserved.

Keywords:  lipin1; membrane integrity; muscle regeneration; necroptosis; skeletal muscle

DOI:  https://doi.org/10.1113/JP284085
bioRxiv. 2023 Jan 21. pii: 2023.01.20.524967. [Epub ahead of print]

Fusion of dysfunction muscle stem cells with myofibers induces sarcopenia in mice.

Xun Wang, Prashant Mishra.

Sarcopenia, or age-associated muscle atrophy, is a progressive condition which affects âˆ¼10-30% of the human geriatric population ( 1, 2 ). A number of contributors to sarcopenia have been proposed, including the progressive loss of muscle stem cells (MuSCs) with age. However, studies in mice have provided evidence that MuSC depletion is not sufficient to induce sarcopenia ( 3, 4 ). We recently showed that in response to age-associated mitochondrial damage, MuSCs self-remove by fusing with neighboring myofibers, which depletes the stem cell population of damaged progenitors ( 5 ). Here, we show that MuSC-myofiber fusion is sufficient to initiate myofiber atrophy in mice, which limits their motor function and lifespan. Conversely, inhibition of MuSC-myofiber fusion blocks myofiber atrophy with age, with a concomitant increase in the maximum lifespan of animals. These findings suggest a model where the accumulation fusion of damaged MuSCs with adult myofibers is a key driving feature of sarcopenia, and resolves the findings that MuSC depletion on its own does not initiate myofiber atrophy.

DOI: https://doi.org/10.1101/2023.01.20.524967
PNAS Nexus. 2022 Sep;1(4): pgac173

Skeletal muscle releases extracellular vesicles with distinct protein and microRNA signatures that function in the muscle microenvironment.

Sho Watanabe, Yuri Sudo, Takumi Makino, Satoshi Kimura, Kenji Tomita, Makoto Noguchi, Hidetoshi Sakurai, Makoto Shimizu, Yu Takahashi, Ryuichiro Sato, Yoshio Yamauchi.

  Extracellular vesicles (EVs) contain various regulatory molecules and mediate intercellular communications. Although EVs are secreted from various cell types, including skeletal muscle cells, and are present in the blood, their identity is poorly characterized in vivo, limiting the identification of their origin in the blood. Since skeletal muscle is the largest organ in the body, it could substantially contribute to circulating EVs as their source. However, due to the lack of defined markers that distinguish skeletal muscle-derived EVs (SkM-EVs) from others, whether skeletal muscle releases EVs in vivo and how much SkM-EVs account for plasma EVs remain poorly understood. In this work, we perform quantitative proteomic analyses on EVs released from C2C12 cells and human iPS cell-derived myocytes and identify potential marker proteins that mark SkM-EVs. These markers we identified apply to in vivo tracking of SkM-EVs. The results show that skeletal muscle makes only a subtle contribution to plasma EVs as their source in both control and exercise conditions in mice. On the other hand, we demonstrate that SkM-EVs are concentrated in the skeletal muscle interstitium. Furthermore, we show that interstitium EVs are highly enriched with the muscle-specific miRNAs and repress the expression of the paired box transcription factor Pax7, a master regulator for myogenesis. Taken together, our findings confirm previous studies showing that skeletal muscle cells release exosome-like EVs with specific protein and miRNA profiles in vivo and suggest that SkM-EVs mainly play a role within the muscle microenvironment where they accumulate.

Keywords:  exosomes; extracellular vesicles; interstitium; skeletal muscle

DOI:  https://doi.org/10.1093/pnasnexus/pgac173
J Physiol. 2023 Feb 01.

Circulating exosome-like vesicle and skeletal muscle microRNAs are altered with age and resistance training.

Donald Xhuti, Mats I Nilsson, Katherine Manta, Mark A Tarnopolsky, Joshua P Nederveen.

  The age-related loss of skeletal muscle mass and functionality, known as sarcopenia, is a critical risk factor for morbidity and all-cause mortality. Resistance exercise training (RET) is the primary countermeasure to fight sarcopenia and aging. Altered intercellular communication is a hallmark of aging, which is not well elucidated. Circulating extracellular vesicles (EVs), including exosomes, contribute to intercellular communication by delivering microRNAs (miRNA), which modulate post-translational modifications, and have been shown to be released following exercise. There is little evidence regarding how EVs or EV-miRNAs are altered with age or RET. Therefore, we sought to characterize circulating EVs in young and older individuals, prior to and following 12-week resistance exercise program. Plasma EVs were isolated using size exclusion chromatography and ultracentrifugation. We found that aging reduced circulating expression markers of CD9, and CD81. Using late passage human myotubes as a model for aging in vitro, we show significantly lower secreted ELVs. Further, levels of circulating ELV-miRNAs associated with muscle health, were lower in older individuals at baseline but increased following RET to levels comparable to young. Muscle biopsies show similar age-related reductions in miRNA expressions, with largely no effect of training. This is reflected in vitro, where aged myotubes show significantly reduced expression of endogenous and secreted myomiRs. Lastly, proteins associated with ELV, and miRNA biogenesis were significantly higher in both older skeletal muscle tissues and aged human myotubes. Together we show that aging significantly affects ELV and miRNA cargo biogenesis, and release. RET can partially normalize this altered intercellular communication. KEY POINTS: We show that aging reduces circulating expression of exosome-like vesicle (ELV) markers, CD9 and CD81. Using late-passage human skeletal myotubes as a model of aging, we show that secreted ELV markers are significantly reduced in vitro. We find circulating ELV miRNAs associated with skeletal muscle health are lower in older individuals but can increase following resistance exercise training (RET). In skeletal muscle, we find altered expression of miRNAs in older individuals, with no effect of RET. Late passage myotubes also appear to have aberrant production of endogenous myomiRs with lower abundance than youthful counterparts In older skeletal muscle and late-passage myotubes, proteins involved with ELV- and miRNA biogenesis are upregulated Abstract figure legend Exosome-like vesicles (ELVs) can mediate intercellular communication, in part due to their unique cargo which include short, non-coding miRNA. With age, we find that there are lower expression of ELVs in circulation and lower abundance of miRNA within these circulating ELVs (top left panel). We also see a lower abundance of select miRNA, despite a greater expression of proteins involved in miRNA biogenesis, in the skeletal muscle with of older men compared to younger counterparts. Following 12wks of progressive resistance exercise training (RET), there is an increase in circulating ELV expression and miRNA abundance (top right panel). Using an in vitro model of skeletal muscle aging, we find that collected media from myotubes cultured from high-passage human primary myoblasts have lower expression of ELVs simultaneous with lower abundance of muscle-specific miRNAs (bottom panel). This article is protected by copyright. All rights reserved.

Keywords:  Alix; aging; exercise; exosomes; extracellular vesicles; miRNAs; resistance training; skeletal muscle

DOI:  https://doi.org/10.1113/JP282663
Aging Cell. 2023 Feb 02. e13789

Three-dimensional chromatin re-organization during muscle stem cell aging.

Benjamin A Yang, Jacqueline A Larouche, Kaitlyn M Sabin, Paula M Fraczek, Stephen C J Parker, Carlos A Aguilar.

  Age-related skeletal muscle atrophy or sarcopenia is a significant societal problem that is becoming amplified as the world's population continues to increase. The regeneration of damaged skeletal muscle is mediated by muscle stem cells, but in old age muscle stem cells become functionally attenuated. The molecular mechanisms that govern muscle stem cell aging encompass changes across multiple regulatory layers and are integrated by the three-dimensional organization of the genome. To quantitatively understand how hierarchical chromatin architecture changes during muscle stem cell aging, we generated 3D chromatin conformation maps (Hi-C) and integrated these datasets with multi-omic (chromatin accessibility and transcriptome) profiles from bulk populations and single cells. We observed that muscle stem cells display static behavior at global scales of chromatin organization during aging and extensive rewiring of local contacts at finer scales that were associated with variations in transcription factor binding and aberrant gene expression. These data provide insights into genome topology as a regulator of molecular function in stem cell aging.

Keywords:  aging; chromatin architecture; muscle stem cells

DOI:  https://doi.org/10.1111/acel.13789
Exp Gerontol. 2023 Jan 25. pii: S0531-5565(23)00030-X. [Epub ahead of print]173 112109

Regular exercise effectively protects against the aging-associated decline in skeletal muscle NAD content.

Sabina Chubanava, Jonas T Treebak.

  Skeletal muscle is a tissue integral to general health. Due to its high abundance and oxidative capacity, its metabolism is intimately linked to whole-body physiology. In the elderly population, mobility correlates positively with life expectancy and survival. Furthermore, regular physical activity is one of the most effective health-promoting interventions that delay the onset of aging-associated chronic diseases. Data from preclinical studies show that aging of various tissues is accompanied by a decrease in the concentration of nicotinamide adenine dinucleotide (NAD), which plays a central role in energy homeostasis. Thus, a hypothesis has emerged that normalization of its content would ameliorate the age-related decline in tissue function and therefore improve health of the elderly. This idea, along with the documented safety and high tolerability of NAD precursor supplementation, makes NAD metabolism a prospective target for anti-aging interventions. Interestingly, muscle NAD biosynthesis pathways are stimulated by exercise training, which suggests that training-induced adaptations rely on tissue NAD levels. However, while the relationship between muscle fitness and regular physical activity is well-characterized, the proposed synergy between muscle NAD replenishment and exercise training has not been established. Here, we review the published data on the role of NAD metabolism in exercise in the context of young and aged skeletal muscle and discuss the current challenges relevant to the field.

Keywords:  Aging; Exercise training; NAD precursor supplementation; Skeletal muscle

DOI:  https://doi.org/10.1016/j.exger.2023.112109
Am J Physiol Regul Integr Comp Physiol. 2023 Jan 30.

Adult skeletal muscle PRC is involved in maintaining mitochondrial content.

Drue Benefield, Yazeed Abdelmageed, Jahmel Fowler, Serenah Smith, Kassandra Arias-Parbul, Courtney Dunning, Glenn C Rowe.

  The peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family of transcriptional coactivators are regulators of mitochondrial oxidative capacity and content in skeletal muscle. Many of these conclusions are based primarily on gain-of-function studies using muscle-specific overexpression of PGC1s. We have previously reported that genetic deletion of both PGC-1α and PGC-1β in adult skeletal muscle resulted in a significant reduction in oxidative capacity with no effect on mitochondrial content. However, the contribution of PGC-1-related coactivator (PRC), the third PGC-1 family member, in regulating skeletal muscle mitochondria is unknown. Therefore, we generated an inducible skeletal muscle-specific PRC knockout mouse (iMS-PRC-KO) to assess the contribution of PRC in skeletal muscle mitochondrial function. We measured mRNA expression of electron transport chain (ETC) subunits as well as markers of mitochondrial content in the iMS-PRC-KO animals and observed an increase in ETC gene expression and mitochondrial content. Furthermore, the increase in ETC gene expression and mitochondrial content was associated with increased expression of PGC-1α and PGC-1β. We therefore generated an adult inducible PGC-1 knockout mouse in which all PGC-1 family members are deleted (iMS-PGC-1TKO). The iMS-PGC-1TKO animals exhibited a reduction in ETC mRNA expression and mitochondrial content. These data suggest that in the absence of PRC alone, compensation occurs by increasing PGC-1α and PGC-1β to maintain mitochondrial content. Moreover, removal of all three PGC-1s in skeletal muscle result in a reduction in both ETC mRNA expression and mitochondrial content. Taken together, these results suggests that PRC plays a role in maintaining baseline mitochondrial content in skeletal muscle.

Keywords:  PRC; mitochondria; mitochondrial biogenesis; skeletal muscle

DOI:  https://doi.org/10.1152/ajpregu.00241.2022
J Cell Sci. 2023 Feb 02. pii: jcs.260496. [Epub ahead of print]

Re-organization of nucleolar architecture in myogenic differentiation.

Tetsuaki Miyake, John C McDermott.

  Myogenesis, the process of muscle differentiation, requires an extensive remodeling of the cellular transcriptome and proteome. While the transcriptional program underpinning myogenesis is well characterized, the required adaptation in protein synthesis is incompletely understood. Enhanced protein synthesis necessitates ribosome biogenesis at the nucleolus. Nucleolar size and activity are inextricably linked with altered gene expression. Here, we report changes in nucleolar morphology and function during myogenic differentiation. Immunofluorescence analysis revealed alterations in nucleolar morphology that were dependent on the cellular state: proliferative or quiescent myogenic progenitors (myoblasts or reserve cells) contain multiple small nucleoli with a characteristic spherical shape, whereas multinucleated myotubes typically contain one large, often irregularly shaped nucleolus. These morphological alterations are consistent with changes to nucleolar phase separation properties. Re-organization of the nucleolar structure was correlated with enhanced rRNA production and protein translation. Inhibition of mTOR signaling with Rapamycin perturbed nucleolar re-organization. Conversely, hyperactivated mTOR enhanced alterations in nucleolar morphology. These findings support an mTOR dependent re-organization of nucleolar structure during myogenesis, enhancing our understanding of myogenesis and possibly facilitating new approaches to therapeutic interventions in muscle pathologies.

Keywords:  MTOR; Myogenesis; Nucleolus; Ribosome; Translation

DOI:  https://doi.org/10.1242/jcs.260496
Exerc Sport Sci Rev. 2023 Feb 01.

Controlling Inflammation Improves Aging Skeletal Muscle Health.

William A Fountain, Masatoshi Naruse, Alex Claiborne, Scott Trappe, Todd A Trappe.

SUMMARY FOR TABLE OF CONTENTS: Controlling cyclooxygenase pathway regulated inflammation may help protect the health and plasticity of aging skeletal muscle.

DOI: https://doi.org/10.1249/JES.0000000000000313
J Cachexia Sarcopenia Muscle. 2023 Feb 01.

Chemical reprogramming of melanocytes to skeletal muscle cells.

Wenjun Yang, Yaqi Wang, Yuanyuan Du, Jiyong Li, Minzhi Jia, Sheng Li, Ruimiao Ma, Cheng Li, Hongkui Deng, Ping Hu.

  BACKGROUND: Direct cell-fate conversion by chemical reprogramming is promising for regenerative cell therapies. However, this process requires the reactivation of a set of master transcription factors (TFs) of the target cell type, which has proven challenging using only small molecules.METHODS: We developed a novel small-molecule cocktail permitting robust skin cell to muscle cell conversion. By single cell sequencing analysis, we identified a Pax3 (Paired box 3)-expressing melanocyte population holding a superior myogenic potential outperforming other seven types of skin cells. We further validated the single cell sequencing analysis results using immunofluorescence staining, in situ hybridization and FACS sorting and confirmed the myogenic potential of melanocytes during chemical reprogramming. We used single cell RNA-seq that detect the potential converted cell type, uncovering a unique role of Pax3 in facilitating chemical reprogramming from melanocytes to muscle cells.
RESULTS: In this study, we demonstrated that the Pax3-expressing melanocytes to be a skin cell type for skeletal muscle cell fate conversion in chemical reprogramming. By developing a small-molecule cocktail, we showed an efficient melanocyte reprogramming to skeletal muscle cells (40%, P < 0.001). The endogenous expression of specific TFs may circumvent the additional requirement for TF reactivation and form a shortcut for cell fate conversion, suggesting a basic principle that could ease cell fate conversion.
CONCLUSIONS: Our study demonstrates the first report of melanocyte-to-muscle conversion by small molecules, suggesting a novel strategy for muscle regeneration. Furthermore, skin is one of the tissues closely located to skeletal muscle, and therefore, our results provide a promising foundation for therapeutic chemical reprogramming in vivo treating skeletal muscle degenerative diseases.

Keywords:  Melanocytes; Reprogramming; Skeletal muscle cells; Small molecules

DOI:  https://doi.org/10.1002/jcsm.13155
Endocr Rev. 2023 Feb 02. pii: bnad004. [Epub ahead of print]

Intra-cellular to inter-organ mitochondrial communication in striated muscle in health and disease.

Neoma T Boardman, Giulia Trani, Marco Scalabrin, Vanina Romanello, Rob C I Wüst.

  Mitochondria both sense biochemical and energetic input in addition to communicating signals regarding the energetic state of the cell. Increasingly, these signaling organelles are key for regulating different cell functions. This review summarizes recent advances in mitochondrial communication in striated muscle, with specific focus on the processes by which mitochondria communicate with each other, other organelles and across distant organ systems. Inter-mitochondrial communication in striated muscle is mediated via conduction of the mitochondrial membrane potential to adjacent mitochondria, physical interactions, mitochondrial fusion or fission and via nannotunnels, allowing for the exchange of proteins, mitochondrial DNA, nucleotides, and peptides. Within striated muscle cells, mitochondria-organelle communication can modulate overall cell function. The various mechanisms in which mitochondria communicate mitochondrial fitness to the rest of the body suggest that extracellular mitochondrial signaling is key during health and disease. Whereas mitochondrial-derived vesicles might excrete mitochondrial-derived endocrine compounds, stimulation of mitochondrial stress can lead to the release of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) into the circulation to modulate whole-body physiology. Circulating mitochondrial DNA are well-known alarmins that trigger the immune system and may help to explain low-grade inflammation in various chronic diseases. Impaired mitochondrial function and communication are central in common heart and skeletal muscle pathologies, including cardiomyopathies, insulin resistance, and sarcopenia. Lastly, important new advances in research in mitochondrial endocrinology, communication, medical horizons and translational aspects are discussed.

Keywords:  FGF21; GDF15; mitochondria-organelle interactions; mitochondrial cristae; mitochondrial dynamics; myokines; respiratory supercomplexes

DOI:  https://doi.org/10.1210/endrev/bnad004
J Cell Biochem. 2023 Jan 30.

Dexamethasone leads to Zn2+ accumulation and increased unbound Zn2+ in C2C12 muscle and 3T3-L1 adipose cells.

Michelle C Maier, Scott Nankervis, Morgan E Wallace, Tamekha Develyn, Mark A Myers.

  Skeletal muscle atrophy is associated with increases in circulating glucocorticoid levels and insulin resistance. Zinc accumulates in atrophic muscle, but the relationship between atrophy, insulin resistance, and Zn2+ homeostasis remains unclear. In this study, the effect of the glucocorticoid dexamethasone (DEX) on insulin and Zn2+ homeostasis was explored. Treatment of differentiated C2C12 skeletal myotubes and 3T3-L1 adipocytes with DEX significantly increased mRNA expression of the metal-binding proteins Mt1 and 2 and altered energy storage as shown by the increased size of lipid droplets in 3T3-L1 cells. In C2C12 cells the total cellular Zn2+ was higher after DEX treatment, and in both C2C12 and 3T3-L1 adipocytes, free unbound Zn2+ was increased. Insulin treatment led to a gradual increase in free Zn2+ in C2C12 cells, and no significant change in DEX-treated cells such that concentrations were similar 10 min after insulin treatment. These data demonstrate that DEX disturbs Zn2+ homeostasis in muscle and fat cells. Further study of the molecular pathways involved to identify novel therapeutic targets for treatment of skeletal muscle atrophy is warranted.

Keywords:  dexamethasone; glucocorticoids; insulin; zinc

DOI:  https://doi.org/10.1002/jcb.30376
Eur J Appl Physiol. 2023 Jan 30.

Exercise-induced skeletal muscle angiogenesis: impact of age, sex, angiocrines and cellular mediators.

Mark Ross, Christopher K Kargl, Richard Ferguson, Timothy P Gavin, Ylva Hellsten.

  Exercise-induced skeletal muscle angiogenesis is a well-known physiological adaptation that occurs in humans in response to exercise training and can lead to endurance performance benefits, as well as improvements in cardiovascular and skeletal tissue health. An increase in capillary density in skeletal muscle improves diffusive oxygen exchange and waste extraction, and thus greater fatigue resistance, which has application to athletes but also to the general population. Exercise-induced angiogenesis can significantly contribute to improvements in cardiovascular and metabolic health, such as the increase in muscle glucose uptake, important for the prevention of diabetes. Recently, our understanding of the mechanisms by which angiogenesis occurs with exercise has grown substantially. This review will detail the biochemical, cellular and biomechanical signals for exercise-induced skeletal muscle angiogenesis, including recent work on extracellular vesicles and circulating angiogenic cells. In addition, the influence of age, sex, exercise intensity/duration, as well as recent observations with the use of blood flow restricted exercise, will also be discussed in detail. This review will provide academics and practitioners with mechanistic and applied evidence for optimising training interventions to promote physical performance through manipulating capillarisation in skeletal muscle.

Keywords:  Angiogenesis; Capillarisation; Endothelial cells; Exercise; Extracellular vesicles; Muscle blood flow; VEGF; Vascular smooth muscle

DOI:  https://doi.org/10.1007/s00421-022-05128-6
Nat Commun. 2023 Feb 01. 14(1): 535

Transcriptional reprogramming of skeletal muscle stem cells by the niche environment.

Felicia Lazure, Rick Farouni, Korin Sahinyan, Darren M Blackburn, Aldo Hernández-Corchado, Gabrielle Perron, Tianyuan Lu, Adrien Osakwe, Jiannis Ragoussis, Colin Crist, Theodore J Perkins, Arezu Jahani-Asl, Hamed S Najafabadi, Vahab D Soleimani.

Adult stem cells are indispensable for tissue regeneration, but their function declines with age. The niche environment in which the stem cells reside plays a critical role in their function. However, quantification of the niche effect on stem cell function is lacking. Using muscle stem cells (MuSC) as a model, we show that aging leads to a significant transcriptomic shift in their subpopulations accompanied by locus-specific gain and loss of chromatin accessibility and DNA methylation. By combining in vivo MuSC transplantation and computational methods, we show that the expression of approximately half of all age-altered genes in MuSCs from aged male mice can be restored by exposure to a young niche environment. While there is a correlation between gene reversibility and epigenetic alterations, restoration of gene expression occurs primarily at the level of transcription. The stem cell niche environment therefore represents an important therapeutic target to enhance tissue regeneration in aging.

DOI: https://doi.org/10.1038/s41467-023-36265-x
Oxid Med Cell Longev. 2023 ;2023 8408574

TRIM72 Alleviates Muscle Inflammation in mdx Mice via Promoting Mitophagy-Mediated NLRP3 Inflammasome Inactivation.

Mengli Wu, Huan Li, Juanjuan He, Jiahui Liang, Yanmei Liu, Weixi Zhang.

Chronic muscle inflammation exacerbates the pathogenesis of Duchenne muscular dystrophy (DMD), which is characterized by progressive muscle degeneration and weakness. NLRP3 (nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3) inflammasome plays a key role in the inflammatory process, and its abnormal activation leads to a variety of inflammatory or immune diseases. TRIM72 (MG53) is a protective myokine for tissue repair and regeneration. However, little is known about the potential impact of TRIM72 in the crosstalk between mitophagy and inflammatory process of DMD. Here, 10-week-old male mdx mice were injected intramuscularly with adeno-associated virus (AAV-TRIM72) to overexpress TRIM72 protein for 6 weeks. Then, skeletal muscle samples were collected, and relevant parameters were measured by histopathological analysis and molecular biology techniques. C2C12 cell line was transfected with lentivirus (LV-TRIM72) to overexpress or siRNA (si-TRIM72) to suppress the TRIM72 expression for the following experiment. Our data firstly showed that the TRIM72 expression was decreased in skeletal muscles of mdx mice. Then, we observed the increased NLRP3 inflammasome and impaired mitophagy in mdx mice compared with wild type mice. In mdx mice, administration of AAV-TRIM72 alleviated the accumulation of NLRP3 inflammasome and the consequent IL-18 and IL1β maturation by inducing autophagy, while this protective effect was reversed by chloroquine. Mitochondrial reactive oxygen species (mtROS), as a recognized activator for NLRP3 inflammasome, was attenuated by TRIM72 through the induction of mitophagy in C2C12 cells. Additionally, we proposed that the TRIM72 overexpression might promote mitophagy through both the early stage by PI3K-AKT pathway and the late stage by autolysosome fusion. In conclusion, the current study suggests that TRIM72 prevents DMD inflammation via decreasing NLRP3 inflammasomes and enhancing mitophagy. Collectively, our study provides insight into TRIM72 as a promising target for therapeutic intervention for DMD.

DOI: https://doi.org/10.1155/2023/8408574
bioRxiv. 2023 Jan 13. pii: 2023.01.13.523698. [Epub ahead of print]

The mitochondrial multi-omic response to exercise training across tissues.

MoTrPAC Study Group

Mitochondria are adaptable organelles with diverse cellular functions critical to whole-body metabolic homeostasis. While chronic endurance exercise training is known to alter mitochondrial activity, these adaptations have not yet been systematically characterized. Here, the Molecular Transducers of Physical Activity Consortium (MoTrPAC) mapped the longitudinal, multi-omic changes in mitochondrial analytes across 19 tissues in male and female rats endurance trained for 1, 2, 4 or 8 weeks. Training elicited substantial changes in the adrenal gland, brown adipose, colon, heart and skeletal muscle, while we detected mild responses in the brain, lung, small intestine and testes. The colon response was characterized by non-linear dynamics that resulted in upregulation of mitochondrial function that was more prominent in females. Brown adipose and adrenal tissues were characterized by substantial downregulation of mitochondrial pathways. Training induced a previously unrecognized robust upregulation of mitochondrial protein abundance and acetylation in the liver, and a concomitant shift in lipid metabolism. The striated muscles demonstrated a highly coordinated response to increase oxidative capacity, with the majority of changes occurring in protein abundance and post-translational modifications. We identified exercise upregulated networks that are downregulated in human type 2 diabetes and liver cirrhosis. In both cases HSD17B10, a central dehydrogenase in multiple metabolic pathways and mitochondrial tRNA maturation, was the main hub. In summary, we provide a multi-omic, cross-tissue atlas of the mitochondrial response to training and identify candidates for prevention of disease-associated mitochondrial dysfunction.

DOI: https://doi.org/10.1101/2023.01.13.523698
J Virol Methods. 2023 Feb 01. pii: S0166-0934(23)00013-7. [Epub ahead of print] 114688

Local and systemic administration of AAV vectors with alphaherpesvirus latency-associated promoter 2 drives potent transgene expression in mouse liver, kidney, and skeletal muscle.

Carola J Maturana, Angela Chan, Jessica L Verpeut, Esteban A Engel.

  Adeno-associated virus (AAV) has great potential as a source of treatments for conditions that might respond to potent and ubiquitous transgene expression. However, among its drawbacks, the genetic "payload" of AAV vectors is limited to <4.9kb and some commonly used gene promoters are sizeable and susceptible to transcriptional silencing. We recently described a short (404bp), potent, and persistent promoter obtained from the genome of pseudorabies virus (PrV) called alphaherpesvirus latency-associated promoter 2 (LAP2). Here, we evaluated the biodistribution and potency of transgene expression in mouse peripheral tissues in response to local and systemic administration of AAV8-LAP2 and AAV9-LAP2. We found that administration of these vectors resulted in levels of transgene expression that were similar to the larger EF1α promoter. LAP2 drives potent transgene expression in mouse liver and kidney when administered systemically and in skeletal muscle in response to intramuscular delivery. Notably, in skeletal muscle, administration of vectors with LAP2 and EF1α promoters resulted in preferential transduction of myofibers type 2. A direct side-by-side comparison between LAP2 and the EF1α promoter revealed that, despite its smaller size, LAP2 was equally potent to the EF1α promoter and resulted in widespread gene expression after IV and IM administration of AAV8 or AAV9 vectors. Collectively, these findings suggest that constructs that include LAP2 may have the capacity to deliver large therapeutically effective payloads in support of future gene therapy protocols.

Keywords:  AAV; Gene Therapy; Kidney; Liver; Promoter; Skeletal Muscle

DOI:  https://doi.org/10.1016/j.jviromet.2023.114688
Am J Physiol Endocrinol Metab. 2023 Feb 01.

Advanced glycation end products induce skeletal muscle atrophy and insulin resistance via activating ROS-mediated ER stress PERK/FOXO1 signaling.

Haixia Du, Yanpeng Ma, Xiqiang Wang, Yong Zhang, Ling Zhu, Shuang Shi, Shuo Pan, Zhongwei Liu.

  Skeletal muscle atrophy is often found in patients with type 2 diabetes mellitus (T2DM) which is characterized with insulin resistance. As the largest tissue in the body, skeletal muscle plays important roles in insulin resistance. Advanced glycation end products (AGEs) are representative toxic metabolites and associated with multiple pathophysiologic changes of T2DM. In this study, we investigated whether AGEs could exacerbate skeletal muscle atrophy and its related insulin resistance. Mice were exposed to AGEs. Forkhead box O1 (FOXO1) was silenced by a constructed viral vector carrying siRNA. Skeletal muscle atrophy was evaluated by H&E, oil red O, myosin skeletal heavy chain (MHC) and laminin immunofluorescent stains. Reactive oxygen species (ROS) generation was assessed by DHE stain. Western blotting was used to evaluate protein expression and phosphorylation. Insulin resistance was monitored by insulin tolerance test (ITT) and glucose infusion rate (GIR). Mice exposed to AGEs showed insulin resistance which was evidenced by reduced ITT and GIR. H&E and MHC immunofluorescent stains suggested reduced cross-sectional muscle fiber area. Laminin immunofluorescent and Oil red O stains indicated increased intramuscular fibrosis and lipid deposit respectively. AGEs exposure induced ROS generation, increased phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and FOXO1, facilitated FOXO1 nuclear translocation and elevated expression of muscle atrophy F-box (MAFbx) in gastrocnemius muscle. foxo1 silencing significantly suppressed skeletal muscle atrophy and insulin resistance without affecting ROS production. AGEs exacerbated skeletal muscle atrophy and insulin resistance by activating PERK/FOXO1 signaling pathway in skeletal muscle.

Keywords:  Advanced glycation end products; Atrophy; Endoplasmic reticulum stress; Insulin resistance; Skeletal muscle

DOI:  https://doi.org/10.1152/ajpendo.00218.2022
Cell Prolif. 2023 Feb 01. e13410

The m6A reader YTHDC1 regulates muscle stem cell proliferation via PI4K-Akt-mTOR signalling.

Jin Liu, Hongna Zuo, Ziliu Wang, Wei Wang, Xuezhen Qian, Yingyuan Xie, Di Peng, Yubin Xie, Liquan Hong, Wanling You, Huiling Lou, Guanzheng Luo, Jian Ren, Bin Shen, Jinping Zheng, Hu Wang, Zhenyu Ju.

Muscle stem cells are required for the homeostasis and regeneration of mammalian skeletal muscles. It has been reported that RNA N6-methyladenosine (m6A) modifications play a pivotal role in muscle development and regeneration. Nevertheless, we know little about which m6A reader regulates mammalian muscle stem cells. Here, we discovered that the m6A reader Ythdc1 is indispensable for mouse skeletal muscle regeneration and proliferation of muscle stem cells. In the absence of Ythdc1, Muscle stem cells in adult mice are unable to exit from quiescence. Mechanistically, Ythdc1 binds to m6A-modified Pi4k2a and Pi4kb mRNAs to regulate their alternative splicing and thus PI4K-Akt-mTOR signalling. Ythdc1-null muscle stem cells show a deficiency in phosphatidylinositol (PI) 3,4,5-trisphosphate, phospho-Akt and phospho-S6, which correlates with a failure in exit from quiescence. Our findings connect dynamic RNA methylation to the regulation of PI4K-Akt-mTOR signalling during stem cell proliferation and adult tissue regeneration.

DOI: https://doi.org/10.1111/cpr.13410
Cell Rep. 2023 Jan 31. pii: S2211-1247(23)00062-1. [Epub ahead of print]42(2): 112051

Spatial compartmentalization of signaling imparts source-specific functions on secreted factors.

Elena Groppa, Paolo Martini, Nima Derakhshan, Marine Theret, Morten Ritso, Lin Wei Tung, Yu Xin Wang, Hesham Soliman, Mark Stephen Hamer, Laura Stankiewicz, Christine Eisner, Le Nevé Erwan, Chihkai Chang, Lin Yi, Jack H Yuan, Sunny Kong, Curtis Weng, Josephine Adams, Lucas Chang, Anne Peng, Helen M Blau, Chiara Romualdi, Fabio M V Rossi.

  Efficient regeneration requires multiple cell types acting in coordination. To better understand the intercellular networks involved and how they change when regeneration fails, we profile the transcriptome of hematopoietic, stromal, myogenic, and endothelial cells over 14 days following acute muscle damage. We generate a time-resolved computational model of interactions and identify VEGFA-driven endothelial engagement as a key differentiating feature in models of successful and failed regeneration. In addition, the analysis highlights that the majority of secreted signals, including VEGFA, are simultaneously produced by multiple cell types. To test whether the cellular source of a factor determines its function, we delete VEGFA from two cell types residing in close proximity: stromal and myogenic progenitors. By comparing responses to different types of damage, we find that myogenic and stromal VEGFA have distinct functions in regeneration. This suggests that spatial compartmentalization of signaling plays a key role in intercellular communication networks.

Keywords:  CP: Stem cell research; FAP; VEGFA; angiogenesis; bioinformatics; muscle progenitor; signaling redundancy; skeletal muscle

DOI:  https://doi.org/10.1016/j.celrep.2023.112051
Am J Physiol Cell Physiol. 2023 Jan 30.

Normal muscle fiber type distribution is recapitulated in aged ephrin-A3-/- mice that previously lacked most slow myofibers.

Robert W Arpke, Timothy C Moritz, Kevin L Hahn, Danny A Stark, Eric Villalón, Christian L Lorson, Ddw Cornelison.

  Individual limb muscles have characteristic representation and spatial distribution of muscle fiber types (one slow and up to three fast isoforms) appropriate to their unique anatomical location and function. This distribution can be altered by physiological stimuli such as training (i.e., for increased endurance or force) or pathological conditions such as aging. Our group previously showed that ephrin-A3 is expressed only on slow myofibers, and that adult mice lacking ephrin-A3 have dramatically reduced numbers of slow myofibers due to postnatal innervation of previously slow myofibers by fast motor neurons. In this study, fiber type composition of hindlimb muscles of aged and denervated/reinnervated C57BL/6 and ephrin-A3-/- mice was analyzed to determine whether the loss of slow myofibers persists across the lifespan. Surprisingly, fiber type composition of ephrin-A3-/- mouse muscles at two years of age was nearly indistinguishable from age-matched C57BL/6 mice. After challenge with nerve crush, the percentage of IIa and I/IIa hybrid myofibers increased significantly in aged ephrin-A3-/- mice. While EphA8, the receptor for ephrin-A3, is present at all NMJs on fast fibers in 3-6 month old C57BL/6 and ephrin-A3-/- mice, this exclusive localization is lost with aging, with EphA8 expression now found on a subset of NMJs on some slow muscle fibers. This return to appropriate fiber type distribution given time and under use reinforces the role of activity in determining fiber type representation and suggests that, rather than being a passive baseline, the developmentally and evolutionarily selected fiber type pattern may instead be actively reinforced by daily living.

Keywords:  Eph/ephrin; Skeletal muscle; aging; fiber type

DOI:  https://doi.org/10.1152/ajpcell.00519.2022
Appl Physiol Nutr Metab. 2023 Feb 03.

Protein quality and the food matrix: Defining optimal vs. maximal meal-based protein intakes for stimulating muscle protein synthesis.

Takeshi M Barnes, Max T Deutz, Žan Zupančič, Andrew T Askow, Daniel R Moore, Nicholas A Burd.

This paper examines the opinion that we should aim to optimize, rather than maximize, protein intakes to avoid over-emphasizing muscle-centric protein requirements. An optimal eating approach strives to minimize amino acid oxidative waste and more efficiently stimulate postprandial muscle protein accretion. To do this, practitioners should acknowledge that higher quality protein foods as better in delivering target amounts of amino acids into circulation, and the food matrix (e.g., nutrient-nutrient interactions) can be leveraged to potentiate essential amino acid incorporation into skeletal muscle protein.

DOI: https://doi.org/10.1139/apnm-2022-0373
Neurotherapeutics. 2023 Jan 30.

Bicalutamide and Trehalose Ameliorate Spinal and Bulbar Muscular Atrophy Pathology in Mice.

Mariarita Galbiati, Marco Meroni, Marina Boido, Matilde Cescon, Paola Rusmini, Valeria Crippa, Riccardo Cristofani, Margherita Piccolella, Veronica Ferrari, Barbara Tedesco, Elena Casarotto, Marta Chierichetti, Marta Cozzi, Francesco Mina, Maria Elena Cicardi, Silvia Pedretti, Nico Mitro, Anna Caretto, Patrizia Risè, Angelo Sala, Andrew P Lieberman, Paolo Bonaldo, Maria Pennuto, Alessandro Vercelli, Angelo Poletti.

  Spinal and bulbar muscular atrophy (SBMA) is characterized by motor neuron (MN) degeneration that leads to slowly progressive muscle weakness. It is considered a neuromuscular disease since muscle has a primary role in disease onset and progression. SBMA is caused by a CAG triplet repeat expansion in the androgen receptor (AR) gene. The translated poly-glutamine (polyQ) tract confers a toxic gain of function to the mutant AR altering its folding, causing its aggregation into intracellular inclusions, and impairing the autophagic flux. In an in vitro SBMA neuronal model, we previously showed that the antiandrogen bicalutamide and trehalose, a natural disaccharide stimulating autophagy, block ARpolyQ activation, reduce its nuclear translocation and toxicity and facilitate the autophagic degradation of cytoplasmic AR aggregates. Here, in a knock-in SBMA mouse model (KI AR113Q), we show that bicalutamide and trehalose ameliorated SBMA pathology. Bicalutamide reversed the formation of the AR insoluble forms in KI AR113Q muscle, preventing autophagic flux blockage. We demonstrated that apoptosis is activated in KI AR113Q muscle, and that both compounds prevented its activation. We detected a decrease of mtDNA and an increase of OXPHOS enzymes, already at early symptomatic stages; these alterations were reverted by trehalose. Overall, bicalutamide and/or trehalose led to a partial recovery of muscle morphology and function, and improved SBMA mouse motor behavior, inducing an extension of their survival. Thus, bicalutamide and trehalose, by counteracting ARpolyQ toxicity in skeletal muscle, are valuable candidates for future clinical trials in SBMA patients.

Keywords:  Androgen receptor; Autophagy; Motor neuron; SBMA; Skeletal muscle

DOI:  https://doi.org/10.1007/s13311-023-01343-x
bioRxiv. 2023 Jan 12. pii: 2023.01.10.523450. [Epub ahead of print]

Multiomic identification of key transcriptional regulatory programs during endurance exercise training.

MoTrPAC Study Group

Transcription factors (TFs) play a key role in regulating gene expression and responses to stimuli. We conducted an integrated analysis of chromatin accessibility and RNA expression across various rat tissues following endurance exercise training (EET) to map epigenomic changes to transcriptional changes and determine key TFs involved. We uncovered tissue-specific changes across both omic layers, including highly correlated differentially accessible regions (DARs) and differentially expressed genes (DEGs). We identified open chromatin regions associated with DEGs (DEGaPs) and found tissue-specific and genomic feature-specific TF motif enrichment patterns among both DARs and DEGaPs. Accessible promoters of up-vs. down-regulated DEGs per tissue showed distinct TF enrichment patterns. Further, some EET-induced TFs in skeletal muscle were either validated at the proteomic level (MEF2C and NUR77) or correlated with exercise-related phenotypic changes. We provide an in-depth analysis of the epigenetic and trans-factor-dependent processes governing gene expression during EET.

DOI: https://doi.org/10.1101/2023.01.10.523450
Front Biosci (Landmark Ed). 2023 Jan 18. 28(1): 16

Muscle FOXO-Specific Overexpression and Endurance Exercise Protect Skeletal Muscle and Heart from Defects Caused by a High-Fat Diet in Young Drosophila.

Jun-Hui Jin, Deng-Tai Wen, Yi-Ling Chen, Wen-Qi Hou.

  BACKGROUND: Obesity appears to significantly reduce physical activity, but it remains unclear whether this is related to obesity-induced damage to skeletal muscle (SM) and heart muscle (HM). Endurance exercise (EE) reduces obesity-induced defects in SM and HM, but its molecular mechanism is poorly understood.METHODS: The UAS/GAL4 system was used to construct the regulation of SM-specific FOXO gene expression in Drosophila, and the transgenic drosophila was subjected to EE and high-fat diet (HFD) intervention.
RESULTS: The structure and function of SM and HM were impaired by a HFD and muscle-FOXO-specific RNAi (MFSR), including reduced climbing speed and climbing endurance, reduced fractional shortening of the heart, damaged myofibrils, and reduced mitochondria in HM. Besides, a HFD and MFSR increased triglyceride level and malondialdehyde level, decreased the Sirt1 and FOXO protein level, and reduced carnitine palmityl transferase I, superoxide dismutase, and catalase activity level, and they dow-regulated FOXO and bmm expression level in SM and HM. On the contrary, both muscle FOXO-specific overexpression (MFSO) and EE prevented abnormal changes of SM and HM in function, structure, or physiology caused by HFD and MFSR. Besides, EE also prevented defects of SM and HM induced by MFSR.
CONCLUSIONS: Current findings confirmed MFSO and EE protected SM and heart from defects caused by a HFD via enhancing FOXO-realated antioxidant pathways and lipid catabolism. FOXO played a vital role in regulating HFD-induced defects in SM and HM, but FOXO was not a key regulatory gene of EE against damages in SM and HM. The mechanism was related to activity of Sirt1/FOXO/SOD (superoxide dismutase), CAT (catalase) pathways and lipid catabolism in SM and HM.

Keywords:  FOXO/SOD/CAT; exercise; high-fat diet; lipid metabolism; muscle/heart

DOI:  https://doi.org/10.31083/j.fbl2801016
J Gerontol A Biol Sci Med Sci. 2023 Feb 04. pii: glad033. [Epub ahead of print]

Challenges and Future Prospects of Targeting Myostatin/Activin A Signaling to Treat Diseases of Muscle Loss and Metabolic Dysfunction.

Se-Jin Lee, Shalender Bhasin, Lloyd Klickstein, Venkatesh Krishnan, Daniel Rooks.

  Over the past 25 years, considerable progress has been made in terms of elucidating the regulatory and signaling mechanisms underlying the control of skeletal muscle mass by myostatin and other secreted proteins belonging to the transforming growth factor-ß superfamily. Preclinical studies demonstrating the potential benefits of targeting the activities of these ligands have fueled the development of numerous biologics capable of perturbing this signaling pathway and increasing muscle mass and function. These biologics have been tested in numerous clinical trials for a wide range of indications characterized by muscle loss and excess adiposity. Here, we review the results of these trials and discuss some of the challenges and future prospects for targeting this signaling pathway to treat muscle and metabolic diseases. Myostatin inhibitors may improve metabolic outcomes by increasing muscle mass, and metabolic disorders may be attractive potential indications for these molecules.

Keywords:  Activin A; Metabolic dysfunction; Mobility-disability; Muscle loss; Myostatin

DOI:  https://doi.org/10.1093/gerona/glad033
Sci Adv. 2023 Feb 03. 9(5): eadd0455

Spatial metabolomics reveals skeletal myofiber subtypes.

Lanfang Luo, Wenwu Ma, Kun Liang, Yuefan Wang, Jiali Su, Ruirui Liu, Taoyan Liu, Ng Shyh-Chang.

Skeletal muscle myofibers are heterogeneous in their metabolism. However, metabolomic profiling of single myofibers has remained difficult. Mass spectrometry imaging (MSI) is a powerful tool for imaging molecular distributions. In this work, we optimized the workflow of matrix-assisted laser desorption/ionization (MALDI)-based MSI from cryosectioning to metabolomics data analysis to perform high-spatial resolution metabolomic profiling of slow- and fast-twitch myofibers. Combining the advantages of MSI and liquid chromatography-MS (LC-MS), we produced spatial metabolomics results that were more reliable. After the combination of high-spatial resolution MSI and LC-MS metabolomic analysis, we also discovered a new subtype of superfast type 2B myofibers that were enriched for fatty acid oxidative metabolism. Our technological workflow could serve as an engine for metabolomics discoveries, and our approach has the potential to provide critical insights into the metabolic heterogeneity and pathways that underlie fundamental biological processes and disease states.

DOI: https://doi.org/10.1126/sciadv.add0455