bims-moremu 2024-09-08 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2024–09–08
thirty-two papers selected by
Anna Vainshtein, Craft Science Inc.

Myosin ATPase inhibition fails to rescue the metabolically dysregulated proteome of nebulin-deficient muscle.
Fibre-specific mitochondrial protein abundance is linked to resting and post-training mitochondrial content in the muscle of men.
Matrisome proteomics reveals novel mediators of muscle remodeling with aerobic exercise training.
GSDMD knockout alleviates sepsis-associated skeletal muscle atrophy by inhibiting IL18/AMPK signaling.
Unacylated Ghrelin Protects Against Age-Related Loss of Muscle Mass and Contractile Dysfunction in Skeletal Muscle.
Muscle-specific mitophagy: insights into hindlimb and diaphragm responses during health and sepsis.
Muscle-enriched microRNA-486-mediated regulation of muscular atrophy and exercise.
Mechanical Loading Modulates AMPK and mTOR Signaling in Muscle Cells.
Mitochondrial Adaptations in Aging Skeletal Muscle: Implications for Resistance Exercise Training to Treat Sarcopenia.
Modeling the mechanism of Ca2+ release in skeletal muscle by DHPRs easing inhibition at RyR I1-sites.
Strain-dependent dynamic re-alignment of collagen fibers in skeletal muscle extracellular matrix.
Tic-tac-mito: The relationship between the biological clock with mitochondria dynamics and skeletal muscle function in humans.
Imbalanced Skeletal Muscle Mitochondrial Proteostasis Causes Bone Loss.
A 2-hydroxybutyrate-mediated feedback loop regulates muscular fatigue.
Gut-muscle axis mechanism of exercise prevention of sarcopenia.
Integrative insights into PNI: Low-grade chronic inflammation, skeletal muscle wasting, and brain impairments.
Artificial neural network inference analysis identified novel genes and gene interactions associated with skeletal muscle aging.
Diarylpropionitrile-stimulated ERβ nuclear accumulation promotes MyoD-induced muscle regeneration in mdx mice by interacting with FOXO3A.
Analysis of potential TAK1/Map3k7 phosphorylation targets in hypertrophy and cachexia models of skeletal muscle.
eEF1α2 is required for actin cytoskeleton homeostasis in the aging muscle.
Skeletal muscle atrophy induces memory dysfunction via hemopexin action in healthy young mice.
Therapeutic targeting of GDF11 in muscle atrophy: Insights and strategies.
Ectopic expression of Myomaker and Myomixer in slow muscle cells induces slow muscle fusion and myofiber death.
A Neural Basis for Mutant ATAXIN-1 Induced Respiratory Dysfunction in Mouse Models of Spinocerebellar Ataxia Type 1.
Nicotinamide riboside kinase 2: A unique target for skeletal muscle and cardiometabolic diseases.
Exploring Circadian Changes in Muscle Physiology: Methodological Considerations.
Along- and cross-muscle fiber shear moduli in skeletal muscle.
Neuromuscular impairment at different stages of human sarcopenia.
Local muscle pressure stimulates the principal receptors for proprioception.
Liver-secreted FGF21 induces sarcopenia by inhibiting satellite cell myogenesis via klotho beta in decompensated cirrhosis.
Discovery of fibroblast growth factor 2-derived peptides for enhancing mice skeletal muscle satellite cell proliferation.
Invitations to join a new 2024 section of Ejtm and the 2025 Pdm3 from 25 to 29 March, Euganean Thermae, Padua, Italy.

J Physiol. 2024 Aug 31.

Myosin ATPase inhibition fails to rescue the metabolically dysregulated proteome of nebulin-deficient muscle.

Jenni Laitila, Robert A E Seaborne, Natasha Ranu, Justin S Kolb, Carina Wallgren-Pettersson, Nanna Witting, John Vissing, Juan Jesus Vilchez, Edmar Zanoteli, Johanna Palmio, Sanna Huovinen, Henk Granzier, Julien Ochala.

  Nemaline myopathy (NM) is a genetic muscle disease, primarily caused by mutations in the NEB gene (NEB-NM) and with muscle myosin dysfunction as a major molecular pathogenic mechanism. Recently, we have observed that the myosin biochemical super-relaxed state was significantly impaired in NEB-NM, inducing an aberrant increase in ATP consumption and remodelling of the energy proteome in diseased muscle fibres. Because the small-molecule Mavacamten is known to promote the myosin super-relaxed state and reduce the ATP demand, we tested its potency in the context of NEB-NM. We first conducted in vitro experiments in isolated single myofibres from patients and found that Mavacamten successfully reversed the myosin ATP overconsumption. Following this, we assessed its short-term in vivo effects using the conditional nebulin knockout (cNeb KO) mouse model and subsequently performing global proteomics profiling in dissected soleus myofibres. After a 4 week treatment period, we observed a remodelling of a large number of proteins in both cNeb KO mice and their wild-type siblings. Nevertheless, these changes were not related to the energy proteome, indicating that short-term Mavacamten treatment is not sufficient to properly counterbalance the metabolically dysregulated proteome of cNeb KO mice. Taken together, our findings emphasize Mavacamten potency in vitro but challenge its short-term efficacy in vivo. KEY POINTS: No cure exists for nemaline myopathy, a type of genetic skeletal muscle disease mainly derived from mutations in genes encoding myofilament proteins. Applying Mavacamten, a small molecule directly targeting the myofilaments, to isolated membrane-permeabilized muscle fibres from human patients restored myosin energetic disturbances. Treating a mouse model of nemaline myopathy in vivo with Mavacamten for 4 weeks, remodelled the skeletal muscle fibre proteome without any noticeable effects on energetic proteins. Short-term Mavacamten treatment may not be sufficient to reverse the muscle phenotype in nemaline myopathy.

Keywords:  Mavacamten; myosin; nebulin; nemaline myopathy; proteomics; skeletal muscle

DOI:  https://doi.org/10.1113/JP286870
Nat Commun. 2024 Sep 03. 15(1): 7677

Fibre-specific mitochondrial protein abundance is linked to resting and post-training mitochondrial content in the muscle of men.

Elizabeth G Reisman, Javier Botella, Cheng Huang, Ralf B Schittenhelm, David A Stroud, Cesare Granata, Owala S Chandrasiri, Georg Ramm, Viola Oorschot, Nikeisha J Caruana, David J Bishop.

Analyses of mitochondrial adaptations in human skeletal muscle have mostly used whole-muscle samples, where results may be confounded by the presence of a mixture of type I and II muscle fibres. Using our adapted mass spectrometry-based proteomics workflow, we provide insights into fibre-specific mitochondrial differences in the human skeletal muscle of men before and after training. Our findings challenge previous conclusions regarding the extent of fibre-type-specific remodelling of the mitochondrial proteome and suggest that most baseline differences in mitochondrial protein abundances between fibre types reported by us, and others, might be due to differences in total mitochondrial content or a consequence of adaptations to habitual physical activity (or inactivity). Most training-induced changes in different mitochondrial functional groups, in both fibre types, were no longer significant in our study when normalised to changes in markers of mitochondrial content.

DOI: https://doi.org/10.1038/s41467-024-50632-2
Matrix Biol Plus. 2024 Aug;23 100159

Matrisome proteomics reveals novel mediators of muscle remodeling with aerobic exercise training.

Pattarawan Pattamaprapanont, Eileen M Cooney, Tara L MacDonald, Joao A Paulo, Hui Pan, Jonathan M Dreyfuss, Sarah J Lessard.

  Skeletal muscle has a unique ability to remodel in response to stimuli such as contraction and aerobic exercise training. Phenotypic changes in muscle that occur with training such as a switch to a more oxidative fiber type, and increased capillary density contribute to the well-known health benefits of aerobic exercise. The muscle matrisome likely plays an important role in muscle remodeling with exercise. However, due to technical limitations in studying muscle ECM proteins, which are highly insoluble, little is known about the muscle matrisome and how it contributes to muscle remodeling. Here, we utilized two-fraction methodology to extract muscle proteins, combined with multiplexed tandem mass tag proteomic technology to identify 161 unique ECM proteins in mouse skeletal muscle. In addition, we demonstrate that aerobic exercise training induces remodeling of a significant proportion of the muscle matrisome. We performed follow-up experiments to validate exercise-regulated ECM targets in a separate cohort of mice using Western blotting and immunofluorescence imaging. Our data demonstrate that changes in several key ECM targets are strongly associated with muscle remodeling processes such as increased capillary density in mice. We also identify LOXL1 as a novel muscle ECM target associated with aerobic capacity in humans. In addition, publically available data and databases were used for in silico modeling to determine the likely cellular sources of exercise-induced ECM remodeling targets and identify ECM interaction networks. This work greatly enhances our understanding of ECM content and function in skeletal muscle and demonstrates an important role for ECM remodeling in the adaptive response to exercise. The raw MS data have been deposited to the ProteomeXchange with identifier PXD053003.

Keywords:  Core matrisome; Exercise; Matrisome-associated; Proteomics; Remodeling; Skeletal muscle

DOI:  https://doi.org/10.1016/j.mbplus.2024.100159
Shock. 2024 Sep 03.

GSDMD knockout alleviates sepsis-associated skeletal muscle atrophy by inhibiting IL18/AMPK signaling.

Yongsheng Zhang, Tonghan Li, Yukun Liu, Chuntao Wang, Dongfang Wang, Ligang Xu, Hong Zhao, Xiangjun Bai, Zhanfei Li, Yuchang Wang.

BACKGROUND: Sepsis commonly leads to skeletal muscle atrophy, characterized by substantial muscle weakness and degeneration, ultimately contributing to an adverse prognosis. Studies have shown that programmed cell death is an important factor in the progression of muscle loss in sepsis. However, the precise role and mechanism of pyroptosis in skeletal muscle atrophy are not yet fully comprehended. Therefore, we aimed to examine the role and mechanism of action of the pyroptosis effector protein GSDMD in recognized cellular and mouse models of sepsis.
METHODS: The levels of GSDMD and N-GSDMD in skeletal muscle were evaluated 2, 4, and 8 days after CLP. Sepsis was produced in mice that lacked the Gsdmd gene (Gsdmd knockout) and in mice with the normal Gsdmd gene (wild-type) using a procedure called cecal ligation and puncture (CLP). The degree of muscular atrophy in the gastrocnemius and tibialis anterior muscles was assessed 72 hours after surgery in the septic mouse model. In addition, the architecture of skeletal muscles, protein expression, and markers associated with pathways leading to muscle atrophy were examined in mice from various groups 72 hours after surgery. The in vitro investigations entailed the use of siRNA to suppress Gsdmd expression in C2C12 cells, followed by stimulation of these cells with lipopolysaccharide (LPS) to evaluate the impact of Gsdmd downregulation on muscle atrophy and the related signaling cascades.
RESULTS: This study has demonstrated that the GSDMD protein, known as the "executive" protein of pyroptosis, plays a crucial role in the advancement of skeletal muscle atrophy in septic mice. The expression of N-GSDMD in the skeletal muscle of septic mice was markedly higher compared to the control group. The Gsdmd knockout mice exhibited notable enhancements in survival, muscle strength, and body weight compared to the septic mice. Deletion of the Gsdmd gene reduced muscular wasting in the gastrocnemius and tibialis anterior muscles caused by sepsis. Studies conducted in living organisms (in vivo) and in laboratory conditions (in vitro) have shown that the absence of the Gsdmd gene decreases indicators of muscle loss associated with sepsis by blocking the IL18/AMPK signaling pathway.
CONCLUSION: The results of this study demonstrate that the lack of Gsdmd has a beneficial effect on septic skeletal muscle atrophy by reducing the activation of IL18/AMPK and inhibiting the UPS and autophagy pathways. Therefore, our research provides vital insights into the role of pyroptosis in sepsis-related skeletal muscle wasting, which could potentially lead to the development of therapeutic and interventional approaches for preventing septic skeletal muscle atrophy.

DOI: https://doi.org/10.1097/SHK.0000000000002430
Aging Cell. 2024 Sep 02. e14323

Unacylated Ghrelin Protects Against Age-Related Loss of Muscle Mass and Contractile Dysfunction in Skeletal Muscle.

Hyunyoung Kim, Rojina Ranjit, Dennis R Claflin, Constantin Georgescu, Jonathan D Wren, Susan V Brooks, Benjamin F Miller, Bumsoo Ahn.

  Sarcopenia, the progressive loss of muscle mass and function, universally affects older adults and is closely associated with frailty and reduced quality of life. Despite the inevitable consequences of sarcopenia and its relevance to healthspan, no pharmacological therapies are currently available. Ghrelin is a gut-released hormone that increases appetite and body weight through acylation. Acylated ghrelin activates its receptor, growth hormone secretagogue receptor 1a (GHSR1a), in the brain by binding to it. Studies have demonstrated that acyl and unacylated ghrelin (UnAG) both have protective effects against acute pathological conditions independent of receptor activation. Here, we investigated the long-term effects of UnAG in age-associated muscle atrophy and contractile dysfunction in mice. Four-month-old and 18-month-old mice were subjected to either UnAG or control treatment for 10 months. UnAG did not affect food consumption or body weight. Gastrocnemius and quadriceps muscle weights were reduced by 20%-30% with age, which was partially protected against by UnAG. Specific force, force per cross-sectional area, measured in isolated extensor digitorum longus muscle was diminished by 30% in old mice; however, UnAG prevented the loss of specific force. UnAG also protected from decreases in mitochondrial respiration and increases in hydrogen peroxide generation of skeletal muscle of old mice. Results of bulk mRNA-seq analysis and our contractile function data show that UnAG reversed neuromuscular junction impairment that occurs with age. Collectively, our data revealed the direct role of UnAG in mitigating sarcopenia in mice, independent of food consumption or body weight, implicating UnAG treatment as a potential therapy against sarcopenia.

Keywords:  loss of muscle mass; mitochondria; neurogenic atrophy; neuromuscular junction; protein synthesis and degradation; sarcopenia; unacylated ghrelin

DOI:  https://doi.org/10.1111/acel.14323
J Physiol. 2024 Sep 02.

Muscle-specific mitophagy: insights into hindlimb and diaphragm responses during health and sepsis.

Jordan D Fuqua, Paulo H C Mesquita, Michael E Taylor, Agnieszka K Borowik.



Keywords:  autophagy; mitochondria; skeletal muscle

DOI:  https://doi.org/10.1113/JP287151
J Physiol Biochem. 2024 Sep 02.

Muscle-enriched microRNA-486-mediated regulation of muscular atrophy and exercise.

Dayong Qiu, Yan Zhang, Pinshi Ni, Zhuangzhi Wang, Luodan Yang, Fanghui Li.

  The objectives of this review were to understand the impact of microRNA-486 on myogenesis and muscle atrophy, and the change of microRNA-486 following exercise, and provide valuable information for improving muscle atrophy based on exercise intervention targeting microRNA-486. Muscle-enriched microRNAs (miRNAs), also referred to as myomiRs, control various processes in skeletal muscles, from myogenesis and muscle homeostasis to different responses to environmental stimuli such as exercise. MicroRNA-486 is a miRNA in which a stem-loop sequence is embedded within the ANKYRIN1 (ANK1) locus and is strictly conserved across mammals. MicroRNA-486 is involved in the development of muscle atrophy caused by aging, immobility, prolonged exposure to microgravity, or muscular and neuromuscular disorders. PI3K/AKT signaling is a positive pathway, as it increases muscle mass by increasing protein synthesis and decreasing protein degradation. MicroRNA-486 can activate this pathway by inhibiting phosphatase and tensin homolog (PTEN), it may also indirectly inhibit the HIPPO signaling pathway to promote cell growth. Exercises regulate microRNA-486 expression both in blood and muscle. This review focused on the recent elucidation of sarcopenia regulation by microRNA-486 and its effects on pathological states, including primary muscular disease, secondary muscular disorders, and age-related sarcopenia. Additionally, the role of exercise in regulating skeletal muscle-enriched microRNA-486 was highlighted, along with its physiological significance. Growing evidence indicates that microRNA-486 significantly impacts the development of muscle atrophy. MicroRNA-486 has great potential to become a therapeutic target for improving muscle atrophy through exercise intervention.

Keywords:  Aging; Exercise; Muscle atrophy; Sarcopenia; microRNA-486

DOI:  https://doi.org/10.1007/s13105-024-01043-w
J Proteome Res. 2024 Aug 30.

Mechanical Loading Modulates AMPK and mTOR Signaling in Muscle Cells.

Xin Zhou, Shaochun Zhu, Junhong Li, Andre Mateus, Chloe Williams, Jonathan Gilthorpe, Ludvig J Backman.

  Skeletal muscle adaptation to exercise involves various phenotypic changes that enhance the metabolic and contractile functions. One key regulator of these adaptive responses is the activation of AMPK, which is influenced by exercise intensity. However, the mechanistic understanding of AMPK activation during exercise remains incomplete. In this study, we utilized an in vitro model to investigate the effects of mechanical loading on AMPK activation and its interaction with the mTOR signaling pathway. Proteomic analysis of muscle cells subjected to static loading (SL) revealed distinct quantitative protein alterations associated with RNA metabolism, with 10% SL inducing the most pronounced response compared to lower intensities of 5% and 2% as well as the control. Additionally, 10% SL suppressed RNA and protein synthesis while activating AMPK and inhibiting the mTOR pathway. We also found that SRSF2, necessary for pre-mRNA splicing, is regulated by AMPK and mTOR signaling, which, in turn, is regulated in an intensity-dependent manner by SL with the highest expression in 2% SL. Further examination showed that the ADP/ATP ratio was increased after 10% SL compared to the control and that SL induced changes in mitochondrial biogenesis. Furthermore, Seahorse assay results indicate that 10% SL enhances mitochondrial respiration. These findings provide novel insights into the cellular responses to mechanical loading and shed light on the intricate AMPK-mTOR regulatory network in muscle cells.

Keywords:  ADP/ATP ratio; AMPK; RNA sequencing; exercise adaptation; mTOR; mechanical loading; mitochondrial biogenesis; protein synthesis; proteomics analysis; skeletal muscle

DOI:  https://doi.org/10.1021/acs.jproteome.4c00242
Life (Basel). 2024 Jul 31. pii: 962. [Epub ahead of print]14(8):

Mitochondrial Adaptations in Aging Skeletal Muscle: Implications for Resistance Exercise Training to Treat Sarcopenia.

Ilyoung Jeong, Eun-Jeong Cho, Jang-Soo Yook, Youngju Choi, Dong-Ho Park, Ju-Hee Kang, Seok-Hun Lee, Dae-Yun Seo, Su-Jeen Jung, Hyo-Bum Kwak.

  Sarcopenia, the age-related decline in muscle mass and function, poses a significant health challenge as the global population ages. Mitochondrial dysfunction is a key factor in sarcopenia, as evidenced by the role of mitochondrial reactive oxygen species (mtROS) in mitochondrial biogenesis and dynamics, as well as mitophagy. Resistance exercise training (RET) is a well-established intervention for sarcopenia; however, its effects on the mitochondria in aging skeletal muscles remain unclear. This review aims to elucidate the relationship between mitochondrial dynamics and sarcopenia, with a specific focus on the implications of RET. Although aerobic exercise training (AET) has traditionally been viewed as more effective for mitochondrial enhancement, emerging evidence suggests that RET may also confer beneficial effects. Here, we highlight the potential of RET to modulate mtROS, drive mitochondrial biogenesis, optimize mitochondrial dynamics, and promote mitophagy in aging skeletal muscles. Understanding this interplay offers insights for combating sarcopenia and preserving skeletal muscle health in aging individuals.

Keywords:  aging; mitochondria; resistance exercise training; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.3390/life14080962
J Gen Physiol. 2024 Oct 07. pii: e202213113. [Epub ahead of print]156(10):

Modeling the mechanism of Ca2+ release in skeletal muscle by DHPRs easing inhibition at RyR I1-sites.

D George Stephenson.

Ca2+ release from the sarcoplasmic reticulum (SR) plays a central role in excitation-contraction coupling (ECC) in skeletal muscles. However, the mechanism by which activation of the voltage-sensors/dihydropyridine receptors (DHPRs) in the membrane of the transverse tubular system leads to activation of the Ca2+-release channels/ryanodine receptors (RyRs) in the SR is not fully understood. Recent observations showing that a very small Ca2+ leak through RyR1s in mammalian skeletal muscle can markedly raise the background [Ca2+] in the junctional space (JS) above the Ca2+ level in the bulk of the cytosol indicate that there is a diffusional barrier between the JS and the cytosol at large. Here, I use a mathematical model to explore the hypothesis that a sudden rise in Ca2+ leak through DHPR-coupled RyR1s, caused by reduced inhibition at the RyR1 Ca2+/Mg2+ inhibitory I1-sites when the associated DHPRs are activated, is sufficient to enable synchronized responses that trigger a regenerative rise of Ca2+ release that remains under voltage control. In this way, the characteristic response to Ca2+ of RyR channels is key not only for the Ca2+ release mechanism in cardiac muscle and other tissues, but also for the DHPR-dependent Ca2+ release in skeletal muscle.

DOI: https://doi.org/10.1085/jgp.202213113
Acta Biomater. 2024 Aug 30. pii: S1742-7061(24)00479-3. [Epub ahead of print]

Strain-dependent dynamic re-alignment of collagen fibers in skeletal muscle extracellular matrix.

Ross P Wohlgemuth, Sathvik Sriram, Kyle E Henricson, Daryl T Dinh, Sarah E Brashear, Lucas R Smith.

  Collagen fiber architecture within the skeletal muscle extracellular matrix (ECM) is significant to passive muscle mechanics. While it is thought that collagen fibers re-orient themselves in response to changes in muscle length, this has not been dynamically visualized and quantified within a muscle. The goal of this study was to measure changes in collagen alignment across a range of muscle lengths and compare the corresponding alignment to muscle mechanics. We hypothesized that collagen fibers dynamically increase alignment in response to muscle stretching, and this change in alignment is related to passive muscle stiffness. Further, we hypothesized that digesting collagen fibers with collagenase would reduce the re-alignment response to muscle stretching. Using DBA/2J and D2.mdx mice, we isolated extensor digitorum longus (EDL), soleus, and diaphragm muscles for collagenase or sham treatment and decellularization to isolate intact or collagenase-digested decellularized muscles (DCMs). These DCMs were mechanically tested and imaged using second harmonic generation microscopy to measure collagen alignment across a range of strains. We found that collagen alignment increased in a strain-dependent fashion, but collagenase did not significantly affect the strain-dependent change in alignment. We also saw that the collagen fibers in the diaphragm epimysium (surface ECM) and perimysium (deep ECM) started at different angles, but still re-oriented in the same direction in response to stretching. These robust changes in collagen alignment were weakly related to passive DCM stiffness. Overall, we demonstrated that the architecture of muscle ECM is dynamic in response to strain and is related to passive muscle mechanics. STATEMENT OF SIGNIFICANCE: Our study presents a unique visualization and quantification of strain-induced changes in muscle collagen fiber alignment as they relate to passive mechanics. Using dynamic imaging of collagen in skeletal muscle we demonstrate that as skeletal muscle is stretched, collagen fibers re-orient themselves along the axis of stretch and increase their alignment. The degree of alignment and the increase in alignment are each weakly related to passive muscle stiffness. Collagenase treatments further demonstrate that the basis for muscle Extracellular matrix stiffness is dependent on factors beyond collagen crosslinking and alignment. Together the study contributes to the knowledge of the structure-function relationships of muscle extracellular matrix to tissue stiffness relevant to conditions of fibrosis and aberrant stiffness.

Keywords:  Collagen architecture; Extracellular matrix; Muscle mechanics; Second harmonic generation; Skeletal muscle

DOI:  https://doi.org/10.1016/j.actbio.2024.08.035
J Physiol. 2024 Sep 02.

Tic-tac-mito: The relationship between the biological clock with mitochondria dynamics and skeletal muscle function in humans.

Itamar C G Jesus, Flavia M Araujo.



Keywords:  biological clock; metabolism; mitochondria; protein synthesis; skeletal muscle

DOI:  https://doi.org/10.1113/JP287210
Research (Wash D C). 2024 ;7 0465

Imbalanced Skeletal Muscle Mitochondrial Proteostasis Causes Bone Loss.

Zhen Jin, Yan Mao, Qiqi Guo, Yujing Yin, Abdukahar Kiram, Danxia Zhou, Jing Yang, Zheng Zhou, Jiachen Xue, Zhenhua Feng, Zhen Liu, Yong Qiu, Tingting Fu, Zhenji Gan, Zezhang Zhu.

Although microgravity has been implicated in osteoporosis, the precise molecular mechanism remains elusive. Here, we found that microgravity might induce mitochondrial protein buildup in skeletal muscle, alongside reduced levels of LONP1 protein. We revealed that disruptions in mitochondrial proteolysis, induced by the targeted skeletal muscle-specific deletion of the essential mitochondrial protease LONP1 or by the acute inducible deletion of muscle LONP1 in adult mice, cause reduced bone mass and compromised mechanical function. Moreover, the bone loss and weakness phenotypes were recapitulated in skeletal muscle-specific overexpressing ΔOTC mice, a known protein degraded by LONP1. Mechanistically, mitochondrial proteostasis imbalance triggered the mitochondrial unfolded protein response (UPRmt) in muscle, leading to an up-regulation of multiple myokines, including FGF21, which acts as a pro-osteoclastogenic factor. Surprisingly, this mitochondrial proteostasis stress influenced muscle-bone crosstalk independently of ATF4 in skeletal muscle. Furthermore, we established a marked association between serum FGF21 levels and bone health in humans. These findings emphasize the pivotal role of skeletal muscle mitochondrial proteostasis in responding to alterations in loading conditions and in coordinating UPRmt to modulate bone metabolism.

DOI: https://doi.org/10.34133/research.0465
Elife. 2024 Sep 03. pii: RP92707. [Epub ahead of print]12

A 2-hydroxybutyrate-mediated feedback loop regulates muscular fatigue.

Brennan J Wadsworth, Marina Leiwe, Eleanor A Minogue, Pedro P Cunha, Viktor Engman, Carolin Brombach, Christos Asvestis, Shiv K Sah-Teli, Emilia Marklund, Peppi Karppinen, Jorge L Ruas, Helene Rundqvist, Johanna T Lanner, Randall S Johnson.

  Several metabolites have been shown to have independent and at times unexpected biological effects outside of their metabolic pathways. These include succinate, lactate, fumarate, and 2-hydroxyglutarate. 2-Hydroxybutyrate (2HB) is a byproduct of endogenous cysteine synthesis, produced during periods of cellular stress. 2HB rises acutely after exercise; it also rises during infection and is also chronically increased in a number of metabolic disorders. We show here that 2HB inhibits branched-chain aminotransferase enzymes, which in turn triggers a SIRT4-dependent shift in the compartmental abundance of protein ADP-ribosylation. The 2HB-induced decrease in nuclear protein ADP-ribosylation leads to a C/EBPβ-mediated transcriptional response in the branched-chain amino acid degradation pathway. This response to 2HB exposure leads to an improved oxidative capacity in vitro. We found that repeated injection with 2HB can replicate the improvement to oxidative capacity that occurs following exercise training. Together, we show that 2-HB regulates fundamental aspects of skeletal muscle metabolism.

Keywords:  Exercise; biochemistry; chemical biology; metabolite; mouse; muscle fiber

DOI:  https://doi.org/10.7554/eLife.92707
Front Nutr. 2024 ;11 1418778

Gut-muscle axis mechanism of exercise prevention of sarcopenia.

Tao Li, Danyang Yin, Rengfei Shi.

  Sarcopenia refers to an age-related systemic skeletal muscle disorder, which is characterized by loss of muscle mass and weakening of muscle strength. Gut microbiota can affect skeletal muscle through a variety of mechanisms. Gut microbiota present distinct features among elderly people and sarcopenia patients, including a decrease in microbial diversity, which might be associated with the quality and function of the skeletal muscle. There might be a gut-muscle axis; where gut microbiota and skeletal muscle may affect each other bi-directionally. Skeletal muscle can affect the biodiversity of the gut microbiota, and the latter can, in turn, affect the anabolism of skeletal muscle. This review examines recent studies exploring the relationship between gut microbiota and skeletal muscle, summarizes the effects of exercise on gut microbiota, and discusses the possible mechanisms of the gut-muscle axis.

Keywords:  SCFAs; exercise; gut microbiota; gut-muscle axis; sarcopenia

DOI:  https://doi.org/10.3389/fnut.2024.1418778
Brain Behav Immun Health. 2024 Oct;40 100838

Integrative insights into PNI: Low-grade chronic inflammation, skeletal muscle wasting, and brain impairments.

Daniela Sayuri Inoue, Mariana Janini Gomes.

  Skeletal muscle has been recognized as an endocrine organ which communicates with different systems, including the brain. In conditions involving systemic low-grade chronic inflammation , the skeletal muscle can be negatively impacted, culminating in its quantity (mass) and quality (function) losses, referred to here as muscle wasting. The inflammatory milieu, as well known, also impairs the brain function, however there are some particularities involving skeletal muscle-brain crosstalk, including cognitive function and mental health impairments . Psychoneuroimmunology (PNI) is an important field of neuroendocrine-immune-behavior science and an approach between PNI, and the movement science, or kinesiology, field can enrich future research about the relationship between skeletal muscle wasting and brain health. Thus, in this short review, we present an overview about the interplay between skeletal muscle, inflammatory mediator markers, and brain function with the purpose to strengthen the ties between kinesiology and PNI research to enhance futures discoveries and advances in health sciences.

Keywords:  BDNF; Myokines; Neuromuscular junction; Physical activity; Sarcopenia

DOI:  https://doi.org/10.1016/j.bbih.2024.100838
J Cachexia Sarcopenia Muscle. 2024 Aug 29.

Artificial neural network inference analysis identified novel genes and gene interactions associated with skeletal muscle aging.

Janelle Tarum, Graham Ball, Thomas Gustafsson, Mikael Altun, Lívia Santos.

   BACKGROUND: Sarcopenia is an age-related muscle disease that increases the risk of falls, disabilities, and death. It is associated with increased muscle protein degradation driven by molecular signalling pathways including Akt and FOXO1. This study aims to identify genes, gene interactions, and molecular pathways and processes associated with muscle aging and exercise in older adults that remained undiscovered until now leveraging on an artificial intelligence approach called artificial neural network inference (ANNi).
METHODS: Four datasets reporting the profile of muscle transcriptome obtained by RNA-seq of young (21-43 years) and older adults (63-79 years) were selected and retrieved from the Gene Expression Omnibus (GEO) data repository. Two datasets contained the transcriptome profiles associated to muscle aging and two the transcriptome linked to resistant exercise in older adults, the latter before and after 6 months of exercise training. Each dataset was individually analysed by ANNi based on a swarm neural network approach integrated into a deep learning model (Intelligent Omics). This allowed us to identify top 200 genes influencing (drivers) or being influenced (targets) by aging or exercise and the strongest interactions between such genes. Downstream gene ontology (GO) analysis of these 200 genes was performed using Metacore (Clarivate™) and the open-source software, Metascape. To confirm the differential expression of the genes showing the strongest interactions, real-time quantitative PCR (RT-qPCR) was employed on human muscle biopsies obtained from eight young (25 ± 4 years) and eight older men (78 ± 7.6 years), partaking in a 6-month resistance exercise training programme.
RESULTS: CHAD, ZDBF2, USP54, and JAK2 were identified as the genes with the strongest interactions predicting aging, while SCFD1, KDM5D, EIF4A2, and NIPAL3 were the main interacting genes associated with long-term exercise in older adults. RT-qPCR confirmed significant upregulation of USP54 (P = 0.005), CHAD (P = 0.03), and ZDBF2 (P = 0.008) in the aging muscle, while exercise-related genes were not differentially expressed (EIF4A2 P = 0.99, NIPAL3 P = 0.94, SCFD1 P = 0.94, and KDM5D P = 0.64). GO analysis related to skeletal muscle aging suggests enrichment of pathways linked to bone development (adj P-value 0.006), immune response (adj P-value <0.001), and apoptosis (adj P-value 0.01). In older exercising adults, these were ECM remodelling (adj P-value <0.001), protein folding (adj P-value <0.001), and proteolysis (adj P-value <0.001).
CONCLUSIONS: Using ANNi and RT-qPCR, we identified three strongly interacting genes predicting muscle aging, ZDBF2, USP54, and CHAD. These findings can help to inform the design of nonpharmacological and pharmacological interventions that prevent or mitigate sarcopenia.

Keywords:  Aging; Artificial neural network; Exercise; Machine learning; Skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.13562
Pharmacol Res. 2024 Aug 30. pii: S1043-6618(24)00321-9. [Epub ahead of print]208 107376

Diarylpropionitrile-stimulated ERβ nuclear accumulation promotes MyoD-induced muscle regeneration in mdx mice by interacting with FOXO3A.

Haowei Tong, Shusheng Fan, Wanting Hu, Huna Wang, Guangyao Guo, Xiaofei Huang, Lei Zhao, Xihua Li, Luyong Zhang, Zhenzhou Jiang, Qinwei Yu.

  Duchenne muscular dystrophy (DMD) is an X-linked recessive progressive degenerative disease of skeletal muscle, characterized by intramuscular inflammation, muscle regeneration disorder and replacement of muscle with fibroadipose tissue. DMD is caused by the absence of normal dystrophy. Impaired self-renew ability and limited differentiation capacity of satellite cells are proved as main reasons for muscle regeneration failure. The deficiency of estrogen impedes the process of muscle regeneration. However, the role of estrogen receptor β (ERβ) in muscle regeneration is still unclear. This study aims to investigate the role and the pharmacological effect of ERβ activation on muscle regeneration in mdx mice. This study showed that mRNA levels of ERβ and myogenic-related genes both witnessed increasing trends in dystrophic context. Our results revealed that treatment with selective ERβ agonist (DPN, diarylpropionitrile) significantly increased myogenic differentiation 1 (MyoD-1) level and promoted muscle regeneration in mdx mice. Similarly, in mdx mice with muscle-specific estrogen receptor α (ERα) ablation, DPN treatment still promoted muscle regeneration. Moreover, we demonstrated that myoblasts differentiation was accompanied by raised nuclear accumulation of ERβ. DPN treatment augmented the nuclear accumulation of ERβ and, thus, contributed to myotubes formation. One important finding was that forkhead box O3A (FOXO3A), as a pivotal transcription factor in Myod-1 transcription, participated in the ERβ-promoted muscle regeneration. Overall, we offered an interesting explanation about the crucial role of ERβ during myogenesis.

Keywords:  Diarylpropionitrile; Diarylpropionitrile (PubChem CID：102614); Duchenne muscular dystrophy; Estrogen receptor β; Forkhead box O3A; Muscle regeneration; Nuclear translocation

DOI:  https://doi.org/10.1016/j.phrs.2024.107376
Biol Open. 2024 Aug 30. pii: bio.060487. [Epub ahead of print]

Analysis of potential TAK1/Map3k7 phosphorylation targets in hypertrophy and cachexia models of skeletal muscle.

F Nasehi, C Rylance, E Schnell, M Greene, C Conway, Z Hough, S Duckett, R Muise-Helmericks, A C Foley.

  TGFβ-activated kinase-1 (TAK1) is phosphorylated during both muscle growth and muscle wasting. To understand how this can lead to such opposite effects, we first performed multiplex kinase array of mouse embryonic stem cells with and without stimulation of TAK1 to determine its potential downstream targets. The phosphorylation of these targets was then compared in three different models: hypertrophic longissimus muscle of Texel Sheep, tibialis anterior muscle of mice with cancer-induced cachexia and C2C12-derived myofibers, with and without blockade of TAK1 phosphorylation. In both Texel sheep and in cancer-induced cachexia, phosphorylation of both TAK1 and p38 was increased. Whereas p90RSK was increased in Texel sheep but not cachexia and the phosphorylation of HSP27 and total Jnk were increased in cachexia but not Texel. To understand this further, we examined the expression of these proteins in C2C12 cells as they differentiated into myotubes, with and without blockade of TAK1 phosphorylation. In C2C12 cells, decreased phosphorylation of TAK1 leads to reduced phosphorylation of p38, JNK, and HSP27 after 16 hours and muscle fiber hypertrophy after three days. However, continuous blockade of this pathway leads to muscle fiber failure, suggesting that the timing of TAK1 activation controls the expression of context-dependent targets.

Keywords:  Cachexia; Kinase signaling; Muscle hypertrophy; TGFβ-activated kinase (TAK1); Texel sheep

DOI:  https://doi.org/10.1242/bio.060487
Dis Model Mech. 2024 Sep 01. pii: dmm050729. [Epub ahead of print]17(9):

eEF1α2 is required for actin cytoskeleton homeostasis in the aging muscle.

Hidetaka Katow, Hyung Don Ryoo.

  The translation elongation factor eEF1α (eukaryotic elongation factor 1α) mediates mRNA translation by delivering aminoacyl-tRNAs to ribosomes. eEF1α also has other reported roles, including the regulation of actin dynamics. However, these distinct roles of eEF1α are often challenging to uncouple and remain poorly understood in aging metazoan tissues. The genomes of mammals and Drosophila encode two eEF1α paralogs, with eEF1α1 expressed ubiquitously and eEF1α2 expression more limited to neurons and muscle cells. Here, we report that eEF1α2 plays a unique role in maintaining myofibril homeostasis during aging in Drosophila. Specifically, we generated an eEF1α2 null allele, which was viable and showed two distinct muscle phenotypes. In young flies, the mutants had thinner myofibrils in indirect flight muscles that could be rescued by expressing eEF1α1. With aging, the muscles of the mutant flies began showing abnormal distribution of actin and myosin in muscles, but without a change in actin and myosin protein levels. This age-related phenotype could not be rescued by eEF1α1 overexpression. These findings support an unconventional role of Drosophila eEF1α2 in age-related homeostasis of muscle myofibers.

Keywords:   Drosophila ; Actin; Aging; Muscle; Myosin; eEF1α2

DOI:  https://doi.org/10.1242/dmm.050729
Biochem Biophys Res Commun. 2024 Aug 24. pii: S0006-291X(24)01142-2. [Epub ahead of print]733 150606

Skeletal muscle atrophy induces memory dysfunction via hemopexin action in healthy young mice.

Tsukasa Iki, Chihiro Tohda.

  Age-related morbidity has become an increasingly significant issue worldwide. Sarcopenia, the decline in skeletal muscle mass and strength with age, has been reported to be a risk factor for cognitive impairment. Our previous study revealed that skeletal muscle atrophy shifts the onset of memory dysfunction earlier in young Alzheimer's disease mice and found that hemopexin is a myokine responsible for memory loss. This study aimed to elucidate the occurrence of memory impairment due to skeletal muscle atrophy in non-genetically engineered healthy young mice and the involvement of hemopexin. Closed-colony ddY mice at 12-13 weeks of age were used. Both hind limbs were immobilized by cast attachment for 14 d. Casting for 2 weeks induced a loss of skeletal muscle weight. The memory function of the mice was evaluated using a novel object recognition test. The cast-attached mice exhibited memory impairment. Hemopexin levels in the conditioned medium of the skeletal muscle, plasma, and hippocampus were increased in cast-attached mice. Continuous intracerebroventricular hemopexin infusion induced memory deficits in non-cast mice. To investigate whether hemopexin is the main causative factor of cognitive impairment, cast-attached mice were intracerebroventricularly infused with an anti-hemopexin antibody. Cast-induced memory impairment was reversed by the infusion of an anti-hemopexin antibody. These findings provide new evidence that skeletal muscle atrophy causes memory impairment in healthy young mice through the action of hemopexin in the brain.

Keywords:  Cast model; Cognitive impairment; Hemopexin; Muscle atrophy; Myokine

DOI:  https://doi.org/10.1016/j.bbrc.2024.150606
Int J Biol Macromol. 2024 Sep 03. pii: S0141-8130(24)06128-2. [Epub ahead of print] 135321

Therapeutic targeting of GDF11 in muscle atrophy: Insights and strategies.

Chuanzhi Wang, Xiaocao Liu, Xilong Hu, Tao Wu, Rui Duan.

  The exploration of novel therapeutic avenues for skeletal muscle atrophy is imperative due to its significant health impact. Recent studies have spotlighted growth differentiation factor 11 (GDF11), a TGFβ superfamily member, for its rejuvenating role in reversing age-related tissue dysfunction. This review synthesizes current findings on GDF11, elucidating its distinct biological functions and the ongoing debates regarding its efficacy in muscle homeostasis. By addressing discrepancies in current research outcomes and its ambiguous role due to its homological identity to myostatin, a negative regulator of muscle mass, this review aims to clarify the role of GDF11 in muscle homeostasis and its potential as a therapeutic target for muscle atrophy. Through a thorough examination of GDF11's mechanisms and effects, this review provides insights that could pave the way for innovative treatments for muscle atrophy, emphasizing the need and strategies to boost endogenous GDF11 levels for therapeutic potential.

Keywords:  GDF11; Growth differentiation factor 11; Muscle atrophy; TGFβ superfamily; Therapeutic strategy

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.135321
J Genet Genomics. 2024 Aug 27. pii: S1673-8527(24)00214-5. [Epub ahead of print]

Ectopic expression of Myomaker and Myomixer in slow muscle cells induces slow muscle fusion and myofiber death.

Pengzheng Yong, Zhanxiong Zhang, Shaojun Du.

  Zebrafish embryos possess two major types of myofibers, the slow and fast fibers, with distinct patterns of cell fusion. The fast muscle cells can fuse, while the slow muscle cells cannot. Here, we show that myomaker is expressed in both slow and fast muscle precursors, while myomixer is exclusive to fast muscle cells. The loss of Prdm1a, a regulator of slow muscle differentiation, results in strong myomaker and myomixer expression and slow muscle cell fusion. This abnormal fusion is further confirmed by the direct ectopic expression of myomaker or myomixer in slow muscle cells of transgenic models. Using the transgenic models, we show that the heterologous fusion between slow and fast muscle cells can alter slow muscle cell migration and gene expression. Furthermore, the overexpression of myomaker and myomixer also disrupts membrane integrity, resulting in muscle cell death. Collectively, this study identifies that the fiber-type-specific expression of fusogenic proteins is critical for preventing inappropriate fusion between slow and fast fibers in fish embryos, highlighting the need for precise regulation of fusogenic gene expression to maintain muscle fiber integrity and specificity.

Keywords:  Fiber specificity; Muscle cell fusion; Myofiber death; Myomaker; Myomixer; Transgenic zebrafish model

DOI:  https://doi.org/10.1016/j.jgg.2024.08.006
bioRxiv. 2024 Aug 20. pii: 2024.08.20.608114. [Epub ahead of print]

A Neural Basis for Mutant ATAXIN-1 Induced Respiratory Dysfunction in Mouse Models of Spinocerebellar Ataxia Type 1.

Alyssa Soles, Jessica Grittner, Kaia Douglas, Praseuth Yang, Ryan Barnett, Christine Chau, Roj Cosiquien, Lisa Duvick, Orion Rainwater, Shannah Serres, Harry Orr, Brendan Dougherty, Marija Cvetanovic.

Spinocerebellar ataxia type 1 (SCA1), a dominantly inherited neurodegenerative disorder caused by an expanded trinucleotide repeat in the ATAXIN-1 (ATXN1) gene, is characterized by motor dysfunction, cognitive impairment, and death from compromised swallowing and respiration. To delineate specific cell types that contribute to respiratory dysfunction, we utilized the floxed conditional knock-in f-ATXN1 146Q/2Q mouse. Whole body plethysmography during spontaneous respiration and respiratory challenge showed that f-ATXN1 146Q/2Q mice exhibit a spontaneous respiratory phenotype characterized by elevated respiratory frequency, volumes, and respiratory output. Consequently, the ability of f-ATXN1 146Q/2Q mice to increase ventilation during the challenge is impaired. To investigate the role of mutant ATXN1 expression in neural and skeletal muscle lineages, f-ATXN1 146Q/2Q mice were bred to Nestin-Cre and Acta1-Cre mice respectively. These analyses revealed that the abnormal spontaneous respiration in f-ATXN1 146Q/2Q mice involved two aspects: a behavioral phenotype in which SCA1 mice exhibit increased motor activity during respiratory testing and functional dysregulation of central respiratory control centers. Both aspects of spontaneous respiration were partially ameliorated by removing mutant ATXN1 from neural, but not skeletal muscle, cell lineages.

DOI: https://doi.org/10.1101/2024.08.20.608114
Biochim Biophys Acta Mol Basis Dis. 2024 Aug 30. pii: S0925-4439(24)00481-2. [Epub ahead of print]1870(8): 167487

Nicotinamide riboside kinase 2: A unique target for skeletal muscle and cardiometabolic diseases.

Firdos Ahmad, Rizwan Qaisar.

  Myopathy leads to skeletal and cardiac muscle degeneration which is a major cause of physical disability and heart failure. Despite the therapeutic advancement the prevalence of particularly cardiac diseases is rising at an alarming rate and novel therapeutic targets are required. Nicotinamide riboside kinase-2 (NRK-2 or NMRK2) is a muscle-specific β1-integrin binding protein abundantly expressed in the skeletal muscle while only a trace amount is detected in the healthy cardiac muscle. The level in cardiac tissue is profoundly upregulated under pathogenic conditions such as ischemia and hypertension. NRK-2 was initially identified to regulate myoblast differentiation and to enhance the levels of NAD+, an important coenzyme that potentiates cellular energy production and stress resilience. Recent advancement has shown that NRK-2 critically regulates numerous cellular and molecular processes under pathogenic conditions to modulate the disease severity. Therefore, given its restricted expression in the cardiac and skeletal muscle, NRK-2 may serve as a unique therapeutic target. In this review, we provided a comprehensive overview of the diverse roles of NRK-2 played in different cardiac and muscular diseases and discussed the underlying molecular mechanisms in detail. Moreover, this review precisely examined how NRK-2 regulates metabolism in cardiac muscle, and how dysfunctional NRK-2 is associated with energetic deficit and impaired muscle function, manifesting various cardiac and skeletal muscle disease conditions.

Keywords:  Cardiac; Cell signaling; Metabolism; Myopathy; NMRK2; Skeletal muscle

DOI:  https://doi.org/10.1016/j.bbadis.2024.167487
Function (Oxf). 2024 Sep 03. pii: zqae038. [Epub ahead of print]

Exploring Circadian Changes in Muscle Physiology: Methodological Considerations.

Mark R Viggars, Karyn A Esser.



Keywords:  Muscle; circadian; glucose; mechanics; metabolism; physiology

DOI:  https://doi.org/10.1093/function/zqae038
bioRxiv. 2024 Aug 03. pii: 2024.07.31.605692. [Epub ahead of print]

Along- and cross-muscle fiber shear moduli in skeletal muscle.

Ridhi Sahani, William E Reyna, Thomas Royston, Eric J Perreault, Daniel Ludvig.

The material properties of muscle play a central role in how muscle resists joint motion, transmits forces internally, and repairs itself. While many studies have evaluated muscle's tensile material properties, few have investigated muscle's shear properties. The objective of this study was to quantify the shear moduli of skeletal muscle both along (along-muscle fiber) and perpendicular (cross-muscle fiber) to the direction of muscle fibers. We collected data from the extensor digitorum longus, tibialis anterior, and soleus muscles harvested from both hindlimbs of 12 rats. These muscles were chosen to further evaluate the consistency of shear moduli across muscles with different architectures. We applied strains and measured stress in three configurations: parallel, perpendicular, and across the muscle fibers to characterize the along- and cross-muscle fiber tensile and shear material parameters. We found no significant difference between the shear modulus measured parallel to the fibers (along-muscle fiber) and the shear modulus in the plane perpendicular to the fibers (cross-muscle fiber). Although the shear moduli were not significantly different, there was a greater difference with increasing strain, suggesting that there is greater anisotropy at larger strains. We also found no significant difference in moduli between the muscles with differing muscle architecture. These results characterize the shear behavior of skeletal muscle and are relevant to understanding the role of shear in force transmission and injury.

DOI: https://doi.org/10.1101/2024.07.31.605692
J Cachexia Sarcopenia Muscle. 2024 Sep 05.

Neuromuscular impairment at different stages of human sarcopenia.

Fabio Sarto, Martino V Franchi, Jamie S McPhee, Daniel W Stashuk, Matteo Paganini, Elena Monti, Maira Rossi, Giuseppe Sirago, Sandra Zampieri, Evgeniia S Motanova, Giacomo Valli, Tatiana Moro, Antonio Paoli, Roberto Bottinelli, Maria A Pellegrino, Giuseppe De Vito, Helen M Blau, Marco V Narici.

   BACKGROUND: Degeneration of the motoneuron and neuromuscular junction (NMJ) and loss of motor units (MUs) contribute to age-related muscle wasting and weakness associated with sarcopenia. However, these features have not been comprehensively investigated in humans. This study aimed to compare neuromuscular system integrity and function at different stages of sarcopenia, with a particular focus on NMJ stability and MU properties.
METHODS: We recruited 42 young individuals (Y) (aged 25.98 ± 4.6 years; 57% females) and 88 older individuals (aged 75.9 ± 4.7 years; 55% females). The older group underwent a sarcopenia screening according to the revised guidelines of the European Working Group on Sarcopenia in Older People 2. In all groups, knee extensor muscle force was evaluated by isometric dynamometry, muscle morphology by ultrasound and MU potential properties by intramuscular electromyography (iEMG). MU number estimate (iMUNE) and blood samples were obtained. Muscle biopsies were collected in a subgroup of 16 Y and 52 older participants.
RESULTS: Thirty-nine older individuals were non-sarcopenic (NS), 31 pre-sarcopenic (PS) and 18 sarcopenic (S). A gradual decrease in quadriceps force, cross-sectional area and appendicular lean mass was observed across the different stages of sarcopenia (for all P < 0.0001). Handgrip force and the Short Physical Performance Battery score also showed a diminishing trend. iEMG analyses revealed elevated near fibre segment jitter in NS, PS and S compared with Y (Y vs. NS and S: P < 0.0001; Y vs. PS: P = 0.0169), suggestive of age-related impaired NMJ transmission. Increased C-terminal agrin fragment (P < 0.0001) and altered caveolin 3 protein expression were consistent with age-related NMJ instability in all the older groups. The iMUNE was lower in all older groups (P < 0.0001), confirming age-related loss of MUs. An age-related increase in MU potential complexity was also observed. These observations were accompanied by increased muscle denervation and axonal damage, evinced by the increase in neural cell adhesion molecule-positive fibres (Y vs. NS: P < 0.0001; Y vs. S: P = 0.02) and the increase in serum concentration of neurofilament light chain (P < 0.0001), respectively. Notably, most of these MU and NMJ parameters did not differ when comparing older individuals with or without sarcopenia.
CONCLUSIONS: Alterations in MU properties, axonal damage, an altered innervation profile and NMJ instability are prominent features of the ageing of the neuromuscular system. These neuromuscular alterations are accompanied by muscle wasting and weakness; however, they appear to precede clinically diagnosed sarcopenia, as they are already detectable in older NS individuals.

Keywords:  electromyography; fibre denervation; motoneuron; motor units; muscle atrophy; neuromuscular junction

DOI:  https://doi.org/10.1002/jcsm.13531
Cell Rep. 2024 Aug 29. pii: S2211-1247(24)01050-7. [Epub ahead of print]43(9): 114699

Local muscle pressure stimulates the principal receptors for proprioception.

Frida Torell, Michael Dimitriou.

  Proprioception plays a crucial role in motor coordination and self-perception. Muscle spindles are the principal receptors for proprioception. They are believed to encode muscle stretch and signal limb position and velocity. Here, we applied percutaneous pressure to a small area of extensor muscles at the forearm while recording spindle afferent responses, skeletal muscle activity, and hand kinematics. Three levels of sustained pressure were applied on the spindle-bearing muscle when the hand was relaxed and immobile ("isometric" condition) and when the participant's hand moved rhythmically at the wrist. As hypothesized to occur due to compression of the spindle capsule, we show that muscle pressure is an "adequate" stimulus for human spindles in isometric conditions and that pressure enhances spindle responses during stretch. Interestingly, release of sustained pressure in isometric conditions lowered spindle firing below baseline rates. Our findings urge a re-evaluation of muscle proprioception in sensorimotor function and various neuromuscular pathologies.

Keywords:  CP: Neuroscience; afferent; intramuscular pressure; muscle pressure; muscle spindle; proprioception; somatosensory

DOI:  https://doi.org/10.1016/j.celrep.2024.114699
Redox Biol. 2024 Aug 30. pii: S2213-2317(24)00311-2. [Epub ahead of print]76 103333

Liver-secreted FGF21 induces sarcopenia by inhibiting satellite cell myogenesis via klotho beta in decompensated cirrhosis.

Da Zhou, Yifan Shi, Donghua Zhang, Junbo Zuo, Chenghao Zeng, Gulsudum Mamtawla, LongChang Huang, Xuejin Gao, Li Zhang, Xinying Wang.

   BACKGROUND & AIMS: Sarcopenia, a prevalent condition, significantly impacts the prognosis of patients with decompensated cirrhosis (DC). Serum fibroblast growth factor 21 (FGF21) levels are significantly higher in DC patients with sarcopenia. Satellite cells (SCs) play a role in aging- and cancer-induced sarcopenia. Here, we investigated the roles of FGF21 and SCs in DC-related sarcopenia as well as the underlying mechanisms.
METHODS: We developed two DC mouse models and performed in vivo and in vitro experiments. Klotho beta (KLB) knockout mice in SCs were constructed to investigate the role of KLB downstream of FGF21. In addition, biological samples were collected from patients with DC and control patients to validate the results.
RESULTS: Muscle wasting and impaired SC myogenesis were observed in the DC mouse model and patients with DC. Elevated circulating levels of liver-derived FGF21 were observed, which were significantly negatively correlated with skeletal muscle mass/skeletal muscle index. Liver-secreted FGF21 induces SC dysfunction, contributing to sarcopenia. Mechanistically, FGF21 in the DC state exhibits enhanced interactions with KLB on SC surfaces, leading to downstream phosphatase and tensin homolog upregulation. This inhibits the protein kinase B (PI3K/Akt) pathway, hampering SC proliferation and differentiation, and blocking new myotube formation to repair atrophy. Neutralizing circulating FGF21 using neutralizing antibodies, knockdown of hepatic FGF21 by adeno-associated virus, or knockout of KLB in SCs effectively improved or reversed DC-related sarcopenia.
CONCLUSIONS: Hepatocyte-derived FGF21 mediates liver-muscle crosstalk, which impairs muscle regeneration via the inhibition of the PI3K/Akt pathway, thereby demonstrating a novel therapeutic strategy for DC-related sarcopenia.

Keywords:  Decompensated cirrhosis; Fibroblast growth factor 21; Klotho beta; PI3K/Akt; Sarcopenia; Satellite cell

DOI:  https://doi.org/10.1016/j.redox.2024.103333
Biotechnol J. 2024 Aug;19(8): e2400278

Discovery of fibroblast growth factor 2-derived peptides for enhancing mice skeletal muscle satellite cell proliferation.

Itsuki Fujii, Remi Kinoshita, Hirokazu Akiyama, Ayasa Nakamura, Kanako Iwamori, So-Ichiro Fukada, Hiroyuki Honda, Kazunori Shimizu.

  Skeletal muscle satellite cells (SCs) are essential for muscle regeneration. Their proliferation and differentiation are influenced by fibroblast growth factor (FGF)-2. In this study, we screened for FGF-2-derived peptides that promote SC proliferation. Utilizing photocleavable peptide array technology, a library of 7-residue peptides was synthesized, and its effect on SC proliferation was examined using a mixture of five peptides. The results showed that peptides 1-5 (136%), 21-25 (136%), 26-30 (141%), 31-35 (159%), 71-75 (135%), 76-80 (144%), and 126-130 (137%) significantly increased SC proliferation. Further experiments revealed that peptide 33, CKNGGFF, enhanced SC proliferation. Furthermore, its extended form, peptide 33-13, CKNGGFFLRIHPD, promoted SC proliferation and increased the percentage of Pax7-positive cells, indicating that SCs were maintained in an undifferentiated state. The addition of FGF-2 and peptide 33-13 further induced cell proliferation but did not increase the percentage of Pax7-positive cells. A proliferation assay using an FGF receptor (FGFR) inhibitor suggested that peptide 33-13 acts through the FGFR-mediated and other pathways. Although further research is necessary to explore the mechanisms of action of these peptides and their potential for in vivo and in vitro use, the high sequence conservation of peptides 33 and 33-13 in FGF-2 across multiple species suggests their broad application prospects in biomedical engineering and biotechnology.

Keywords:  FGF‐2; cell proliferation; peptide; skeletal muscle satellite cell

DOI:  https://doi.org/10.1002/biot.202400278
Eur J Transl Myol. 2024 Aug 28.

Invitations to join a new 2024 section of Ejtm and the 2025 Pdm3 from 25 to 29 March, Euganean Thermae, Padua, Italy.

Ugo Carraro.

This issue of the European Journal of Translational Myology (Ejtm) 34 (3) 2024 opens with a historic article by Roger Sabbadini, who recalls his years spent as a guest scientist at the Institute of General Pathology of the University of Padua, Italy and the many years spent valorising a fortuitous observation made in collaboration with the scientific group of Professor Giovanni Salviati, University of Padua, Italy. A further side effect of those years is the decision I recently made to add a new Section to the Ejtm Editorial board, namely: Myokines, Bioactive lipids, Adipokines, RNAkines (ncRNAs), Antonio Musarò, Roger Sabbadini, and Daniela Tavian, Editors. Readers are therefore warmly invited to contribute typescripts to this section. I am confident that young readers will be motivated to test preliminary in vitro and in vivo options for drug development, especially for the bioactive lipids. Furthermore, it is time to send your presentation proposals and registration/accommodation forms to participate in the International Meeting: Padua Days on Muscle and Mobility Medicine, which will be held at the Hotel Petrarca of the Euganean Thermae (Padua, Italy) from 25 to 29 March 2025 (2025Pdm3). The Preliminary Program is included, hoping that you will submit your abstract and the Registration forms by November 15, 2024.

DOI: https://doi.org/10.4081/ejtm.2024.12970