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Nucleic Acids Research Jul 2023Although targeting TfR1 to deliver oligonucleotides to skeletal muscle has been demonstrated in rodents, effectiveness and pharmacokinetic/pharmacodynamic (PKPD)...
Although targeting TfR1 to deliver oligonucleotides to skeletal muscle has been demonstrated in rodents, effectiveness and pharmacokinetic/pharmacodynamic (PKPD) properties remained unknown in higher species. We developed antibody-oligonucleotide conjugates (AOCs) towards mice or monkeys utilizing anti-TfR1 monoclonal antibodies (αTfR1) conjugated to various classes of oligonucleotides (siRNA, ASOs and PMOs). αTfR1 AOCs delivered oligonucleotides to muscle tissue in both species. In mice, αTfR1 AOCs achieved a > 15-fold higher concentration to muscle tissue than unconjugated siRNA. A single dose of an αTfR1 conjugated to an siRNA against Ssb mRNA produced > 75% Ssb mRNA reduction in mice and monkeys, and mRNA silencing was greatest in skeletal and cardiac (striated) muscle with minimal to no activity in other major organs. In mice the EC50 for Ssb mRNA reduction in skeletal muscle was >75-fold less than in systemic tissues. Oligonucleotides conjugated to control antibodies or cholesterol produced no mRNA reduction or were 10-fold less potent, respectively. Tissue PKPD of AOCs demonstrated mRNA silencing activity primarily driven by receptor-mediated delivery in striated muscle for siRNA oligonucleotides. In mice, we show that AOC-mediated delivery is operable across various oligonucleotide modalities. AOC PKPD properties translated to higher species, providing promise for a new class of oligonucleotide therapeutics.
Topics: Mice; Animals; Oligonucleotides; Oligonucleotides, Antisense; Antibodies; RNA, Small Interfering; RNA, Messenger; Muscle, Skeletal
PubMed: 37224533
DOI: 10.1093/nar/gkad415 -
Journal of Translational Medicine Jul 2023Mitochondria play important roles in maintaining cellular homeostasis and skeletal muscle health, and damage to mitochondria can lead to a series of pathophysiological... (Review)
Review
Mitochondria play important roles in maintaining cellular homeostasis and skeletal muscle health, and damage to mitochondria can lead to a series of pathophysiological changes. Mitochondrial dysfunction can lead to skeletal muscle atrophy, and its molecular mechanism leading to skeletal muscle atrophy is complex. Understanding the pathogenesis of mitochondrial dysfunction is useful for the prevention and treatment of skeletal muscle atrophy, and finding drugs and methods to target and modulate mitochondrial function are urgent tasks in the prevention and treatment of skeletal muscle atrophy. In this review, we first discussed the roles of normal mitochondria in skeletal muscle. Importantly, we described the effect of mitochondrial dysfunction on skeletal muscle atrophy and the molecular mechanisms involved. Furthermore, the regulatory roles of different signaling pathways (AMPK-SIRT1-PGC-1α, IGF-1-PI3K-Akt-mTOR, FoxOs, JAK-STAT3, TGF-β-Smad2/3 and NF-κB pathways, etc.) and the roles of mitochondrial factors were investigated in mitochondrial dysfunction. Next, we analyzed the manifestations of mitochondrial dysfunction in muscle atrophy caused by different diseases. Finally, we summarized the preventive and therapeutic effects of targeted regulation of mitochondrial function on skeletal muscle atrophy, including drug therapy, exercise and diet, gene therapy, stem cell therapy and physical therapy. This review is of great significance for the holistic understanding of the important role of mitochondria in skeletal muscle, which is helpful for researchers to further understanding the molecular regulatory mechanism of skeletal muscle atrophy, and has an important inspiring role for the development of therapeutic strategies for muscle atrophy targeting mitochondria in the future.
Topics: Humans; Phosphatidylinositol 3-Kinases; Muscular Atrophy; Muscle, Skeletal; Mitochondria; Signal Transduction; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
PubMed: 37495991
DOI: 10.1186/s12967-023-04369-z -
Annals of Medicine Dec 2023Technological advances of hand-held ultrasound devices and educational programmes for their use, such as point-of-care ultrasonography (POCUS) training, have contributed... (Review)
Review
Technological advances of hand-held ultrasound devices and educational programmes for their use, such as point-of-care ultrasonography (POCUS) training, have contributed to the increasing application of these devices in clinical practice. With the greater impact of frailty and sarcopenia in aging societies, attention is being focused on the use of ultrasound for skeletal muscle assessment. In this narrative review, we discuss how ultrasound can be applied to skeletal muscle assessment, especially that of the quadriceps muscle, in clinical practice. Muscle thickness by ultrasound has been shown to have good reliability and validity for the evaluation of muscle size, and echo intensity has been used to evaluate muscle quality. Muscle ultrasound has not only been useful to diagnose sarcopenia in various settings, but has also been validated to predict health-related outcomes such as death and functional disability. Recommended methods for muscle ultrasound was published recently, and the results of future studies are expected to be comparable. Although several challenging issues with muscle ultrasound remain, if it could be incorporated into educational programmes such as POCUS training, more clinicians may be able to use ultrasound for skeletal muscle assessment in the future.KEY MESSAGESThe evolution of hand-held ultrasound devices enables physicians to perform ultrasound at the bedside as part of regular medical examinations.Muscle ultrasound is considered an effective tool for evaluating muscle size and quality, and has been studied in various settings.More clinicians may be able to evaluate skeletal muscle assessment with the development of educational programmes on muscle ultrasound in the future.
Topics: Humans; Sarcopenia; Point-of-Care Systems; Reproducibility of Results; Muscle, Skeletal; Ultrasonography
PubMed: 36538042
DOI: 10.1080/07853890.2022.2157871 -
Cell Metabolism Oct 2023Muscle-residing regulatory T cells (Tregs) control local tissue integrity and function. However, the molecular interface connecting Treg-based regulation with muscle...
Muscle-residing regulatory T cells (Tregs) control local tissue integrity and function. However, the molecular interface connecting Treg-based regulation with muscle function and regeneration remains largely unexplored. Here, we show that exercise fosters a stable induction of highly functional muscle-residing Tregs with increased expression of amphiregulin (Areg), EGFR, and ST2. Mechanistically, we find that mice lacking IL6Rα on T cells (TKO) harbor significant reductions in muscle Treg functionality and satellite and fibro-adipogenic progenitor cells, which are required for muscle regeneration. Using exercise and sarcopenia models, IL6Rα TKO mice demonstrate deficits in Tregs, their functional maturation, and a more pronounced decline in muscle mass. Muscle injury models indicate that IL6Rα TKO mice have significant disabilities in muscle regeneration. Treg gain of function restores impaired muscle repair in IL6Rα TKO mice. Of note, pharmacological IL6R blockade in WT mice phenocopies deficits in muscle function identified in IL6Rα TKO mice, thereby highlighting the clinical implications of the findings.
Topics: Mice; Animals; T-Lymphocytes, Regulatory; Muscle, Skeletal; Signal Transduction; Adipogenesis; Receptors, Interleukin-6
PubMed: 37734370
DOI: 10.1016/j.cmet.2023.08.010 -
Cell Metabolism Feb 2024The risk associated with multiple cancers, cardiovascular disease, diabetes, and all-cause mortality is decreased in individuals who meet the current recommendations for... (Review)
Review
The risk associated with multiple cancers, cardiovascular disease, diabetes, and all-cause mortality is decreased in individuals who meet the current recommendations for physical activity. Therefore, regular exercise remains a cornerstone in the prevention and treatment of non-communicable diseases. An acute bout of exercise results in the coordinated interaction between multiple tissues to meet the increased energy demand of exercise. Over time, the associated metabolic stress of each individual exercise bout provides the basis for long-term adaptations across tissues, including the cardiovascular system, skeletal muscle, adipose tissue, liver, pancreas, gut, and brain. Therefore, regular exercise is associated with a plethora of benefits throughout the whole body, including improved cardiorespiratory fitness, physical function, and glycemic control. Overall, we summarize the exercise-induced adaptations that occur within multiple tissues and how they converge to ultimately improve cardiometabolic health.
Topics: Humans; Exercise; Muscle, Skeletal; Cardiovascular System; Cardiovascular Diseases; Adipose Tissue
PubMed: 38183980
DOI: 10.1016/j.cmet.2023.12.008 -
Cell Reports Jun 2023Physiology is regulated by interconnected cell and tissue circadian clocks. Disruption of the rhythms generated by the concerted activity of these clocks is associated...
Physiology is regulated by interconnected cell and tissue circadian clocks. Disruption of the rhythms generated by the concerted activity of these clocks is associated with metabolic disease. Here we tested the interactions between clocks in two critical components of organismal metabolism, liver and skeletal muscle, by rescuing clock function either in each organ separately or in both organs simultaneously in otherwise clock-less mice. Experiments showed that individual clocks are partially sufficient for tissue glucose metabolism, yet the connections between both tissue clocks coupled to daily feeding rhythms support systemic glucose tolerance. This synergy relies in part on local transcriptional control of the glucose machinery, feeding-responsive signals such as insulin, and metabolic cycles that connect the muscle and liver. We posit that spatiotemporal mechanisms of muscle and liver play an essential role in the maintenance of systemic glucose homeostasis and that disrupting this diurnal coordination can contribute to metabolic disease.
Topics: Mice; Animals; Circadian Clocks; Circadian Rhythm; Liver; Muscle, Skeletal; Glucose
PubMed: 37267101
DOI: 10.1016/j.celrep.2023.112588 -
International Journal of Molecular... Jun 2023Skeletal muscle is continuously exposed during its activities to mechanical/oxidative damage [...].
Skeletal muscle is continuously exposed during its activities to mechanical/oxidative damage [...].
Topics: Oxidative Stress; Muscle, Skeletal
PubMed: 37373372
DOI: 10.3390/ijms241210227 -
Nature Communications Nov 2023MyoD is a skeletal muscle-specifically expressed transcription factor and plays a critical role in regulating myogenesis during muscle development and regeneration....
MyoD is a skeletal muscle-specifically expressed transcription factor and plays a critical role in regulating myogenesis during muscle development and regeneration. However, whether myofibers-expressed MyoD exerts its metabolic function in regulating whole body energy homeostasis in vivo remains largely unknown. Here, we report that genetic deletion of Myod in male mice enhances the oxidative metabolism of muscle and, intriguingly, renders the male mice resistant to high fat diet-induced obesity. By performing lipidomic analysis in muscle-conditioned medium and serum, we identify 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) as a muscle-released lipid that is responsible for MyoD-orchestrated body energy homeostasis in male Myod KO mice. Functionally, the administration of DLPC significantly ameliorates HFD-induced obesity in male mice. Mechanistically, DLPC is found to induce white adipose browning via lipid peroxidation-mediated p38 signaling in male mice. Collectively, our findings not only uncover a novel function of MyoD in controlling systemic energy homeostasis through the muscle-derived lipokine DLPC but also suggest that the DLPC might have clinical potential for treating obesity in humans.
Topics: Humans; Male; Animals; Mice; Obesity; Muscle, Skeletal; Transcription Factors; Gene Expression Regulation; Homeostasis; Diet, High-Fat; Energy Metabolism; Mice, Inbred C57BL; Adipose Tissue, White; Adipose Tissue, Brown
PubMed: 38036537
DOI: 10.1038/s41467-023-43402-z -
Nature Metabolism Jul 2023Adaptive thermogenesis by brown adipose tissue (BAT) dissipates calories as heat, making it an attractive anti-obesity target. Yet how BAT contributes to circulating...
Adaptive thermogenesis by brown adipose tissue (BAT) dissipates calories as heat, making it an attractive anti-obesity target. Yet how BAT contributes to circulating metabolite exchange remains unclear. Here, we quantified metabolite exchange in BAT and skeletal muscle by arteriovenous metabolomics during cold exposure in fed male mice. This identified unexpected metabolites consumed, released and shared between organs. Quantitative analysis of tissue fluxes showed that glucose and lactate provide ~85% of carbon for adaptive thermogenesis and that cold and CL316,243 trigger markedly divergent fuel utilization profiles. In cold adaptation, BAT also dramatically increases nitrogen uptake by net consuming amino acids, except glutamine. Isotope tracing and functional studies suggest glutamine catabolism concurrent with synthesis via glutamine synthetase, which avoids ammonia buildup and boosts fuel oxidation. These data underscore the ability of BAT to function as a glucose and amino acid sink and provide a quantitative and comprehensive landscape of BAT fuel utilization to guide translational studies.
Topics: Male; Animals; Mice; Adipose Tissue, Brown; Glutamine; Glucose; Thermogenesis; Muscle, Skeletal
PubMed: 37337122
DOI: 10.1038/s42255-023-00825-8 -
Journal of Applied Physiology... Jan 2024Skeletal muscle is a highly complex tissue that is studied by scientists from a wide spectrum of disciplines, including motor control, biomechanics, exercise science,... (Review)
Review
Skeletal muscle is a highly complex tissue that is studied by scientists from a wide spectrum of disciplines, including motor control, biomechanics, exercise science, physiology, cell biology, genetics, regenerative medicine, orthopedics, and engineering. Although this diversity in perspectives has led to many important discoveries, historically, there has been limited overlap in discussions across fields. This has led to misconceptions and oversimplifications about muscle biology that can create confusion and potentially slow scientific progress across fields. The purpose of this synthesis paper is to bring together research perspectives across multiple muscle fields to identify common assumptions related to muscle fiber type that are points of concern to clarify. These assumptions include ) classification by myosin isoform and fiber oxidative capacity is equivalent, ) fiber cross-sectional area (CSA) is a surrogate marker for myosin isoform or oxidative capacity, and ) muscle force-generating capacity can be inferred from myosin isoform. We address these three fiber-type traps and provide some context for how these misunderstandings can and do impact experimental design, computational modeling, and interpretations of findings, from the perspective of a range of fields. We stress the dangers of generalizing findings about "muscle fiber types" among muscles or across species or sex, and we note the importance for precise use of common terminology across the muscle fields.
Topics: Biomechanical Phenomena; Muscle Fibers, Skeletal; Muscle, Skeletal; Myosins; Protein Isoforms; Biology; Myosin Heavy Chains
PubMed: 37994416
DOI: 10.1152/japplphysiol.00337.2023