bims-moremu 2024-03-17 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2024‒03‒17
29 papers selected by
Anna Vainshtein, Craft Science Inc.

Affinity Purification-Mass Spectrometry and Single Fiber Physiology/Proteomics Reveals Mechanistic Insights of C18ORF25.
Deficiency of skeletal muscle Agrin contributes to the pathogenesis of age-related sarcopenia in mice.
Insights into post-translational regulation of skeletal muscle contractile function by the acetyltransferases, p300 and CBP.
Advancing cancer cachexia diagnosis with -omics technology and exercise as molecular medicine.
The Acute, Short-, and Long-Term Effects of Endurance Exercise on Skeletal Muscle Transcriptome Profiles.
Studying the Effect of MBNL1 and MBNL2 Loss in Skeletal Muscle Regeneration.
High-Resolution Spatial Transcriptomic Atlas of Mouse Soleus Muscle: Unveiling Single Cell and Subcellular Heterogeneity in Health and Denervation.
Exercise Training Differentially Affects Skeletal Muscle Mitochondria in Rats with Inherited High or Low Exercise Capacity.
A serine metabolic enzyme is flexing its muscle to help repair skeletal muscle.
A novel imaging method (FIM-ID) reveals that myofibrillogenesis plays a major role in the mechanically induced growth of skeletal muscle.
YTHDF2 governs muscle size through a targeted modulation of proteostasis.
Integrative cross-species analysis reveals conserved and unique signatures in fatty skeletal muscles.
Muscle fibre size and myonuclear positioning in trained and aged humans.
Enhanced Diaphragm Muscle Function upon Satellite Cell Transplantation in Dystrophic Mice.
Skeletal Muscle Electrical Stimulation Prevents Progression of Disuse Muscle Atrophy via Forkhead Box O Dynamics Mediated by Phosphorylated Protein Kinase B and Peroxisome Proliferator-Activated Receptor gamma Coactivator-1alpha.
Age-related and cancer-related sarcopenia: is there a difference?
Zebrafish and cellular models of SELENON -Related Myopathy exhibit novel embryonic and metabolic phenotypes.
Skeletal muscle effects of antisense oligonucleotides targeting glycogen synthase 1 in a mouse model of Pompe disease.
Lmod2 is necessary for effective skeletal muscle contraction.
Restoration of epigenetic impairment in the skeletal muscle and chronic inflammation resolution as a therapeutic approach in sarcopenia.
Sporadic Inclusion Body Myositis at the Crossroads between Muscle Degeneration, Inflammation, and Aging.
Belt electrode tetanus muscle stimulation reduces denervation-induced atrophy of rat multiple skeletal muscle groups.
Sodium-glucose cotransporter 2 inhibitors influence skeletal muscle pathology in patients with heart failure and reduced ejection fraction.
The roles of sex hormones in the pathophysiology of age-related sarcopenia and frailty.
Estrogen promotes fetal skeletal muscle mitochondrial distribution and ATP synthase activity important for insulin sensitivity in offspring.
Age-related muscle atrophy? Mitofusin 2 the rescue.
Eccentric exercise ≠ eccentric contraction.
Metabolic plasticity and obesity-associated changes in diurnal postexercise metabolism in mice.
Enhancing healthy aging with small molecules: A mitochondrial perspective.

J Proteome Res. 2024 Mar 13.

Affinity Purification-Mass Spectrometry and Single Fiber Physiology/Proteomics Reveals Mechanistic Insights of C18ORF25.

Yaan-Kit Ng, Ronnie Blazev, James W McNamara, Mriga Dutt, Jeffrey Molendijk, Enzo R Porrello, David A Elliott, Benjamin L Parker.

  C18ORF25 was recently shown to be phosphorylated at S67 by AMP-activated protein kinase (AMPK) in the skeletal muscle, following acute exercise in humans. Phosphorylation was shown to improve the ex vivo skeletal muscle contractile function in mice, but our understanding of the molecular mechanisms is incomplete. Here, we profiled the interactome of C18ORF25 in mouse myotubes using affinity purification coupled to mass spectrometry. This analysis included an investigation of AMPK-dependent and S67-dependent protein/protein interactions. Several nucleocytoplasmic and contractile-associated proteins were identified, which revealed a subset of GTPases that associate with C18ORF25 in an AMPK- and S67 phosphorylation-dependent manner. We confirmed that C18ORF25 is localized to the nucleus and the contractile apparatus in the skeletal muscle. Mice lacking C18Orf25 display defects in calcium handling specifically in fast-twitch muscle fibers. To investigate these mechanisms, we developed an integrated single fiber physiology and single fiber proteomic platform. The approach enabled a detailed assessment of various steps in the excitation-contraction pathway including SR calcium handling and force generation, followed by paired single fiber proteomic analysis. This enabled us to identify >700 protein/phenotype associations and 36 fiber-type specific differences, following loss of C18Orf25. Taken together, our data provide unique insights into the function of C18ORF25 and its role in skeletal muscle physiology.

Keywords:  C18ORF25; single cell proteomics; single fiber physiology; single fiber proteomics; skeletal muscle

DOI:  https://doi.org/10.1021/acs.jproteome.3c00716
Cell Death Dis. 2024 Mar 09. 15(3): 201

Deficiency of skeletal muscle Agrin contributes to the pathogenesis of age-related sarcopenia in mice.

Jie Chen, Hong Chen, Xia Dong, Tiankun Hui, Min Yan, Dongyan Ren, Suqi Zou, Shunqi Wang, Erkang Fei, Wenhua Zhang, Xinsheng Lai.

Sarcopenia, a progressive and prevalent neuromuscular disorder, is characterized by age-related muscle wasting and weakening. Despite its widespread occurrence, the molecular underpinnings of this disease remain poorly understood. Herein, we report that levels of Agrin, an extracellular matrix (ECM) protein critical for neuromuscular formation, were decreased with age in the skeletal muscles of mice. The conditional loss of Agrin in myogenic progenitors and satellite cells (SCs) (Pax7 Cre:: Agrin flox/flox) causes premature muscle aging, manifesting a distinct sarcopenic phenotype in mice. Conversely, the elevation of a miniaturized form of Agrin in skeletal muscle through adenovirus-mediated gene transfer induces enhanced muscle capacity in aged mice. Mechanistic investigations suggest that Agrin-mediated improvement in muscle function occurs through the stimulation of Yap signaling and the concurrent upregulation of dystroglycan expression. Collectively, our findings underscore the pivotal role of Agrin in the aging process of skeletal muscles and propose Agrin as a potential therapeutic target for addressing sarcopenia.

DOI: https://doi.org/10.1038/s41419-024-06581-1
bioRxiv. 2024 Feb 29. pii: 2024.02.27.582179. [Epub ahead of print]

Insights into post-translational regulation of skeletal muscle contractile function by the acetyltransferases, p300 and CBP.

Gretchen A Meyer, Jeremie L A Ferey, James A Sanford, Liam S Fitzgerald, Akiva E Greenberg, Kristoffer Svensson, Michael J Greenberg, Simon Schenk.

Mice with skeletal muscle-specific inducible double knockout of the lysine acetyltransferases, p300 (E1A binding protein p300) and CBP (cAMP-response element-binding protein binding protein), referred to as i-mPCKO, demonstrate a dramatic loss of contractile function in skeletal muscle and ultimately die within 7 days. Given that many proteins involved in ATP generation and cross-bridge cycling are acetylated, we investigated whether these processes are dysregulated in skeletal muscle from i-mPCKO mice and thus could underlie the rapid loss of muscle contractile function. Just 4-5 days after inducing knockout of p300 and CBP in skeletal muscle from adult i-mPCKO mice, there was ∼90% reduction in ex vivo contractile function in the extensor digitorum longus (EDL) and a ∼65% reduction in in vivo ankle dorsiflexion torque, as compared to wildtype (WT; i.e. Cre negative) littermates. Despite the profound loss of contractile force in i-mPCKO mice, there were no genotype-driven differences in fatigability during repeated contractions, nor were there genotype differences in mitochondrial specific pathway enrichment of the proteome, intermyofibrillar mitochondrial volume or mitochondrial respiratory function. As it relates to cross-bridge cycling, remarkably, the overt loss of contractile function in i-mPCKO muscle was reversed in permeabilized fibers supplied with exogenous Ca 2+ and ATP, with active tension being similar between i-mPCKO and WT mice, regardless of Ca 2+ concentration. Actin-myosin motility was also similar in skeletal muscle from i-mPCKO and WT mice. In conclusion, neither mitochondrial abundance/function, nor actomyosin cross-bridge cycling, are the underlying driver of contractile dysfunction in i-mPCKO mice.New & Noteworthy: The mechanism underlying dramatic loss of muscle contractile function with inducible deletion of both p300 and CBP in skeletal muscle remains unknown. Here we find that impairments in mitochondrial function or cross-bridge cycling are not the underlying mechanism of action. Future work will investigate other aspects of excitation-contraction coupling, such as Ca 2+ handling and membrane excitability, as contractile function could be rescued by permeabilizing skeletal muscle, which provides exogenous Ca 2+ and bypasses membrane depolarization.

DOI: https://doi.org/10.1101/2024.02.27.582179
Sports Med Health Sci. 2024 Mar;6(1): 1-15

Advancing cancer cachexia diagnosis with -omics technology and exercise as molecular medicine.

Stuart J Hesketh.

  Muscle atrophy exacerbates disease outcomes and increases mortality, whereas the preservation of skeletal muscle mass and function play pivotal roles in ensuring long-term health and overall quality-of-life. Muscle atrophy represents a significant clinical challenge, involving the continued loss of muscle mass and strength, which frequently accompany the development of numerous types of cancer. Cancer cachexia is a highly prevalent multifactorial syndrome, and although cachexia is one of the main causes of cancer-related deaths, there are still no approved management strategies for the disease. The etiology of this condition is based on the upregulation of systemic inflammation factors and catabolic stimuli, resulting in the inhibition of protein synthesis and enhancement of protein degradation. Numerous necessary cellular processes are disrupted by cachectic pathology, which mediate intracellular signalling pathways resulting in the net loss of muscle and organelles. However, the exact underpinning molecular mechanisms of how these changes are orchestrated are incompletely understood. Much work is still required, but structured exercise has the capacity to counteract numerous detrimental effects linked to cancer cachexia. Primarily through the stimulation of muscle protein synthesis, enhancement of mitochondrial function, and the release of myokines. As a result, muscle mass and strength increase, leading to improved mobility, and quality-of-life. This review summarises existing knowledge of the complex molecular networks that regulate cancer cachexia and exercise, highlighting the molecular interplay between the two for potential therapeutic intervention. Finally, the utility of mass spectrometry-based proteomics is considered as a way of establishing early diagnostic biomarkers of cachectic patients.

Keywords:  Cancer cachexia; Exercise; Molecular medicine; Muscle atrophy; Omics

DOI:  https://doi.org/10.1016/j.smhs.2024.01.006
Int J Mol Sci. 2024 Mar 01. pii: 2881. [Epub ahead of print]25(5):

The Acute, Short-, and Long-Term Effects of Endurance Exercise on Skeletal Muscle Transcriptome Profiles.

Thomas Beiter, Martina Zügel, Jens Hudemann, Marius Schild, Annunziata Fragasso, Christof Burgstahler, Karsten Krüger, Frank C Mooren, Jürgen M Steinacker, Andreas M Nieß.

  A better understanding of the cellular and molecular mechanisms that are involved in skeletal muscle adaptation to exercise is fundamentally important to take full advantage of the enormous benefits that exercise training offers in disease prevention and therapy. The aim of this study was to elucidate the transcriptional signatures that distinguish the endurance-trained and untrained muscles in young adult males (24 ± 3.5 years). We characterized baseline differences as well as acute exercise-induced transcriptome responses in vastus lateralis biopsy specimens of endurance-trained athletes (ET; n = 8; VO2max, 67.2 ± 8.9 mL/min/kg) and sedentary healthy volunteers (SED; n = 8; VO2max, 40.3 ± 7.6 mL/min/kg) using microarray technology. A second cohort of SED volunteers (SED-T; n = 10) followed an 8-week endurance training program to assess expression changes of selected marker genes in the course of skeletal muscle adaptation. We deciphered differential baseline signatures that reflected major differences in the oxidative and metabolic capacity of the endurance-trained and untrained muscles. SED-T individuals in the training group displayed an up-regulation of nodal regulators of oxidative adaptation after 3 weeks of training and a significant shift toward the ET signature after 8 weeks. Transcriptome changes provoked by 1 h of intense cycling exercise only poorly overlapped with the genes that constituted the differential baseline signature of ETs and SEDs. Overall, acute exercise-induced transcriptional responses were connected to pathways of contractile, oxidative, and inflammatory stress and revealed a complex and highly regulated framework of interwoven signaling cascades to cope with exercise-provoked homeostatic challenges. While temporal transcriptional programs that were activated in SEDs and ETs were quite similar, the quantitative divergence in the acute response transcriptomes implicated divergent kinetics of gene induction and repression following an acute bout of exercise. Together, our results provide an extensive examination of the transcriptional framework that underlies skeletal muscle plasticity.

Keywords:  acute exercise; endurance training; exercise physiology; gene expression; skeletal muscle; skeletal muscle transcriptomics; training status

DOI:  https://doi.org/10.3390/ijms25052881
Int J Mol Sci. 2024 Feb 26. pii: 2687. [Epub ahead of print]25(5):

Studying the Effect of MBNL1 and MBNL2 Loss in Skeletal Muscle Regeneration.

Ramesh S Yadava, Mahua Mandal, Mani S Mahadevan.

  Loss of function of members of the muscleblind-like (MBNL) family of RNA binding proteins has been shown to play a key role in the spliceopathy of RNA toxicity in myotonic dystrophy type 1 (DM1), the most common muscular dystrophy affecting adults and children. MBNL1 and MBNL2 are the most abundantly expressed members in skeletal muscle. A key aspect of DM1 is poor muscle regeneration and repair, leading to dystrophy. We used a BaCl2-induced damage model of muscle injury to study regeneration and effects on skeletal muscle satellite cells (MuSCs) in Mbnl1∆E3/∆E3 and Mbnl2∆E2/∆E2 knockout mice. Similar experiments have previously shown deleterious effects on these parameters in mouse models of RNA toxicity. Muscle regeneration in Mbnl1 and Mbnl2 knockout mice progressed normally with no obvious deleterious effects on MuSC numbers or increased expression of markers of fibrosis. Skeletal muscles in Mbnl1∆E3/∆E3/ Mbnl2∆E2/+ mice showed increased histopathology but no deleterious reductions in MuSC numbers and only a slight increase in collagen deposition. These results suggest that factors beyond the loss of MBNL1/MBNL2 and the associated spliceopathy are likely to play a key role in the defects in skeletal muscle regeneration and deleterious effects on MuSCs that are seen in mouse models of RNA toxicity due to expanded CUG repeats.

Keywords:  RNA binding proteins; RNA toxicity; muscle regeneration; muscleblind; muscular dystrophy; myotonic dystrophy; satellite cells

DOI:  https://doi.org/10.3390/ijms25052687
bioRxiv. 2024 Feb 29. pii: 2024.02.26.582103. [Epub ahead of print]

High-Resolution Spatial Transcriptomic Atlas of Mouse Soleus Muscle: Unveiling Single Cell and Subcellular Heterogeneity in Health and Denervation.

Jer-En Hsu, Lloyd Ruiz, Yongha Hwang, Steve Guzman, Chun-Seok Cho, Weiqiu Cheng, Yichen Si, Peter Macpherson, Mitchell Schrank, Goo Jun, Hyun-Min Kang, Myungjin Kim, Susan Brooks, Jun Hee Lee.

Skeletal muscle is essential for both movement and metabolic processes, characterized by a complex and ordered structure. Despite its importance, a detailed spatial map of gene expression within muscle tissue has been challenging to achieve due to the limitations of existing technologies, which struggle to provide high-resolution views. In this study, we leverage the Seq-Scope technique, an innovative method that allows for the observation of the entire transcriptome at an unprecedented submicron spatial resolution. By applying this technique to the mouse soleus muscle, we analyze and compare the gene expression profiles in both healthy conditions and following denervation, a process that mimics aspects of muscle aging. Our approach reveals detailed characteristics of muscle fibers, other cell types present within the muscle, and specific subcellular structures such as the postsynaptic nuclei at neuromuscular junctions, hybrid muscle fibers, and areas of localized expression of genes responsive to muscle injury, along with their histological context. The findings of this research significantly enhance our understanding of the diversity within the muscle cell transcriptome and its variation in response to denervation, a key factor in the decline of muscle function with age. This breakthrough in spatial transcriptomics not only deepens our knowledge of muscle biology but also sets the stage for the development of new therapeutic strategies aimed at mitigating the effects of aging on muscle health, thereby offering a more comprehensive insight into the mechanisms of muscle maintenance and degeneration in the context of aging and disease.

DOI: https://doi.org/10.1101/2024.02.26.582103
Cells. 2024 Feb 24. pii: 393. [Epub ahead of print]13(5):

Exercise Training Differentially Affects Skeletal Muscle Mitochondria in Rats with Inherited High or Low Exercise Capacity.

Estelle Heyne, Susanne Zeeb, Celina Junker, Andreas Petzinna, Andrea Schrepper, Torsten Doenst, Lauren G Koch, Steven L Britton, Michael Schwarzer.

  Exercise capacity has been related to morbidity and mortality. It consists of an inherited and an acquired part and is dependent on mitochondrial function. We assessed skeletal muscle mitochondrial function in rats with divergent inherited exercise capacity and analyzed the effect of exercise training. Female high (HCR)- and low (LCR)-capacity runners were trained with individually adapted high-intensity intervals or kept sedentary. Interfibrillar (IFM) and subsarcolemmal (SSM) mitochondria from gastrocnemius muscle were isolated and functionally assessed (age: 15 weeks). Sedentary HCR presented with higher exercise capacity than LCR paralleled by higher citrate synthase activity and IFM respiratory capacity in skeletal muscle of HCR. Exercise training increased exercise capacity in both HCR and LCR, but this was more pronounced in LCR. In addition, exercise increased skeletal muscle mitochondrial mass more in LCR. Instead, maximal respiratory capacity was increased following exercise in HCRs' IFM only. The results suggest that differences in skeletal muscle mitochondrial subpopulations are mainly inherited. Exercise training resulted in different mitochondrial adaptations and in higher trainability of LCR. HCR primarily increased skeletal muscle mitochondrial quality while LCR increased mitochondrial quantity in response to exercise training, suggesting that inherited aerobic exercise capacity differentially affects the mitochondrial response to exercise training.

Keywords:  exercise training; inherited exercise capacity; skeletal muscle mitochondria

DOI:  https://doi.org/10.3390/cells13050393
Genes Dev. 2024 Mar 14.

A serine metabolic enzyme is flexing its muscle to help repair skeletal muscle.

Benjámin R Baráth, Laszlo Nagy.

  Metabolic reprogramming of stem cells is a targetable pathway to control regeneration. Activation of stem cells results in down-regulation of oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) and turns on glycolysis to provide fuel for proliferation and specific signaling events. How cell type-specific events are regulated is unknown. In this issue of Genes & Development Ciuffoli and colleagues (pp. XXX-XXX) use metabolomic, gene inactivation, and functional approaches to show that phosphoserine aminotransferase (Psat1), an enzyme in serine biosynthesis, is activated in muscle stem cells and contributes to cell expansion and skeletal muscle regeneration via the production of α-ketoglutarate and glutamine.

Keywords:  aging; glutamine; ketoglutarate; muscle regeneration; muscle stem cells

DOI:  https://doi.org/10.1101/gad.351666.124
Elife. 2024 Mar 11. pii: RP92674. [Epub ahead of print]12

A novel imaging method (FIM-ID) reveals that myofibrillogenesis plays a major role in the mechanically induced growth of skeletal muscle.

Kent W Jorgenson, Jamie E Hibbert, Ramy K A Sayed, Anthony N Lange, Joshua S Godwin, Paulo H C Mesquita, Bradley A Ruple, Mason C McIntosh, Andreas N Kavazis, Michael D Roberts, Troy A Hornberger.

  An increase in mechanical loading, such as that which occurs during resistance exercise, induces radial growth of muscle fibers (i.e. an increase in cross-sectional area). Muscle fibers are largely composed of myofibrils, but whether radial growth is mediated by an increase in the size of the myofibrils (i.e. myofibril hypertrophy) and/or the number of myofibrils (i.e. myofibrillogenesis) is not known. Electron microscopy (EM) can provide images with the level of resolution that is needed to address this question, but the acquisition and subsequent analysis of EM images is a time- and cost-intensive process. To overcome this, we developed a novel method for visualizing myofibrils with a standard fluorescence microscope (fluorescence imaging of myofibrils with image deconvolution [FIM-ID]). Images from FIM-ID have a high degree of resolution and contrast, and these properties enabled us to develop pipelines for automated measurements of myofibril size and number. After extensively validating the automated measurements, we used both mouse and human models of increased mechanical loading to discover that the radial growth of muscle fibers is largely mediated by myofibrillogenesis. Collectively, the outcomes of this study offer insight into a fundamentally important topic in the field of muscle growth and provide future investigators with a time- and cost-effective means to study it.

Keywords:  cell biology; exercise; growth; hypertrophy; mouse; myofibril; skeletal muscle; ultrastructure

DOI:  https://doi.org/10.7554/eLife.92674
Nat Commun. 2024 Mar 11. 15(1): 2176

YTHDF2 governs muscle size through a targeted modulation of proteostasis.

Christopher J Gilbert, Charles P Rabolli, Volha A Golubeva, Kristina M Sattler, Meifang Wang, Arsh Ketabforoush, W David Arnold, Christoph Lepper, Federica Accornero.

The regulation of proteostasis is fundamental for maintenance of muscle mass and function. Activation of the TGF-β pathway drives wasting and premature aging by favoring the proteasomal degradation of structural muscle proteins. Yet, how this critical post-translational mechanism is kept in check to preserve muscle health remains unclear. Here, we reveal the molecular link between the post-transcriptional regulation of m6A-modified mRNA and the modulation of SMAD-dependent TGF-β signaling. We show that the m6A-binding protein YTHDF2 is essential to determining postnatal muscle size. Indeed, muscle-specific genetic deletion of YTHDF2 impairs skeletal muscle growth and abrogates the response to hypertrophic stimuli. We report that YTHDF2 controls the mRNA stability of the ubiquitin ligase ASB2 with consequences on anti-growth gene program activation through SMAD3. Our study identifies a post-transcriptional to post-translational mechanism for the coordination of gene expression in muscle.

DOI: https://doi.org/10.1038/s41467-024-46546-8
Sci Data. 2024 Mar 12. 11(1): 290

Integrative cross-species analysis reveals conserved and unique signatures in fatty skeletal muscles.

Liyi Wang, Yanbing Zhou, Yizhen Wang, Tizhong Shan.

Fat infiltration in skeletal muscle is now recognized as a standard feature of aging and is directly related to the decline in muscle function. However, there is still a limited systematic integration and exploration of the mechanisms underlying the occurrence of myosteatosis in aging across species. Here, we re-analyzed bulk RNA-seq datasets to investigate the association between fat infiltration in skeletal muscle and aging. Our integrated analysis of single-nucleus transcriptomics in aged humans and Laiwu pigs with high intramuscular fat content, identified species-preference subclusters and revealed core gene programs associated with myosteatosis. Furthermore, we found that fibro/adipogenic progenitors (FAPs) had potential capacity of differentiating into PDE4D+/PDE7B+ preadipocytes across species. Additionally, cell-cell communication analysis revealed that FAPs may be associated with other adipogenic potential clusters via the COL4A2 and COL6A3 pathways. Our study elucidates the correlation mechanism between aging and fat infiltration in skeletal muscle, and these consensus signatures in both humans and pigs may contribute to increasing reproducibility and reliability in future studies involving in the field of muscle research.

DOI: https://doi.org/10.1038/s41597-024-03114-5
Exp Physiol. 2024 Mar 10.

Muscle fibre size and myonuclear positioning in trained and aged humans.

Edmund Battey, Yotam Levy, Ross D Pollock, Jamie N Pugh, Graeme L Close, Michaeljohn Kalakoutis, Norman R Lazarus, Stephen D R Harridge, Julien Ochala, Matthew J Stroud.

  Changes in myonuclear architecture and positioning are associated with exercise adaptations and ageing. However, data on the positioning and number of myonuclei following exercise are inconsistent. Additionally, whether myonuclear domains (MNDs; i.e., the theoretical volume of cytoplasm within which a myonucleus is responsible for transcribing DNA) and myonuclear positioning are altered with age remains unclear. The aim of this investigation was to investigate relationships between age and activity status and myonuclear domains and positioning. Vastus lateralis muscle biopsies from younger endurance-trained (YT) and older endurance-trained (OT) individuals were compared with age-matched untrained counterparts (YU and OU; OU samples were acquired during surgical operation). Serial, optical z-slices were acquired throughout isolated muscle fibres and analysed to give three-dimensional coordinates for myonuclei and muscle fibre dimensions. The mean cross-sectional area (CSA) of muscle fibres from OU individuals was 33%-53% smaller compared with the other groups. The number of nuclei relative to fibre CSA was 90% greater in OU compared with YU muscle fibres. Additionally, scaling of MND volume with fibre size was altered in older untrained individuals. The myonuclear arrangement, in contrast, was similar across groups. Fibre CSA and most myonuclear parameters were significantly associated with age in untrained individuals, but not in trained individuals. These data indicate that regular endurance exercise throughout the lifespan might better preserve the size of muscle fibres in older age and maintain the relationship between fibre size and MND volumes. Inactivity, however, might result in reduced muscle fibre size and altered myonuclear parameters.

Keywords:  ageing; cross-sectional area; exercise; myonuclear domains; nuclei

DOI:  https://doi.org/10.1113/EP091567
Int J Mol Sci. 2024 Feb 21. pii: 2503. [Epub ahead of print]25(5):

Enhanced Diaphragm Muscle Function upon Satellite Cell Transplantation in Dystrophic Mice.

Karim Azzag, Heather M Gransee, Alessandro Magli, Aline M S Yamashita, Sudheer Tungtur, Aaron Ahlquist, Wen-Zhi Zhan, Chiemelie Onyebu, Sarah M Greising, Carlos B Mantilla, Rita C R Perlingeiro.

  The diaphragm muscle is essential for breathing, and its dysfunctions can be fatal. Many disorders affect the diaphragm, including muscular dystrophies. Despite the clinical relevance of targeting the diaphragm, there have been few studies evaluating diaphragm function following a given experimental treatment, with most of these involving anti-inflammatory drugs or gene therapy. Cell-based therapeutic approaches have shown success promoting muscle regeneration in several mouse models of muscular dystrophy, but these have focused mainly on limb muscles. Here we show that transplantation of as few as 5000 satellite cells directly into the diaphragm results in consistent and robust myofiber engraftment in dystrophin- and fukutin-related protein-mutant dystrophic mice. Transplanted cells also seed the stem cell reservoir, as shown by the presence of donor-derived satellite cells. Force measurements showed enhanced diaphragm strength in engrafted muscles. These findings demonstrate the feasibility of cell transplantation to target the diseased diaphragm and improve its contractility.

Keywords:  diaphragm; engraftment; muscle stem cells; muscular dystrophy; pre-injury; regeneration; satellite cells; specific force; transplantation

DOI:  https://doi.org/10.3390/ijms25052503
Physiol Res. 2024 Mar 11. 73(1): 105-115

Skeletal Muscle Electrical Stimulation Prevents Progression of Disuse Muscle Atrophy via Forkhead Box O Dynamics Mediated by Phosphorylated Protein Kinase B and Peroxisome Proliferator-Activated Receptor gamma Coactivator-1alpha.

A Takahashi, Y Honda, N Tanaka, J Miyake, S Maeda, H Kataoka, J Sakamoto, M Okita.

Although electrical muscle stimulation (EMS) of skeletal muscle effectively prevents muscle atrophy, its effect on the breakdown of muscle component proteins is unknown. In this study, we investigated the biological mechanisms by which EMS-induced muscle contraction inhibits disuse muscle atrophy progression. Experimental animals were divided into a control group and three experimental groups: immobilized (Im; immobilization treatment), low-frequency (LF; immobilization treatment and low-frequency muscle contraction exercise), and high-frequency (HF; immobilization treatment and high-frequency muscle contraction exercise). Following the experimental period, bilateral soleus muscles were collected and analyzed. Atrogin-1 and Muscle RING finger 1 (MuRF-1) mRNA expression levels were significantly higher for the experimental groups than for the control group but were significantly lower for the HF group than for the Im group. Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) mRNA and protein expression levels in the HF group were significantly higher than those in the Im group, with no significant differences compared to the Con group. Both the Forkhead box O (FoxO)/phosphorylated FoxO and protein kinase B (AKT)/phosphorylated AKT ratios were significantly lower for the Im group than for the control group and significantly higher for the HF group than for the Im group. These results, the suppression of atrogin-1 and MuRF-1 expression for the HF group may be due to decreased nuclear expression of FoxO by AKT phosphorylation and suppression of FoxO transcriptional activity by PGC-1alpha. Furthermore, the number of muscle contractions might be important for effective EMS.
Curr Opin Clin Nutr Metab Care. 2024 Mar 14.

Age-related and cancer-related sarcopenia: is there a difference?

Federico Bozzetti.

PURPOSE: The aim of this review is the attempt to differentiating the pathophysiologic and clinical features of the aging-related sarcopenia from cancer-related sarcopenia. In fact, there is some controversy among the experts mainly regarding two points: is always sarcopenia, even that aging-related one, the expression of a generalized disease or may exist independently and without major alteration of the muscle function? Are always aging-related and cancer-related sarcopenia completely separated entities?RECENT FINDINGS: Literature shows that sarcopenia, defined as simple skeletal muscle mass loss, may range from a mainly focal problem which is common in many healthy elderly people, to a component of a complex multiorgan syndrome as cancer cachexia. Disuse, malnutrition and (neuro)degenerative processes can account for most of the aging-related sarcopenias while systemic inflammation and secretion of cancer-and immune-related molecules play an additional major role in cachexia.
SUMMARY: A multimodal approach including physical exercise and optimized nutritional support are the key measures to offset sarcopenia with some contribution by the anti-inflammatory drugs in cancer patients. Results are more promising in elderly patients and are still pending for cancer patients where a more specific approach will only rely on the identification and contrast of the key mediators of the cachectic process.

DOI: https://doi.org/10.1097/MCO.0000000000001033
bioRxiv. 2024 Feb 26. pii: 2024.02.26.581979. [Epub ahead of print]

Zebrafish and cellular models of SELENON -Related Myopathy exhibit novel embryonic and metabolic phenotypes.

Pamela Barraza-Flores, Behzad Moghadaszadeh, Won Lee, Biju Isaac, Liang Sun, Emily C Troiano, Shira Rockowitz, Piotr Sliz, Alan H Beggs.

SELENON -Related Myopathy ( SELENON -RM) is a rare congenital myopathy caused by mutations of the SELENON gene characterized by axial muscle weakness and progressive respiratory insufficiency. Muscle histopathology commonly includes multiminicores or a dystrophic pattern but is often non-specific. The SELENON gene encodes selenoprotein N (SelN), a selenocysteine-containing redox enzyme located in the endo/sarcoplasmic reticulum membrane where it colocalizes with mitochondria-associated membranes. However, the molecular mechanism(s) by which SelN deficiency causes SELENON -RM are undetermined. A hurdle is the lack of cellular and animal models that show assayable phenotypes. Here we report deep-phenotyping of SelN-deficient zebrafish and muscle cells. SelN-deficient zebrafish exhibit changes in embryonic muscle function and swimming activity in larvae. Analysis of single cell RNAseq data in a zebrafish embryo-atlas revealed coexpression between selenon and genes involved in glutathione redox pathway. SelN-deficient zebrafish and mouse myoblasts exhibit changes in glutathione and redox homeostasis, suggesting a direct relationship with SelN function. We report changes in metabolic function abnormalities in SelN-null myotubes when compared to WT. These results suggest that SelN has functional roles during zebrafish early development and myoblast metabolism.

DOI: https://doi.org/10.1101/2024.02.26.581979
bioRxiv. 2024 Mar 02. pii: 2024.02.22.580414. [Epub ahead of print]

Skeletal muscle effects of antisense oligonucleotides targeting glycogen synthase 1 in a mouse model of Pompe disease.

Lan Weiss, Michele Carrer, Alyaa Shmara, Cheng Cheng, Hong Yin, Lac Ta, Victoria Boock, Yasamin Fazeli, Mindy Chang, Marvin Paguio, Jonathan Lee, Howard Yu, Angela Martin, Nina Raben, John Weiss, Tamar Grossman, Paymaan Jafar-Nejad, Virginia Kimonis.

Pompe disease (PD) is a progressive myopathy caused by the aberrant accumulation of glycogen in skeletal and cardiac muscle resulting from the deficiency of the enzyme acid alpha-glucosidase (GAA). Administration of recombinant human GAA as enzyme replacement therapy (ERT) works well in alleviating the cardiac manifestations of PD but loses sustained benefit in ameliorating the skeletal muscle pathology. The limited efficacy of ERT in skeletal muscle is partially attributable to its inability to curb the accumulation of new glycogen produced by the muscle enzyme glycogen synthase 1 (GYS1). Substrate reduction therapies aimed at knocking down GYS1 expression represent a promising avenue to improve Pompe myopathy. However, finding specific inhibitors for GYS1 is challenging given the presence of the highly homologous GYS2 in the liver. Antisense oligonucleotides (ASOs) are chemically modified oligomers that hybridize to their complementary target RNA to induce their degradation with exquisite specificity. In the present study, we show that ASO-mediated Gys1 knockdown in the Gaa -/- mouse model of PD led to a robust reduction in glycogen accumulation in skeletal and cardiac muscle. In addition, combining Gys1 ASO with ERT further reduced glycogen content in muscle, eliminated autophagic buildup and lysosomal dysfunction, and improved motor function in Gaa -/- mice. Our results provide a strong foundation for further validation of the use of Gys1 ASO, alone or in combination with ERT, as a therapy for PD. We propose that early administration of Gys1 ASO in combination with ERT may be the key to preventative treatment options in PD.

DOI: https://doi.org/10.1101/2024.02.22.580414
Sci Adv. 2024 Mar 15. 10(11): eadk1890

Lmod2 is necessary for effective skeletal muscle contraction.

Tania M Larrinaga, Gerrie P Farman, Rachel M Mayfield, Michaela Yuen, Rebecca C Ahrens-Nicklas, Sandra T Cooper, Christopher T Pappas, Carol C Gregorio.

Muscle contraction is a regulated process driven by the sliding of actin-thin filaments over myosin-thick filaments. Lmod2 is an actin filament length regulator and essential for life since human mutations and complete loss of Lmod2 in mice lead to dilated cardiomyopathy and death. To study the little-known role of Lmod2 in skeletal muscle, we created a mouse model with Lmod2 expressed exclusively in the heart but absent in skeletal muscle. Loss of Lmod2 in skeletal muscle results in decreased force production in fast- and slow-twitch muscles. Soleus muscle from rescued Lmod2 knockout mice have shorter thin filaments, increased Lmod3 levels, and present with a myosin fiber type switch from fast myosin heavy chain (MHC) IIA to the slower MHC I isoform. Since Lmod2 regulates thin-filament length in slow-twitch but not fast-twitch skeletal muscle and force deficits were observed in both muscle types, this work demonstrates that Lmod2 regulates skeletal muscle contraction, independent of its role in thin-filament length regulation.

DOI: https://doi.org/10.1126/sciadv.adk1890
Ageing Res Rev. 2024 Mar 08. pii: S1568-1637(24)00085-0. [Epub ahead of print] 102267

Restoration of epigenetic impairment in the skeletal muscle and chronic inflammation resolution as a therapeutic approach in sarcopenia.

Gregory Livshits, Alexander Kalinkovich.

  Sarcopenia is an age-associated loss of skeletal muscle mass, strength, and function, accompanied by severe adverse health outcomes, such as falls and fractures, functional decline, high health costs, and mortality. Hence, its prevention and treatment have become increasingly urgent. However, despite the wide prevalence and extensive research on sarcopenia, no FDA-approved disease-modifying drugs exist. This is probably due to a poor understanding of the mechanisms underlying its pathophysiology. Recent evidence demonstrate that sarcopenia development is characterized by two key elements: (i) epigenetic dysregulation of multiple molecular pathways associated with sarcopenia pathogenesis, such as protein remodeling, insulin resistance, mitochondria impairments, and (ii) the creation of a systemic, chronic, low-grade inflammation (SCLGI). In this review, we focus on the epigenetic regulators that have been implicated in skeletal muscle deterioration, their individual roles, and possible crosstalk. We also discuss epidrugs, which are the pharmaceuticals with the potential to restore the epigenetic mechanisms deregulated in sarcopenia. In addition, we discuss the mechanisms underlying failed SCLGI resolution in sarcopenia and the potential application of pro-resolving molecules, comprising specialized pro-resolving mediators (SPMs) and their stable mimetics and receptor agonists. These compounds, as well as epidrugs, reveal beneficial effects in preclinical studies related to sarcopenia. Based on these encouraging observations, we propose the combination of epidrugs with SCLI-resolving agents as a new therapeutic approach for sarcopenia that can effectively attenuate of its manifestations.

Keywords:  chronic inflammation; epidrugs; sarcopenia

DOI:  https://doi.org/10.1016/j.arr.2024.102267
Int J Mol Sci. 2024 Feb 27. pii: 2742. [Epub ahead of print]25(5):

Sporadic Inclusion Body Myositis at the Crossroads between Muscle Degeneration, Inflammation, and Aging.

Valeria Guglielmi, Marta Cheli, Paola Tonin, Gaetano Vattemi.

  Sporadic inclusion body myositis (sIBM) is the most common muscle disease of older people and is clinically characterized by slowly progressive asymmetrical muscle weakness, predominantly affecting the quadriceps, deep finger flexors, and foot extensors. At present, there are no enduring treatments for this relentless disease that eventually leads to severe disability and wheelchair dependency. Although sIBM is considered a rare muscle disorder, its prevalence is certainly higher as the disease is often undiagnosed or misdiagnosed. The histopathological phenotype of sIBM muscle biopsy includes muscle fiber degeneration and endomysial lymphocytic infiltrates that mainly consist of cytotoxic CD8+ T cells surrounding nonnecrotic muscle fibers expressing MHCI. Muscle fiber degeneration is characterized by vacuolization and the accumulation of congophilic misfolded multi-protein aggregates, mainly in their non-vacuolated cytoplasm. Many players have been identified in sIBM pathogenesis, including environmental factors, autoimmunity, abnormalities of protein transcription and processing, the accumulation of several toxic proteins, the impairment of autophagy and the ubiquitin-proteasome system, oxidative and nitrative stress, endoplasmic reticulum stress, myonuclear degeneration, and mitochondrial dysfunction. Aging has also been proposed as a contributor to the disease. However, the interplay between these processes and the primary event that leads to the coexistence of autoimmune and degenerative changes is still under debate. Here, we outline our current understanding of disease pathogenesis, focusing on degenerative mechanisms, and discuss the possible involvement of aging.

Keywords:  aging; inflammaging; inflammation; muscle fiber degeneration; protein aggregation; sporadic inclusion body myositis (sIBM)

DOI:  https://doi.org/10.3390/ijms25052742
Sci Rep. 2024 03 11. 14(1): 5848

Belt electrode tetanus muscle stimulation reduces denervation-induced atrophy of rat multiple skeletal muscle groups.

Hiroyuki Uno, Shohei Kamiya, Ryuji Akimoto, Katsu Hosoki, Shunta Tadano, Mako Isemura, Karina Kouzaki, Yuki Tamura, Takaya Kotani, Koichi Nakazato.

Belt electrode-skeletal muscle electrical stimulation (B-SES) involves the use of belt-shaped electrodes to contract multiple muscle groups simultaneously. Twitch contractions have been demonstrated to protect against denervation-induced muscle atrophy in rats, possibly through mitochondrial biosynthesis. This study examined whether inducing tetanus contractions with B-SES suppresses muscle atrophy and identified the underlying molecular mechanisms. We evaluated the effects of acute (60 Hz, 5 min) and chronic (60 Hz, 5 min, every alternate day for one week) B-SES on the tibialis anterior (TA) and gastrocnemius (GAS) muscles in Sprague-Dawley rats using belt electrodes attached to both ankle joints. After acute stimulation, a significant decrease in the glycogen content was observed in the left and right TA and GAS, suggesting that B-SES causes simultaneous contractions in multiple muscle groups. B-SES enhanced p70S6K phosphorylation, an indicator of the mechanistic target of rapamycin complex 1 activity. During chronic stimulations, rats were divided into control (CONT), denervation-induced atrophy (DEN), and DEN + electrically stimulated with B-SES (DEN + ES) groups. After seven days of treatment, the wet weight (n = 8-11 for each group) and muscle fiber cross-sectional area (CSA, n = 6 for each group) of the TA and GAS muscles were reduced in the DEN and DEN + ES groups compared with that in the CON group. The DEN + ES group showed significantly higher muscle weight and CSA than those in the DEN group. Although RNA-seq and pathway analysis suggested that mitochondrial biogenesis is a critical event in this phenomenon, mitochondrial content showed no difference. In contrast, ribosomal RNA 28S and 18S (n = 6) levels in the DEN + ES group were higher than those in the DEN group, even though RNA-seq showed that the ribosome biogenesis pathway was reduced by electrical stimulation. The mRNA levels of the muscle proteolytic molecules atrogin-1 and MuRF1 were significantly higher in DEN than those in CONT. However, they were more suppressed in DEN + ES than those in DEN. In conclusion, tetanic electrical stimulation of both ankles using belt electrodes effectively reduced denervation-induced atrophy in multiple muscle groups. Furthermore, ribosomal biosynthesis plays a vital role in this phenomenon.

DOI: https://doi.org/10.1038/s41598-024-56382-x
Eur J Heart Fail. 2024 Mar 11.

Sodium-glucose cotransporter 2 inhibitors influence skeletal muscle pathology in patients with heart failure and reduced ejection fraction.

Nathanael Wood, Sam Straw, Chew W Cheng, Yu Hirata, Marcelo G Pereira, Harrison Gallagher, Stuart Egginton, Wataru Ogawa, Stephen B Wheatcroft, Klaus K Witte, Lee D Roberts, T Scott Bowen.

  AIMS: Patients with heart failure and reduced ejection fraction (HFrEF) exhibit skeletal muscle pathology, which contributes to symptoms and decreased quality of life. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve clinical outcomes in HFrEF but their mechanism of action remains poorly understood. We aimed, therefore, to determine whether SGLT2i influence skeletal muscle pathology in patients with HFrEF.METHODS AND RESULTS: Muscle biopsies from 28 male patients with HFrEF (New York Heart association class I-III) treated with SGLT2i (>12 months) or without SGLT2i were compared. Comprehensive analyses of muscle structure (immunohistochemistry), transcriptome (RNA sequencing), and metabolome (liquid chromatography-mass spectrometry) were performed, and serum inflammatory profiling (ELISA). Experiments in mice (n = 16) treated with SGLT2i were also performed. Myofiber atrophy was ~20% less in patients taking SGLT2i (p = 0.07). Transcriptomics and follow-up measures identified a unique signature in patients taking SGLT2i related to beneficial effects on atrophy, metabolism, and inflammation. Metabolomics identified influenced tryptophan metabolism in patients taking SGLT2i: kynurenic acid was 24% higher and kynurenine was 32% lower (p < 0.001). Serum profiling identified that SGLT2i treatment was associated with lower (p < 0.05) pro-inflammatory cytokines by 26-64% alongside downstream muscle interleukin (IL)-6-JAK/STAT3 signalling (p = 008 and 0.09). Serum IL-6 and muscle kynurenine were correlated (R = 0.65; p < 0.05). Muscle pathology was lower in mice treated with SGLT2i indicative of a conserved mammalian response to treatment.
CONCLUSIONS: Treatment with SGLT2i influenced skeletal muscle pathology in patients with HFrEF and was associated with anti-atrophic, anti-inflammatory, and pro-metabolic effects. These changes may be regulated via IL-6-kynurenine signalling. Together, clinical improvements following SGLT2i treatment in patients with HFrEF may be partly explained by their positive effects on skeletal muscle pathology.

Keywords:  Atrophy; HFrEF; Metabolism; Muscle; SGLT2 inhibitors

DOI:  https://doi.org/10.1002/ejhf.3192
Reprod Med Biol. 2024 Jan-Dec;23(1):23(1): e12569

The roles of sex hormones in the pathophysiology of age-related sarcopenia and frailty.

Tatsuya Hosoi, Mitsutaka Yakabe, Seiji Hashimoto, Masahiro Akishita, Sumito Ogawa.

  Background: Sarcopenia is an age-related condition characterized by a progressive and systemic decline in skeletal muscle mass, quality, and strength. The incidence of sarcopenia contains sex-specific aspects, indicating the contribution of sex hormones to its pathophysiology. This review focuses on changing trends in sarcopenia, discusses alterations in definitions and diagnostic criteria, and emphasizes the association between sarcopenia and sex hormones.Methods: A literature search was performed on PubMed for related articles published between 1997 and December 2023 using appropriate keywords.
Main Findings Results: Advances in research have emphasized the significance of muscle quality and strength over muscle mass, resulting in new diagnostic criteria for sarcopenia. Androgens demonstrated anabolic effects on skeletal muscles and played a significant role in the pathophysiology of sarcopenia. In clinical settings, androgen replacement therapy has exhibited certain positive outcomes for treating sarcopenia, despite concerns about potential side effects. Conversely, estrogen is involved in skeletal muscle maintenance, but the detailed mechanisms remain unclear. Moreover, results regarding the clinical application of estrogen replacement therapy for treating sarcopenia remained inconsistent.
Conclusion: The elucidation of molecular mechanisms that involve sex hormones is eagerly awaited for novel therapeutic interventions for sarcopenia.

Keywords:  androgen; estrogen; frailty; sarcopenia; sex hormones

DOI:  https://doi.org/10.1002/rmb2.12569
Endocrine. 2024 Mar 13.

Estrogen promotes fetal skeletal muscle mitochondrial distribution and ATP synthase activity important for insulin sensitivity in offspring.

Soon Ok Kim, Eugene D Albrecht, Gerald J Pepe.

  PURPOSE: We previously showed that offspring delivered to baboons in which levels of estradiol (E2) were suppressed during the second half of gestation exhibit insulin resistance. Mitochondria are essential for the production of ATP as the main source of energy for intracellular metabolic pathways, and skeletal muscle of type 2 diabetics exhibit mitochondrial abnormalities. Mitochondria express estrogen receptor β and E2 enhances mitochondrial function in adults. Therefore, the current study ascertained whether exposure of the fetus to E2 is essential for mitochondrial development.METHODS: Levels of ATP synthase and citrate synthase and the morphology of mitochondria were determined in fetal skeletal muscle obtained near term from baboons untreated or treated daily with the aromatase inhibitor letrozole or letrozole plus E2.
RESULTS: Specific activity and amount of ATP synthase were 2-fold lower (P < 0.05) in mitochondria from skeletal muscle of E2 suppressed letrozole-treated fetuses and restored to normal by treatment with letrozole plus E2. Immunocytochemistry showed that in contrast to the punctate formation of mitochondria in myocytes of untreated and letrozole plus E2 treated animals, mitochondria appeared to be diffuse in myocytes of estrogen-suppressed fetuses. However, citrate synthase activity and levels of proteins that control mitochondrial fission/fusion were similar in estrogen replete and suppressed animals.
CONCLUSION: We suggest that estrogen is essential for fetal skeletal muscle mitochondrial development and thus glucose homeostasis in adulthood.

Keywords:  Estrogen; Fetus; Insulin resistance; Mitochondria; Skeletal muscle

DOI:  https://doi.org/10.1007/s12020-024-03764-w
Acta Physiol (Oxf). 2024 Mar 11. e14135

Age-related muscle atrophy? Mitofusin 2 the rescue.

Agustina Creus, David Sebastián.

DOI: https://doi.org/10.1111/apha.14135
J Appl Physiol (1985). 2024 Mar 14.

Eccentric exercise ≠ eccentric contraction.

Paolo Tecchio, Brent J Raiteri, Daniel Hahn.

  Whether eccentric exercise involves active fascicle stretch is unclear due to muscle-tendon unit (MTU) series elasticity. Therefore, this study investigated the impact of changing the activation timing and level (i.e., pre-activation) of the contraction on muscle fascicle kinematics and kinetics of the human tibialis anterior during dynamometer-controlled maximal voluntary MTU-stretch-hold contractions. B-mode ultrasound and surface electromyography were employed to assess muscle fascicle kinematics and muscle activity levels, respectively. While joint kinematics were similar among MTU-stretch-hold contractions (~40° rotation amplitude), increasing pre-activation increased fascicle shortening and stretch amplitudes (9.9-23.2 mm, p ≤ 0.015). This led to increasing positive and negative fascicle work with increasing pre-activation. Despite significantly different fascicle kinematics, similar peak fascicle forces during stretch occurred at similar fascicle lengths and joint angles regardless of pre-activation. Similarly, residual force enhancement (rFE) following MTU stretch was not significantly affected (6.5-7.6%, p = 0.559) by pre-activation, but rFE was strongly correlated with peak fascicle force during stretch (rrm = 0.62, p = 0.003). These findings highlight that apparent eccentric exercise causes shortening-stretch contractions at the fascicle level rather than isolated eccentric contractions. The constant rFE despite different fascicle kinematics and kinetics suggests that a passive element was engaged at a common muscle length among conditions (e.g., optimal fascicle length). Although it remains unclear whether different fascicle mechanics trigger different adaptations to eccentric exercise, this study emphasizes the need to consider MTU series elasticity to better understand the mechanical drivers of adaptation to exercise.

Keywords:  eccentric training; fascicle behavior; history dependence; muscle compliance; muscle stretch

DOI:  https://doi.org/10.1152/japplphysiol.00845.2023
Metabolism. 2024 Mar 11. pii: S0026-0495(24)00060-X. [Epub ahead of print] 155834

Metabolic plasticity and obesity-associated changes in diurnal postexercise metabolism in mice.

Logan A Pendergrast, Stephen P Ashcroft, Amy M Ehrlich, Jonas T Treebak, Anna Krook, Lucile Dollet, Juleen R Zierath.

  BACKGROUND: Circadian disruption is widespread and increases the risk of obesity. Timing of therapeutic interventions may promote coherent and efficient gating of metabolic processes and restore energy homeostasis.AIM: To characterize the diurnal postexercise metabolic state in mice and to identify the influence of diet-induced obesity on identified outcomes.
METHODS: C57BL6/NTac male mice (6wks of age) were fed a standard chow or high-fat diet for 5 weeks. At week 5, mice were subjected to a 60-min (16 m/min, 5 % incline) running bout (or sham) during the early rest (day) or early active (night) phase. Tissue and serum samples were collected immediately post-exercise (n = 6/group). In vivo glucose oxidation was measured after oral administration of 13C-glucose via 13CO2 exhalation analysis in metabolic cages. Basal and isoproterenol-stimulated adipose tissue lipolysis was assessed ex vivo for 1 h following exercise.
RESULTS: Lean mice displayed exercise-timing-specific plasticity in metabolic outcomes, including phase-specificity in systemic glucose metabolism and adipose-tissue-autonomous lipolytic activity depending on time of day. Conversely, obesity impaired temporal postexercise differences in whole-body glucose oxidation, as well as the phase- and exercise-mediated induction of lipolysis in isolated adipose tissue. This obesity-induced alteration in diurnal metabolism, as well as the indistinct response to exercise, was observed concomitant with disruption of core clock gene expression in peripheral tissues.
CONCLUSIONS: Overall, high-fat fed obese mice exhibit metabolic inflexibility, which is also evident in the diurnal exercise response. Our study provides physiological insight into exercise timing-dependent aspects in the dynamic regulation of metabolism and the influence of obesity on this biology.

Keywords:  Adipose tissue; Circadian rhythm; Exercise; Lipolysis; Time of day

DOI:  https://doi.org/10.1016/j.metabol.2024.155834
Med Res Rev. 2024 Mar 14.

Enhancing healthy aging with small molecules: A mitochondrial perspective.

Xiujiao Qin, Hongyuan Li, Huiying Zhao, Le Fang, Xiaohui Wang.

  The pursuit of enhanced health during aging has prompted the exploration of various strategies focused on reducing the decline associated with the aging process. A key area of this exploration is the management of mitochondrial dysfunction, a notable characteristic of aging. This review sheds light on the crucial role that small molecules play in augmenting healthy aging, particularly through influencing mitochondrial functions. Mitochondrial oxidative damage, a significant aspect of aging, can potentially be lessened through interventions such as coenzyme Q10, alpha-lipoic acid, and a variety of antioxidants. Additionally, this review discusses approaches for enhancing mitochondrial proteostasis, emphasizing the importance of mitochondrial unfolded protein response inducers like doxycycline, and agents that affect mitophagy, such as urolithin A, spermidine, trehalose, and taurine, which are vital for sustaining protein quality control. Of equal importance are methods for modulating mitochondrial energy production, which involve nicotinamide adenine dinucleotide boosters, adenosine 5'-monophosphate-activated protein kinase activators, and compounds like metformin and mitochondria-targeted tamoxifen that enhance metabolic function. Furthermore, the review delves into emerging strategies that encourage mitochondrial biogenesis. Together, these interventions present a promising avenue for addressing age-related mitochondrial degradation, thereby setting the stage for the development of innovative treatment approaches to meet this extensive challenge.

Keywords:  aging; mitochondrial; mitophagy; redox homeostasis; unfolded protein response

DOI:  https://doi.org/10.1002/med.22034