bims-moremu 2023-05-14 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2023–05–14
28 papers selected by
Anna Vainshtein, Craft Science Inc.

Skeletal Muscle Memory.
EDA2R-NIK signalling promotes muscle atrophy linked to cancer cachexia.
Hypoxia Resistance Is an Inherent Phenotype of the Mouse Flexor Digitorum Brevis Skeletal Muscle.
Development of skeletal muscle fibrosis in a rodent model of cancer cachexia.
Development and characterization of agonistic antibodies targeting the Ig-like 1 domain of MuSK.
Inflammatory, mitochondrial, and senescence-related markers: Underlying biological pathways of muscle aging and new therapeutic targets.
Combined effects of functional overload and denervation on skeletal muscle mass and its regulatory proteins in mice.
From mitochondria to sarcopenia: role of 17β-estradiol and testosterone.
Resveratrol, a SIRT1 activator, attenuates aging-associated alterations in skeletal muscle and heart in mice.
Ectopic PLAG1 induces muscular dystrophy in the mouse.
Exercise improves homeostasis of the intestinal epithelium by activation of APJ-AMPK signaling.
Exercise Promotes Tissue Regeneration: Mechanisms Involved and Therapeutic Scope.
Integrated multi-omics approach reveals the role of SPEG in skeletal muscle biology including its relationship with myospryn complex.
The crosstalk between BAT thermogenesis and skeletal muscle dysfunction.
Mustn1 ablation in skeletal muscle results in increased glucose tolerance concomitant with upregulated GLUT expression in male mice.
Insights into the development of insulin resistance: Unraveling the interaction of physical inactivity, lipid metabolism and mitochondrial biology.
Skeletal Muscle Mitochondrial Respiration and Exercise Intolerance in Patients With Heart Failure With Preserved Ejection Fraction.
Age-related changes in human skeletal muscle microstructure and architecture assessed by diffusion-tensor magnetic resonance imaging and their association with muscle strength.
Mitochondria-SR interaction and mitochondrial fusion/fission in the regulation of skeletal muscle metabolism.
Resistance exercise counteracts the impact of androgen deprivation therapy on muscle characteristics in cancer patients.
NF-κB-Inducing Kinase Provokes Insulin Resistance in Skeletal Muscle of Obese Mice.
Skeletal muscle delimited myopathy and verapamil toxicity in SUR2 mutant mouse models of AIMS.
Molecular basis for muscle loss that causes cachexia.
Physiological Responses and Adaptations to Lower Load Resistance Training: Implications for Health and Performance.
Immune Responses to Muscle-Directed AAV Gene Transfer in Clinical Studies.
Nesprin-1: novel regulator of striated muscle nuclear positioning and mechanotransduction.
The transcription factor Foxp1 regulates aerobic glycolysis in adipocytes and myocytes.
Influence of internal muscle properties on muscle shape change and gearing in the human gastrocnemii.

Am J Physiol Cell Physiol. 2023 May 08.

Skeletal Muscle Memory.

Adam P Sharples, Daniel C Turner.

  Skeletal muscle memory is an exciting phenomenon gaining significant traction across several scientific communities, and amongst exercise practitioners and the public. Research has demonstrated that skeletal muscle tissue can be 'primed' by earlier positive encounters with exercise training that can enhance adaptation to later training, even following significant periods of exercise cessation or detraining. This review will describe and discuss the most recent research investigating the underlying mechanisms of skeletal muscle memory: 1) 'cellular' muscle memory and, 2) 'epigenetic' muscle memory as well as the emerging evidence of how these theories may work in synergy. We will discuss both 'positive' and 'negative' muscle memory and highlight the importance of investigating muscle memory for optimising exercise interventions and training programmes as well as the development of therapeutic strategies for counteracting muscle wasting conditions and age-related muscle loss. Finally, important directions emerging in the field will be highlighted to advance the next generation of studies in skeletal muscle memory research into the future.

Keywords:  DNA methylation; Epigenetics; atrophy; hypertrophy; myonuclei

DOI:  https://doi.org/10.1152/ajpcell.00099.2023
Nature. 2023 May 10.

EDA2R-NIK signalling promotes muscle atrophy linked to cancer cachexia.

Sevval Nur Bilgic, Aylin Domaniku, Batu Toledo, Samet Agca, Bahar Z C Weber, Dilsad H Arabaci, Zeynep Ozornek, Pascale Lause, Jean-Paul Thissen, Audrey Loumaye, Serkan Kir.

Skeletal muscle atrophy is a hallmark of the cachexia syndrome that is associated with poor survival and reduced quality of life in patients with cancer1. Muscle atrophy involves excessive protein catabolism and loss of muscle mass and strength2. An effective therapy against muscle wasting is currently lacking because mechanisms driving the atrophy process remain incompletely understood. Our gene expression analysis in muscle tissues indicated upregulation of ectodysplasin A2 receptor (EDA2R) in tumour-bearing mice and patients with cachectic cancer. Here we show that activation of EDA2R signalling promotes skeletal muscle atrophy. Stimulation of primary myotubes with the EDA2R ligand EDA-A2 triggered pronounced cellular atrophy by induction of the expression of muscle atrophy-related genes Atrogin1 and MuRF1. EDA-A2-driven myotube atrophy involved activation of the non-canonical NFĸB pathway and was dependent on NFκB-inducing kinase (NIK) activity. Whereas EDA-A2 overexpression promoted muscle wasting in mice, deletion of either EDA2R or muscle NIK protected tumour-bearing mice from loss of muscle mass and function. Tumour-induced oncostatin M (OSM) upregulated muscle EDA2R expression, and muscle-specific oncostatin M receptor (OSMR)-knockout mice were resistant to tumour-induced muscle wasting. Our results demonstrate that EDA2R-NIK signalling mediates cancer-associated muscle atrophy in an OSM-OSMR-dependent manner. Thus, therapeutic targeting of these pathways may be beneficial in prevention of muscle loss.

DOI: https://doi.org/10.1038/s41586-023-06047-y
Function (Oxf). 2023 ;4(3): zqad012

Hypoxia Resistance Is an Inherent Phenotype of the Mouse Flexor Digitorum Brevis Skeletal Muscle.

Adam J Amorese, Everett C Minchew, Michael D Tarpey, Andrew T Readyoff, Nicholas C Williamson, Cameron A Schmidt, Shawna L McMillin, Emma J Goldberg, Zoe S Terwilliger, Quincy A Spangenburg, Carol A Witczak, Jeffrey J Brault, E Dale Abel, Joseph M McClung, Kelsey H Fisher-Wellman, Espen E Spangenburg.

  The various functions of skeletal muscle (movement, respiration, thermogenesis, etc.) require the presence of oxygen (O2). Inadequate O2 bioavailability (ie, hypoxia) is detrimental to muscle function and, in chronic cases, can result in muscle wasting. Current therapeutic interventions have proven largely ineffective to rescue skeletal muscle from hypoxic damage. However, our lab has identified a mammalian skeletal muscle that maintains proper physiological function in an environment depleted of O2. Using mouse models of in vivo hindlimb ischemia and ex vivo anoxia exposure, we observed the preservation of force production in the flexor digitorum brevis (FDB), while in contrast the extensor digitorum longus (EDL) and soleus muscles suffered loss of force output. Unlike other muscles, we found that the FDB phenotype is not dependent on mitochondria, which partially explains the hypoxia resistance. Muscle proteomes were interrogated using a discovery-based approach, which identified significantly greater expression of the transmembrane glucose transporter GLUT1 in the FDB as compared to the EDL and soleus. Through loss-and-gain-of-function approaches, we determined that GLUT1 is necessary for the FDB to survive hypoxia, but overexpression of GLUT1 was insufficient to rescue other skeletal muscles from hypoxic damage. Collectively, the data demonstrate that the FDB is uniquely resistant to hypoxic insults. Defining the mechanisms that explain the phenotype may provide insight towards developing approaches for preventing hypoxia-induced tissue damage.

Keywords:  hypoxia; ischemia; mouse; phenotype; resistance; skeletal muscle

DOI:  https://doi.org/10.1093/function/zqad012
Cell Biochem Funct. 2023 May 07.

Development of skeletal muscle fibrosis in a rodent model of cancer cachexia.

Tyrone A Washington, Eleanor R Schrems, Wesley S Haynie, Megan E Rosa-Caldwell, Jacob L Brown, Landen Saling, Seongkyun Lim, Richard A Perry, Lemuel A Brown, David E Lee, Nicholas P Greene.

  Cachexia is characterized by losses in lean body mass and its progression results in worsened quality of life and exacerbated outcomes in cancer patients. However, the role and impact of fibrosis during the early stages and development of cachexia in under-investigated. The purpose of this study was to determine if fibrosis occurs during cachexia development, and to evaluate this in both sexes. Female and male C57BL6/J mice were injected with phosphate-buffered saline or Lewis Lung Carcinoma (LLC) at 8-week of age, and tumors were allowed to develop for 1, 2, 3, or 4 weeks. 3wk and 4wk female tumor-bearing mice displayed a dichotomy in tumor growth and were reassigned to high tumor (HT) and low tumor (LT) groups. In vitro analyses were also performed on cocultured C2C12 and 3T3 cells exposed to LLC conditioned media. Immunohistochemistry and quantitative polymerase chain reaction (qPCR) analysis were used to investigate fibrosis and fibrosis-related signaling in skeletal muscle. Collagen deposition in skeletal muscle was increased in the 1wk, LT, and HT groups in female mice. However, collagen deposition was only increased in the 4wk group in male mice. In general, female mice displayed earlier alterations in extracellular matrix (ECM)-related genes beginning at 1wk post-LLC injection. Whereas this was not seen in males. While overall tumor burden is tightly correlated to cachexia development in both sexes, fibrotic development is not. Male mice did not exhibit early-stage alterations in ECM-related genes contrary to what was noted in female mice.

Keywords:  biological sex; cancer cachexia; extracellular matrix; fibrosis; muscle wasting

DOI:  https://doi.org/10.1002/cbf.3797
Sci Rep. 2023 May 08. 13(1): 7478

Development and characterization of agonistic antibodies targeting the Ig-like 1 domain of MuSK.

Jamie L Lim, Roy Augustinus, Jaap J Plomp, Kasra Roya-Kouchaki, Dana L E Vergoossen, Yvonne Fillié-Grijpma, Josephine Struijk, Rachel Thomas, Daniela Salvatori, Christophe Steyaert, Christophe Blanchetot, Roeland Vanhauwaert, Karen Silence, Silvère M van der Maarel, Jan J Verschuuren, Maartje G Huijbers.

Muscle-specific kinase (MuSK) is crucial for acetylcholine receptor (AChR) clustering and thereby neuromuscular junction (NMJ) function. NMJ dysfunction is a hallmark of several neuromuscular diseases, including MuSK myasthenia gravis. Aiming to restore NMJ function, we generated several agonist monoclonal antibodies targeting the MuSK Ig-like 1 domain. These activated MuSK and induced AChR clustering in cultured myotubes. The most potent agonists partially rescued myasthenic effects of MuSK myasthenia gravis patient IgG autoantibodies in vitro. In an IgG4 passive transfer MuSK myasthenia model in NOD/SCID mice, MuSK agonists caused accelerated weight loss and no rescue of myasthenic features. The MuSK Ig-like 1 domain agonists unexpectedly caused sudden death in a large proportion of male C57BL/6 mice (but not female or NOD/SCID mice), likely caused by a urologic syndrome. In conclusion, these agonists rescued pathogenic effects in myasthenia models in vitro, but not in vivo. The sudden death in male mice of one of the tested mouse strains revealed an unexpected and unexplained role for MuSK outside skeletal muscle, thereby hampering further (pre-) clinical development of these clones. Future research should investigate whether other Ig-like 1 domain MuSK antibodies, binding different epitopes, do hold a safe therapeutic promise.

DOI: https://doi.org/10.1038/s41598-023-32641-1
Exp Gerontol. 2023 May 09. pii: S0531-5565(23)00125-0. [Epub ahead of print] 112204

Inflammatory, mitochondrial, and senescence-related markers: Underlying biological pathways of muscle aging and new therapeutic targets.

Anna Picca, Biliana Lozanoska-Ochser, Riccardo Calvani, Hélio José Coelho-Júnior, Christiaan Leewenburgh, Emanuele Marzetti.

  The maintenance of functional health is pivotal for achieving independent life in older age. The aged muscle is characterized by ultrastructural changes, including loss of type I and type II myofibers and a greater proportion of cytochrome c oxidase deficient and succinate dehydrogenase positive fibers. Both intrinsic (e.g., altered proteostasis, DNA damage, and mitochondrial dysfunction) and extrinsic factors (e.g., denervation, altered metabolic regulation, declines in satellite cells, and inflammation) contribute to muscle aging. Being a hub for several cellular activities, mitochondria are key to myocyte viability and mitochondrial dysfunction has been implicated in age-associated physical decline. The maintenance of functional organelles via mitochondrial quality control (MQC) processes is, therefore, crucial to skeletal myofiber viability. The autophagy-lysosome pathway has emerged as a critical step of MQC in muscle by disposing organelles and proteins via their tagging for autophagosome incorporation and delivery to the lysosome for clearance. This pathway has been reported to be altered in muscle of physically inactive older people. A relationship between this pathway and muscle tissue composition of the lower extremities as well as physical performance has been identified. Therefore, integrating muscle structure and myocyte quality control measures in the evaluation of muscle health may be a promising strategy for devising interventions fostering muscle health.

Keywords:  Cytokine; Extracellular matrix; Mitochondrial quality; Physical performance; Sarcopenia; Satellite cells

DOI:  https://doi.org/10.1016/j.exger.2023.112204
Physiol Rep. 2023 May;11(9): e15689

Combined effects of functional overload and denervation on skeletal muscle mass and its regulatory proteins in mice.

Kazuki Uemichi, Takanaga Shirai, Tohru Takemasa.

  Skeletal muscle is a highly pliable tissue and various adaptations such as muscle hypertrophy or atrophy are induced by overloading or disuse, respectively. However, the combined effect of overloading and disuse on the quantitative adaptation of skeletal muscle is unknown. Thus, the aim of this study was to investigate the effects of the combined stimuli of overloading and disuse on mouse skeletal muscle mass and the expression of regulatory factors for muscle protein anabolism or catabolism. Male mice from the Institute Cancer Research were subjected to denervation concomitant with unilateral functional overload or functional overload concomitant with unilateral denervation. Disuse and functional overload were induced by sciatic nerve transection (denervation) and synergist ablation, respectively, and the plantaris muscle was harvested 14 days after the operation. Our results showed that denervation attenuated functional overload-induced muscle hypertrophy and functional overload partially ameliorated the denervation-induced muscle atrophy. P70S6K phosphorylation, an indicator of mechanistic target of rapamycin complex 1 (mTORC1) activation, was not increased by unilateral functional overload in denervated muscles or by unilateral denervation in functional overloaded muscles. Denervation did not affect the increase of LC3-II, a marker of autophagy activation, and ubiquitinated protein expression upon unilateral functional overload. Also, functional overload did not affect ubiquitinated protein expression during unilateral denervation. Thus, our findings suggest that functional overload-induced muscle hypertrophy or denervation-induced muscle atrophy was attenuated by the combined stimuli of overload and denervation.

Keywords:  denervation; functional overload; skeletal muscle

DOI:  https://doi.org/10.14814/phy2.15689
Front Endocrinol (Lausanne). 2023 ;14 1156583

From mitochondria to sarcopenia: role of 17β-estradiol and testosterone.

Xu Tian, Shujie Lou, Rengfei Shi.

  Sarcopenia, characterized by a loss of muscle mass and strength with aging, is prevalent in older adults. Although the exact mechanisms underlying sarcopenia are not fully understood, evidence suggests that the loss of mitochondrial integrity in skeletal myocytes has emerged as a pivotal contributor to the complex etiology of sarcopenia. Mitochondria are the primary source of ATP production and are also involved in generating reactive oxygen species (ROS), regulating ion signals, and initiating apoptosis signals in muscle cells. The accumulation of damaged mitochondria due to age-related impairments in any of the mitochondrial quality control (MQC) processes, such as proteostasis, biogenesis, dynamics, and mitophagy, can contribute to the decline in muscle mass and strength associated with aging. Interestingly, a decrease in sex hormones (e.g., 17β-estradiol and testosterone), which occurs with aging, has also been linked to sarcopenia. Indeed, 17β-estradiol and testosterone targeted mitochondria and exhibited activities in regulating mitochondrial functions. Here, we overview the current literature on the key mechanisms by which mitochondrial dysfunction contribute to the development and progression of sarcopenia and the potential modulatory effects of 17β-estradiol and testosterone on mitochondrial function in this context. The advance in its understanding will facilitate the development of potential therapeutic agents to mitigate and manage sarcopenia.

Keywords:  17β-estradiol; aging; mitochondria; sarcopenia; skeletal muscle; testosterone

DOI:  https://doi.org/10.3389/fendo.2023.1156583
J Pharmacol Sci. 2023 Jun;pii: S1347-8613(23)00022-1. [Epub ahead of print]152(2): 112-122

Resveratrol, a SIRT1 activator, attenuates aging-associated alterations in skeletal muscle and heart in mice.

Ryusuke Hosoda, Ryuta Nakashima, Masaki Yano, Naotoshi Iwahara, Seidai Asakura, Iyori Nojima, Yukika Saga, Risa Kunimoto, Yoshiyuki Horio, Atsushi Kuno.

  Aging is associated with impairment of multiple organs, including skeletal muscle and heart. In this study, we investigated whether resveratrol, an activator of an NAD+-dependent protein deacetylase Sirtuin-1 (SIRT1), attenuates age-related sarcopenia and cardiomyocyte hypertrophy in mice. Treatment of mice with resveratrol (0.4 g/kg diet) from 28 weeks of age for 32 weeks prevented aging-associated shortening of rotarod riding time. In the tibialis anterior (TA) muscle, histogram analysis showed that the atrophic muscle was increased in 60-week-old (wo) mice compared with 20-wo mice, which was attenuated by resveratrol. In the heart, resveratrol attenuated an aging-associated increase in the cardiomyocyte diameter. Acetylated proteins were increased and autophagic activity was reduced in the TA muscle of 60-wo mice compared with those of 20-wo mice. Resveratrol treatment reduced levels of acetylated proteins and restored autophagic activity in the TA muscle. Aging-related reduction in myocardial autophagy was also suppressed by resveratrol. Skeletal muscle-specific SIRT1 knockout mice showed increases in acetylated proteins and atrophic muscle fibers and reduced autophagic activity in the TA muscle. These results suggest that activation of SIRT1 by treatment with resveratrol suppresses sarcopenia and cardiomyocyte hypertrophy by restoration of autophagy in mice.

Keywords:  Autophagy; Cardiomyocyte hypertrophy; Resveratrol; Sarcopenia; Sirt1

DOI:  https://doi.org/10.1016/j.jphs.2023.04.001
Biochem Biophys Res Commun. 2023 May 03. pii: S0006-291X(23)00562-4. [Epub ahead of print]665 159-168

Ectopic PLAG1 induces muscular dystrophy in the mouse.

Juan Shugert Aguayo, John M Shelton, Wei Tan, Dinesh Rakheja, Chunyu Cai, Ahmed Shalaby, Jeon Lee, Susan T Iannaccone, Lin Xu, Kenneth Chen, Dennis K Burns, Yanbin Zheng.

  Even though various genetic mutations have been identified in muscular dystrophies (MD), there is still a need to understand the biology of MD in the absence of known mutations. Here we reported a new mouse model of MD driven by ectopic expression of PLAG1. This gene encodes a developmentally regulated transcription factor known to be expressed in developing skeletal muscle, and implicated as an oncogene in certain cancers including rhabdomyosarcoma (RMS), an aggressive soft tissue sarcoma composed of myoblast-like cells. By breeding loxP-STOP-loxP-PLAG1 (LSL-PLAG1) mice into the MCK-Cre line, we achieved ectopic PLAG1 expression in cardiac and skeletal muscle. The Cre/PLAG1 mice died before 6 weeks of age with evidence of cardiomyopathy significantly limiting left ventricle fractional shortening. Histology of skeletal muscle revealed dystrophic features, including myofiber necrosis, fiber size variation, frequent centralized nuclei, fatty infiltration, and fibrosis, all of which mimic human MD pathology. QRT-PCR and Western blot revealed modestly decreased Dmd mRNA and dystrophin protein in the dystrophic muscle, and immunofluorescence staining showed decreased dystrophin along the cell membrane. Repression of Dmd by ectopic PLAG1 was confirmed in dystrophic skeletal muscle and various cell culture models. In vitro studies showed that excess IGF2 expression, a transcriptional target of PLAG1, phenocopied PLAG1-mediated down-regulation of dystrophin. In summary, we developed a new mouse model of a lethal MD due to ectopic expression of PLAG1 in heart and skeletal muscle. Our data support the potential contribution of excess IGF2 in this model. Further studying these mice may provide new insights into the pathogenesis of MD and perhaps lead to new treatment strategies.

Keywords:  Dmd; IGF2; Muscular dystrophy (MD); PLAG1

DOI:  https://doi.org/10.1016/j.bbrc.2023.05.006
J Physiol. 2023 May 08.

Exercise improves homeostasis of the intestinal epithelium by activation of APJ-AMPK signaling.

Song Ah Chae, Min Du, Jun Seok Son, Mei-Jun Zhu.

  Intestinal remodeling is dynamically regulated by energy metabolism. Exercise is beneficial for gut health, but the specific mechanisms remain poorly understood. Both intestine-specific apelin receptor (APJ) knockdown (KD) and wild-type male mice were randomly divided into two subgroups with/without exercise to obtain four groups: WT, WT with exercise, APJ KD, and APJ KD with exercise. Animals in exercise groups were subjected to daily treadmill exercise for 3 weeks. Duodenum was collected at 48h after the last bout of exercise. AMP-activated protein kinase (AMPK) α1 KD and wild-type mice were also utilized for investigating the mediatory role of AMPK on exercise-induced duodenal epithelial development. AMPK and peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1 α) were upregulated by exercise via APJ activation in the intestinal duodenum. Correspondingly, exercise induced permissive histone modifications in the PR domain containing 16 (PRDM16) promoter to activate its expression, which was dependent on APJ activation. In agreement, exercise elevated the expression of mitochondrial oxidative markers. The expression of intestinal epithelial markers was downregulated due to AMPK deficiency, and AMPK signaling facilitated epithelial renewal. These data demonstrate that exercise-induced activation of APJ-AMPK axis facilitates the homeostasis of the intestinal duodenal epithelium. ONE-SENTENCE SUMMARY: Exercise-induced APJ-AMPK axis upregulated the expression of PGC-1α and PRDM16 to improve homeostasis of intestinal epithelium. KEY POINTS: APJ signaling is required for improved epithelial homeostasis of the small intestine in response to exercise. Exercise intervention activates PRDM16 through inducing histone modifications, improving mitochondrial biogenesis and fatty acid metabolism in duodenum. Structure of intestinal epithelium is improved by muscle-derived exerkine apelin through APJ-AMPK axis. Abstract figure legend. Exercise training increases expression of apelin in muscle and the circulating apelin level. Exercise-induced apelin-APJ signaling enhances villus and crypt structure of the small intestine (duodenum) through the activation of AMPK and stimulation of mitochondrial biogenesis. Of note, exercise program induces histone modifications for PRDM16 expression, which enhances mitochondrial oxidative metabolism, thereby improving intestinal epithelial homeostasis. This article is protected by copyright. All rights reserved.

Keywords:  AMPK, APJ, duodenum, exercise; mitochondrial oxidation, PRDM16

DOI:  https://doi.org/10.1113/JP284552
Sports Med Open. 2023 May 06. 9(1): 27

Exercise Promotes Tissue Regeneration: Mechanisms Involved and Therapeutic Scope.

Chang Liu, Xinying Wu, Gururaja Vulugundam, Priyanka Gokulnath, Guoping Li, Junjie Xiao.

  Exercise has well-recognized beneficial effects on the whole body. Previous studies suggest that exercise could promote tissue regeneration and repair in various organs. In this review, we have summarized the major effects of exercise on tissue regeneration primarily mediated by stem cells and progenitor cells in skeletal muscle, nervous system, and vascular system. The protective function of exercise-induced stem cell activation under pathological conditions and aging in different organs have also been discussed in detail. Moreover, we have described the primary molecular mechanisms involved in exercise-induced tissue regeneration, including the roles of growth factors, signaling pathways, oxidative stress, metabolic factors, and non-coding RNAs. We have also summarized therapeutic approaches that target crucial signaling pathways and molecules responsible for exercise-induced tissue regeneration, such as IGF1, PI3K, and microRNAs. Collectively, the comprehensive understanding of exercise-induced tissue regeneration will facilitate the discovery of novel drug targets and therapeutic strategies.

Keywords:  Cardiomyocytes; Exercise; Molecular mechanism; Muscle stem cells; Neural stem cells; Regenerative therapy; Tissue regeneration

DOI:  https://doi.org/10.1186/s40798-023-00573-9
bioRxiv. 2023 Apr 24. pii: 2023.04.24.538136. [Epub ahead of print]

Integrated multi-omics approach reveals the role of SPEG in skeletal muscle biology including its relationship with myospryn complex.

Qifei Li, Jasmine Lin, Shiyu Luo, Klaus Schmitz-Abe, Rohan Agrawal, Melissa Meng, Behzad Moghadaszadeh, Alan H Beggs, Xiaoli Liu, Mark A Perrella, Pankaj B Agrawal.

Autosomal-recessive mutations in SPEG (striated muscle preferentially expressed protein kinase) have been linked to centronuclear myopathy. Loss of SPEG is associated with defective triad formation, abnormal excitation-contraction coupling, and calcium mishandling in skeletal muscles. To elucidate the underlying molecular pathways, we have utilized multi-omics tools and analysis to obtain a comprehensive view of the complex biological processes. We identified that SPEG interacts with myospryn complex proteins (CMYA5, FSD2, RyR1), and SPEG deficiency results in myospryn complex abnormalities. In addition, transcriptional and protein profiles of SPEG-deficient muscle revealed defective mitochondrial function including aberrant accumulation of enlarged mitochondria on electron microscopy. Furthermore, SPEG regulates RyR1 phosphorylation at S2902, and its loss affects JPH2 phosphorylation at multiple sites. On analyzing the transcriptome, the most dysregulated pathways affected by SPEG deficiency included extracellular matrix-receptor interaction and peroxisome proliferator-activated receptors signaling, which may be due to defective triad and mitochondrial abnormalities. In summary, we have elucidated the critical role of SPEG in triad as it works closely with myospryn complex, phosphorylates JPH2 and RyR1, and demonstrated that its deficiency is associated with mitochondrial abnormalities. This study emphasizes the importance of using multi-omics techniques to comprehensively analyze the molecular anomalies of rare diseases.
Synopsis: We have previously linked mutations in SPEG (striated preferentially expressed protein) with a recessive form of centronuclear myopathy and/or dilated cardiomyopathy and have characterized a striated muscle-specific SPEG-deficient mouse model that recapitulates human disease with disruption of the triad structure and calcium homeostasis in skeletal muscles. In this study, we applied multi-omics approaches (interactomic, proteomic, phosphoproteomic, and transcriptomic analyses) in the skeletal muscles of SPEG-deficient mice to assess the underlying pathways associated with the pathological and molecular abnormalities. SPEG interacts with myospryn complex proteins (CMYA5, FSD2, RyR1), and its deficiency results in myospryn complex abnormalities.SPEG regulates RyR1 phosphorylation at S2902, and its loss affects JPH2 phosphorylation at multiple sites.SPEGα and SPEGβ have different interacting partners suggestive of differential function.Transcriptome analysis indicates dysregulated pathways of ECM-receptor interaction and peroxisome proliferator-activated receptor signaling.Mitochondrial defects on the transcriptome, proteome, and electron microscopy, may be a consequence of defective calcium signaling.

DOI: https://doi.org/10.1101/2023.04.24.538136
Front Physiol. 2023 ;14 1132830

The crosstalk between BAT thermogenesis and skeletal muscle dysfunction.

Yao Chen, Qian Hu, Changyi Wang, Tiantian Wang.

  Metabolic defects increase the risk of skeletal muscle diseases, and muscle impairment might worsen metabolic disruption, leading to a vicious cycle. Both brown adipose tissue (BAT) and skeletal muscle play important roles in non-shivering thermogenesis to regulate energy homeostasis. BAT regulates body temperature, systemic metabolism, and seretion of batokines that have positive or negative impacts on skeletal muscle. Conversely, muscle can secrete myokines that regulate BAT function. This review explained the crosstalk between BAT and skeletal muscle, and then discussed the batokines and highlighted their impact on skeletal muscle under physiological conditions. BAT is now considered a potential therapeutic target for obesity and diabetes treatment. Moreover, manipulation of BAT may be an attractive approach for the treatment of muscle weakness by correcting metabolic deficits. Therefore, exploring BAT as a potential treatment for sarcopenia could be a promising avenue for future research.

Keywords:  brown adipose tissue; insulin resistance; metabolic defects; skeletal muscle; thermogenesis

DOI:  https://doi.org/10.3389/fphys.2023.1132830
Physiol Rep. 2023 May;11(9): e15674

Mustn1 ablation in skeletal muscle results in increased glucose tolerance concomitant with upregulated GLUT expression in male mice.

Charles J Kim, Chanpreet Singh, Christine Lee, Kevin DiMagno, Madison O'Donnell, Marina Kaczmarek, Arhum Ahmed, Jessica Salvo-Schaich, Alexis Perez, William Letsou, Maria-Alicia Carrillo Sepulveda, Raddy L Ramos, Michael Hadjiargyrou.

  Glucose homeostasis is closely regulated to maintain energy requirements of vital organs and skeletal muscle plays a crucial role in this process. Mustn1 is expressed during embryonic and postnatal skeletal muscle development and its function has been implicated in myogenic differentiation and myofusion. Whether Mustn1 plays a role in glucose homeostasis in anyway remains largely unknown. As such, we deleted Mustn1 in skeletal muscle using a conditional knockout (KO) mouse approach. KO mice did not reveal any specific gross phenotypic alterations in skeletal muscle. However, intraperitoneal glucose tolerance testing (IPGTT) revealed that 2-month-old male KO mice had significantly lower glycemia than their littermate wild type (WT) controls. These findings coincided with mRNA changes in genes known to be involved in glucose metabolism, tolerance, and insulin sensitivity; 2-month-old male KO mice had significantly higher expression of GLUT1 and GLUT10 transporters, MUP-1 while OSTN expression was lower. These differences in glycemia and gene expression were statistically insignificant after 4 months. Identical experiments in female KO and WT control mice did not indicate any differences at any age. Our results suggest a link between Mustn1 expression and glucose homeostasis during a restricted period of skeletal muscle development/maturation. While this is an observational study, Mustn1's relationship to glucose homeostasis appears to be more complex with a possible connection to other key proteins such as GLUTs, MUP-1, and OSTN. Additionally, our data indicate temporal and sex differences. Lastly, our findings strengthen the notion that Mustn1 plays a role in the metabolic capacity of skeletal muscle.

Keywords:   Mustn1 ; GLUT; glucose; insulin; skeletal muscle

DOI:  https://doi.org/10.14814/phy2.15674
Front Physiol. 2023 ;14 1151389

Insights into the development of insulin resistance: Unraveling the interaction of physical inactivity, lipid metabolism and mitochondrial biology.

Rachel M Handy, Graham P Holloway.

  While impairments in peripheral tissue insulin signalling have a well-characterized role in the development of insulin resistance and type 2 diabetes (T2D), the specific mechanisms that contribute to these impairments remain debatable. Nonetheless, a prominent hypothesis implicates the presence of a high-lipid environment, resulting in both reactive lipid accumulation and increased mitochondrial reactive oxygen species (ROS) production in the induction of peripheral tissue insulin resistance. While the etiology of insulin resistance in a high lipid environment is rapid and well documented, physical inactivity promotes insulin resistance in the absence of redox stress/lipid-mediated mechanisms, suggesting alternative mechanisms-of-action. One possible mechanism is a reduction in protein synthesis and the resultant decrease in key metabolic proteins, including canonical insulin signaling and mitochondrial proteins. While reductions in mitochondrial content associated with physical inactivity are not required for the induction of insulin resistance, this could predispose individuals to the detrimental effects of a high-lipid environment. Conversely, exercise-training induced mitochondrial biogenesis has been implicated in the protective effects of exercise. Given mitochondrial biology may represent a point of convergence linking impaired insulin sensitivity in both scenarios of chronic overfeeding and physical inactivity, this review aims to describe the interaction between mitochondrial biology, physical (in)activity and lipid metabolism within the context of insulin signalling.

Keywords:  bioenergetics; insulin resistance; metabolism; mitochondria; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2023.1151389
JAMA Cardiol. 2023 May 10.

Skeletal Muscle Mitochondrial Respiration and Exercise Intolerance in Patients With Heart Failure With Preserved Ejection Fraction.

Lina Scandalis, Dalane W Kitzman, Barbara J Nicklas, Mary Lyles, Peter Brubaker, M Benjamin Nelson, Michelle Gordon, John Stone, Jaclyn Bergstrom, P Darrell Neufer, Erich Gnaiger, Anthony J A Molina.

Importance: The pathophysiology of exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF) remains incompletely understood. Multiple lines of evidence suggest that abnormal skeletal muscle metabolism is a key contributor, but the mechanisms underlying metabolic dysfunction remain unresolved.
Objective: To evaluate the associations of skeletal muscle mitochondrial function using respirometric analysis of biopsied muscle fiber bundles from patients with HFpEF with exercise performance.
Design, Setting, and Participants: In this cross-sectional study, muscle fiber bundles prepared from fresh vastus lateralis biopsies were analyzed by high-resolution respirometry to provide detailed analyses of mitochondrial oxidative phosphorylation, including maximal capacity and the individual contributions of complex I-linked and complex II-linked respiration. These bioenergetic data were compared between patients with stable chronic HFpEF older than 60 years and age-matched healthy control (HC) participants and analyzed for intergroup differences and associations with exercise performance. All participants were treated at a university referral center, were clinically stable, and were not undergoing regular exercise or diet programs. Data were collected from March 2016 to December 2017, and data were analyzed from November 2020 to May 2021.
Main Outcomes and Measures: Skeletal muscle mitochondrial function, including maximal capacity and respiration linked to complex I and complex II. Exercise performance was assessed by peak exercise oxygen consumption, 6-minute walk distance, and the Short Physical Performance Battery.
Results: Of 72 included patients, 50 (69%) were women, and the mean (SD) age was 69.6 (6.1) years. Skeletal muscle mitochondrial function measures were all markedly lower in skeletal muscle fibers obtained from patients with HFpEF compared with HCs, even when adjusting for age, sex, and body mass index. Maximal capacity was strongly and significantly correlated with peak exercise oxygen consumption (R = 0.69; P < .001), 6-minute walk distance (R = 0.70; P < .001), and Short Physical Performance Battery score (R = 0.46; P < .001).
Conclusions and Relevance: In this study, patients with HFpEF had marked abnormalities in skeletal muscle mitochondrial function. Severely reduced maximal capacity and complex I-linked and complex II-linked respiration were associated with exercise intolerance and represent promising therapeutic targets.

DOI: https://doi.org/10.1001/jamacardio.2023.0957
Aging Cell. 2023 May 10. e13851

Age-related changes in human skeletal muscle microstructure and architecture assessed by diffusion-tensor magnetic resonance imaging and their association with muscle strength.

Donnie Cameron, David A Reiter, Fatemeh Adelnia, Ceereena Ubaida-Mohien, Christopher M Bergeron, Seongjin Choi, Kenneth W Fishbein, Richard G Spencer, Luigi Ferrucci.

  Diffusion-tensor magnetic resonance imaging (DT-MRI) offers objective measures of muscle characteristics, providing insights into age-related changes. We used DT-MRI to probe skeletal muscle microstructure and architecture in a large healthy-aging cohort, with the aim of characterizing age-related differences and comparing these to muscle strength. We recruited 94 participants (43 female; median age = 56, range = 22-89 years) and measured microstructure parameters-fractional anisotropy (FA) and mean diffusivity (MD)-in 12 thigh muscles, and architecture parameters-pennation angle, fascicle length, fiber curvature, and physiological cross-sectional area (PCSA)-in the rectus femoris (RF) and biceps femoris longus (BFL). Knee extension and flexion torques were also measured for comparison to architecture measures. FA and MD were associated with age (β = 0.33, p = 0.001, R2 = 0.10; and β = -0.36, p < 0.001, R2 = 0.12), and FA was negatively associated with Type I fiber proportions from the literature (β = -0.70, p = 0.024, and R2 = 0.43). Pennation angle, fiber curvature, fascicle length, and PCSA were associated with age in the RF (β = -0.22, 0.26, -0.23, and -0.31, respectively; p < 0.05), while in the BFL only curvature and fascicle length were associated with age (β = 0.36, and -0.40, respectively; p < 0.001). In the RF, pennation angle and PCSA were associated with strength (β = 0.29, and 0.46, respectively; p < 0.01); in the BFL, only PCSA was associated with strength (β = 0.43; p < 0.001). Our results show skeletal muscle architectural changes with aging and intermuscular differences in the microstructure. DT-MRI may prove useful for elucidating muscle changes in the early stages of sarcopenia and monitoring interventions aimed at preventing age-associated microstructural changes in muscle that lead to functional impairment.

Keywords:  aging; diffusion tensor imaging; muscle strength; sarcopenia; skeletal muscle fibers; thigh

DOI:  https://doi.org/10.1111/acel.13851
Metabolism. 2023 May 08. pii: S0026-0495(23)00181-6. [Epub ahead of print] 155578

Mitochondria-SR interaction and mitochondrial fusion/fission in the regulation of skeletal muscle metabolism.

Mauricio Castro-Sepulveda, Rodrigo Fernández-Verdejo, Hermann Zbinden-Foncea, Jennifer Rieusset.

  Mitochondria-endoplasmic/sarcoplasmic reticulum (ER/SR) interaction and mitochondrial fusion/fission are critical processes that influence substrate oxidation. This narrative review summarizes the evidence on the effects of substrate availability on mitochondrial-SR interaction and mitochondria fusion/fission dynamics to modulate substrate oxidation in human skeletal muscle. Evidence shows that an increase in mitochondria-SR interaction and mitochondrial fusion are associated with elevated fatty acid oxidation. In contrast, a decrease in mitochondria-SR interaction and an increase in mitochondrial fission are associated with an elevated glycolytic activity. Based on the evidence reviewed, we postulate two hypotheses for the link between mitochondrial dynamics and insulin resistance in human skeletal muscle. First, glucose and fatty acid availability modifies mitochondria-SR interaction and mitochondrial fusion/fission to help the cell to adapt substrate oxidation appropriately. Individuals with an impaired response to these substrate challenges will accumulate lipid species and develop insulin resistance in skeletal muscle. Second, a chronically elevated substrate availability (e.g. overfeeding) increases mitochondrial production of reactive oxygen species and induced mitochondrial fission. This decreases fatty acid oxidation, thus leading to the accumulation of lipid species and insulin resistance in skeletal muscle. Altogether, we propose mitochondrial dynamics as a potential target for disturbances associated with low fatty acid oxidation.

Keywords:  Fatty acid oxidation; Metabolic flexibility; Mitochondria dynamics; Mitochondria-associated membranes; Organelle dynamics

DOI:  https://doi.org/10.1016/j.metabol.2023.155578
J Clin Endocrinol Metab. 2023 May 10. pii: dgad245. [Epub ahead of print]

Resistance exercise counteracts the impact of androgen deprivation therapy on muscle characteristics in cancer patients.

Maarten Overkamp, Lisanne H P Houben, Thorben Aussieker, Janneau M X van Kranenburg, Philippe J M Pinckaers, Ulla R Mikkelsen, Milou Beelen, Sandra Beijer, Luc J C van Loon, Tim Snijders.

   CONTEXT: Androgen deprivation therapy (ADT) forms the cornerstone in prostate cancer (PCa) treatment. ADT however also lowers skeletal muscle mass.
OBJECTIVE: To identify the impact of ADT with and without resistance exercise training on muscle fiber characteristics in PCa patients.
METHODS: Twenty-one PCa patients (72 ± 6 y) starting ADT were included. Tissue samples from the vastus lateralis muscle were assessed at baseline and after 20 weeks of usual care (n = 11) or resistance exercise training (n = 10). Type I and II muscle fiber distribution, fiber size, and myonuclear and capillary contents were determined by immunohistochemistry.
RESULTS: Significant decreases in type I (from 7401 ± 1183 to 6489 ± 1293 μm2, P < 0.05) and type II (from 6225 ± 1503 to 5014 ± 714 μm2, P < 0.05) muscle fiber size were observed in the usual care group. In addition, type I and type II individual capillary-to-fiber ratio (C/Fi) declined (-12 ± 12 and -20 ± 21%, respectively, P < 0.05). In contrast, significant increases in type I (from 6700 ± 1464 to 7772 ± 1319 μm2, P < 0.05) and type II (from 5248 ± 892 to 6302 ± 1385 μm2, P < 0.05) muscle fiber size were observed in the training group, accompanied by an increase in type I and type II muscle fiber myonuclear contents (+24 ± 33 and +21 ± 23%, respectively, P < 0.05) and type I C/Fi (+18 ± 14%, P < 0.05).
CONCLUSIONS: The onset of ADT is followed by a decline in both type I and type II muscle fiber size and capillarization in PCa patients. Resistance exercise training offsets the negative impact of androgen deprivation therapy and increases type I and II muscle fiber size and type I muscle fiber capillarization in these patients.

Keywords:  angiogenesis; exercise rehabilitation; older adults; skeletal muscle; testosterone

DOI:  https://doi.org/10.1210/clinem/dgad245
Inflammation. 2023 May 12.

NF-κB-Inducing Kinase Provokes Insulin Resistance in Skeletal Muscle of Obese Mice.

Xueqin Chen, Zhuoqun Liu, Wenjun Liu, Shu Wang, Ran Jiang, Kua Hu, Liang Sheng, Guangxu Xu, Xinhui Kou, Yu Song.

  Skeletal muscle is crucial for preserving glucose homeostasis. Insulin resistance and abnormalities in glucose metabolism result from a range of pathogenic factors attacking skeletal muscle in obese individuals. To relieve insulin resistance and restore glucose homeostasis, blocking the cell signaling pathways induced by those pathogenic factors seems an attractive strategy. It has been discovered that insulin sensitivity in obese people is inversely linked with the activity of NF-κB inducing kinase (NIK) in skeletal muscle. In order to evaluate NIK's pathological consequences, mechanism of action, and therapeutic values, an obese mouse model reproduced by feeding a high-fat diet was treated with a NIK inhibitor, B022. C2C12 myoblasts overexpressing NIK were utilized to assess insulin signaling and glucose uptake. B022 thus prevented high-fat diet-induced NIK activation and insulin desensitization in skeletal muscle. The insulin signaling in C2C12 myoblasts was compromised by the upregulation of NIK brought on by oxidative stress, lipid deposition, inflammation, or adenoviral vector. This inhibition of insulin action is mostly due to an inhibitory serine phosphorylation of IRS1 caused by ERK, JNK, and PKC that were activated by NIK. In summary, NIK integrates signals from several pathogenic factors to impair insulin signaling by igniting a number of IRS1-inhibiting kinases, and it also has significant therapeutic potential for treating insulin resistance.

Keywords:  NF-κB-inducing kinase; insulin receptor substrate 1.; insulin resistance; skeletal muscle

DOI:  https://doi.org/10.1007/s10753-023-01820-7
EMBO Mol Med. 2023 May 08. e16883

Skeletal muscle delimited myopathy and verapamil toxicity in SUR2 mutant mouse models of AIMS.

Conor McClenaghan, Maya A Mukadam, Jacob Roeglin, Robert C Tryon, Manfred Grabner, Anamika Dayal, Gretchen A Meyer, Colin G Nichols.

  ABCC9-related intellectual disability and myopathy syndrome (AIMS) arises from loss-of-function (LoF) mutations in the ABCC9 gene, which encodes the SUR2 subunit of ATP-sensitive potassium (KATP ) channels. KATP channels are found throughout the cardiovascular system and skeletal muscle and couple cellular metabolism to excitability. AIMS individuals show fatigability, muscle spasms, and cardiac dysfunction. We found reduced exercise performance in mouse models of AIMS harboring premature stop codons in ABCC9. Given the roles of KATP channels in all muscles, we sought to determine how myopathy arises using tissue-selective suppression of KATP and found that LoF in skeletal muscle, specifically, underlies myopathy. In isolated muscle, SUR2 LoF results in abnormal generation of unstimulated forces, potentially explaining painful spasms in AIMS. We sought to determine whether excessive Ca2+ influx through CaV 1.1 channels was responsible for myopathology but found that the Ca2+ channel blocker verapamil unexpectedly resulted in premature death of AIMS mice and that rendering CaV 1.1 channels nonpermeable by mutation failed to reverse pathology; results which caution against the use of calcium channel blockers in AIMS.

Keywords:  ABCC9; AIMS; SUR2; myopathy; verapamil

DOI:  https://doi.org/10.15252/emmm.202216883
Nature. 2023 May 10.

Molecular basis for muscle loss that causes cachexia.

Laura Antonio-Herrera, Andreas Bergthaler.



Keywords:  Cancer; Medical research

DOI:  https://doi.org/10.1038/d41586-023-01527-7
Sports Med Open. 2023 May 12. 9(1): 28

Physiological Responses and Adaptations to Lower Load Resistance Training: Implications for Health and Performance.

Jonathon Weakley, Brad J Schoenfeld, Johanna Ljungberg, Shona L Halson, Stuart M Phillips.

  Resistance training is a method of enhancing strength, gait speed, mobility, and health. However, the external load required to induce these benefits is a contentious issue. A growing body of evidence suggests that when lower load resistance training [i.e., loads < 50% of one-repetition maximum (1RM)] is completed within close proximity to concentric failure, it can serve as an effective alternative to traditional higher load (i.e., loads > 70% of 1RM) training and in many cases can promote similar or even superior physiological adaptations. Such findings are important given that confidence with external loads and access to training facilities and equipment are commonly cited barriers to regular resistance training. Here, we review some of the mechanisms and physiological changes in response to lower load resistance training. We also consider the evidence for applying lower loads for those at risk of cardiovascular and metabolic diseases and those with reduced mobility. Finally, we provide practical recommendations, specifically that to maximize the benefits of lower load resistance training, high levels of effort and training in close proximity to concentric failure are required. Additionally, using lower loads 2-3 times per week with 3-4 sets per exercise, and loads no lower than 30% of 1RM can enhance muscle hypertrophy and strength adaptations. Consequently, implementing lower load resistance training can be a beneficial and viable resistance training method for a wide range of fitness- and health-related goals.

Keywords:  Exercise prescription; Function; Health; Hypertrophy; Muscle mass; Strength

DOI:  https://doi.org/10.1186/s40798-023-00578-4
Hum Gene Ther. 2023 May 08.

Immune Responses to Muscle-Directed AAV Gene Transfer in Clinical Studies.

Sandeep R P Kumar, Dongsheng Duan, Roland Herzog.

Muscle-directed gene therapy with adeno-associated viral (AAV) vectors is undergoing clinical development for treating neuromuscular disorders and for systemic delivery of therapeutic proteins. While these approaches show considerable therapeutic benefits, they are also prone to induce potent immune responses against vector or transgene products owing to the immunogenic nature of the intramuscular delivery route, or the high doses required for systemic delivery to muscle. Major immunological concerns include antibody formation against viral capsid, complement activation, and cytotoxic T-cell responses against capsid or transgene products. They can negate therapy and even lead to life-threatening immunotoxicities. Herein we review clinical observations and provide an outlook for how the field addresses these problems through a combination of vector engineering and immune modulation.

DOI: https://doi.org/10.1089/hum.2023.056
Biochem Soc Trans. 2023 May 12. pii: BST20221541. [Epub ahead of print]

Nesprin-1: novel regulator of striated muscle nuclear positioning and mechanotransduction.

Shanelle De Silva, Zhijuan Fan, Baoqiang Kang, Catherine M Shanahan, Qiuping Zhang.

  Nesprins (nuclear envelope spectrin repeat proteins) are multi-isomeric scaffolding proteins. Giant nesprin-1 and -2 localise to the outer nuclear membrane, interact with SUN (Sad1p/UNC-84) domain-containing proteins at the inner nuclear membrane to form the LInker of Nucleoskeleton and Cytoskeleton (LINC) complex, which, in association with lamin A/C and emerin, mechanically couples the nucleus to the cytoskeleton. Despite ubiquitous expression of nesprin giant isoforms, pathogenic mutations in nesprin-1 and -2 are associated with tissue-specific disorders, particularly related to striated muscle such as dilated cardiomyopathy and Emery-Dreifuss muscular dystrophy. Recent evidence suggests this muscle-specificity might be attributable in part, to the small muscle specific isoform, nesprin-1α2, which has a novel role in striated muscle function. Our current understanding of muscle-specific functions of nesprin-1 and its isoforms will be summarised in this review to provide insight into potential pathological mechanisms of nesprin-related muscle disease and may inform potential targets of therapeutic modulation.

Keywords:  DCM and EDMD; mechanotransduction; microtubule; nesprin; nuclear envelope LINC complex; nuclear positioning

DOI:  https://doi.org/10.1042/BST20221541
J Biol Chem. 2023 May 05. pii: S0021-9258(23)01823-9. [Epub ahead of print] 104795

The transcription factor Foxp1 regulates aerobic glycolysis in adipocytes and myocytes.

Haixia Ma, Valentina Sukonina, Wei Zhang, Fang Meng, Santhilal Subhash, Henrik Palmgren, Ida Alexandersson, Huiming Han, Shuping Zhou, Stefano Bartesaghi, Chandrasekhar Kanduri, Sven Enerbäck.

  In recent years, lactate has been recognized as an important circulating energy substrate rather than only a dead-end metabolic waste product generated during glucose oxidation at low levels of oxygen. The term "aerobic glycolysis" has been coined to denote increased glucose uptake and lactate production despite normal oxygen levels and functional mitochondria. Hence, in "aerobic glycolysis" lactate production is a metabolic choice, whereas in "anaerobic glycolysis" it is a metabolic necessity based on inadequate levels of oxygen. Interestingly, lactate can be taken up by cells and oxidized to pyruvate and thus constitutes a source of pyruvate that is independent of insulin. Here, we show that the transcription factor Foxp1 regulates glucose uptake and lactate production in adipocytes and myocytes. Over-expression of Foxp1 leads to increased glucose uptake and lactate production. In addition, protein levels of several enzymes in the glycolytic pathway are upregulated, such as hexokinase 2, phosphofructokinase, aldolase, and lactate dehydrogenase. Using chromatin immunoprecipitation and real-time quantitative PCR (ChIP-qPCR) assays, we demonstrate that Foxp1 directly interacts with promoter consensus cis-elements that regulate expression of several of these target genes. Conversely, knock-down of Foxp1 suppresses these enzyme levels and lowers glucose uptake and lactate production. Moreover, mice with a targeted deletion of Foxp1 in muscle display systemic glucose intolerance with decreased muscle glucose uptake. In primary human adipocytes with induced expression of Foxp1, we find increased glycolysis and glycolytic capacity. Our results indicate Foxp1 may play an important role as a regulator of aerobic glycolysis in adipose tissue and muscle.

Keywords:  Foxp1; Glucose tolerance test; aerobic glycolysis; glucose uptake; lactate production

DOI:  https://doi.org/10.1016/j.jbc.2023.104795
J Appl Physiol (1985). 2023 May 11.

Influence of internal muscle properties on muscle shape change and gearing in the human gastrocnemii.

Nicole Y Kelp, Christofer J Clemente, Kylie Tucker, François Hug, Sabrina Pinel, Taylor J M Dick.

  Skeletal muscles bulge when they contract. These three-dimensional shape changes coupled with fibre rotation, influence a muscle's mechanical performance by uncoupling fibre velocity from muscle belly velocity (i.e., gearing). Muscle shape change and gearing is likely mediated by the interaction between internal muscle properties and contractile forces. Muscles with greater stiffness and intermuscular fat, due to aging or disuse, may limit a muscle's ability to bulge in width, subsequently causing higher gearing. The aim of this study was to determine the influence of internal muscle properties on shape change, fibre rotation, and gearing in the medial (MG) and lateral gastrocnemii (LG) during isometric plantarflexion contractions. Multi-modal imaging techniques were used to measure muscle shear modulus, intramuscular fat, and fat-corrected physiological cross-sectional area (PCSA), at rest, as well as synchronous muscle architecture changes during submaximal and maximal contractions in the MG and LG of 20 young (24±3y) and 13 older (70±4y) participants. Fat-corrected PCSA was positively associated with fibre rotation, gearing, and changes in thickness during submaximal contractions, but negatively associated with changes in thickness at maximal contractions. Muscle stiffness and intramuscular fat were related to muscle bulging and reduced fibre rotation, respectively, but only at high forces. Further, the MG and LG had varied internal muscle properties, which may relate to the differing shape changes, fibre rotations and gearing behaviours observed at each contraction level. These results indicate that internal muscle properties may play an important role in mediating muscle shape change and gearing, especially during high force contractions.

Keywords:  aging; intramuscular fat; physiological cross-sectional area; stiffness; ultrasound

DOI:  https://doi.org/10.1152/japplphysiol.00080.2023