bims-moremu 2023-08-06 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2023‒08‒06
25 papers selected by
Anna Vainshtein
Craft Science Inc.

Myonectin protects against skeletal muscle dysfunction in male mice through activation of AMPK/PGC1α pathway.
Kinetics of skeletal muscle regeneration after mild and severe muscle damage induced by electrically-evoked lengthening contractions.
SIRT1 induction in the skeletal muscle of male mice partially preserves limb muscle mass but not contractile force in response to androgen deprivation.
Females Display Relatively Preserved Muscle Quality Compared to Males During the Onset and Early Stages of C26-induced Cancer-Cachexia.
Skeletal muscle-enriched miRNAs are highly unstable in vivo and may be regulated in a Dicer-independent manner.
Sustained oral spermidine supplementation rescues functional and structural defects in COL6-deficient myopathic mice.
Sex-specific preservation of neuromuscular function and metabolism following systemic transplantation of multipotent adult stem cells in a murine model of progeria.
Muscle specific ER-associated degradation maintains postnatal muscle hypertrophy and systemic energy metabolism.
ER Stress is Activated and Involved in Disuse-Induced Muscle Atrophy.
Induced pluripotent stem cells for modeling physiological and pathological striated muscle complexity.
Resistance wheel running improves contractile strength, but not metabolic capacity, in a murine model of volumetric muscle loss injury.
Enveloped viruses pseudotyped with mammalian myogenic cell fusogens target skeletal muscle for gene delivery.
Mesenchymal stem cells alleviate dexamethasone-induced muscle atrophy in mice and the involvement of ERK1/2 signalling pathway.
Autophagy increase in Merosin-Deficient Congenital Muscular Dystrophy type 1A.
Vamorolone improves Becker muscular dystrophy and increases dystrophin protein in bmx model mice.
Mitophagy-mediated inflammation and oxidative stress contribute to muscle wasting in cancer cachexia.
Locomotor function of skeletal muscle is regulated by vitamin D via adenosine triphosphate metabolism.
Histological characteristics of exercise-induced skeletal muscle remodelling.
Myokines as mediators of exercise-induced cognitive changes in older adults: protocol for a comprehensive living systematic review and meta-analysis.
Targeted screening and identification of chlorhexidine as a pro-myogenic circadian clock activator.
The effects of extracellular vesicles and their cargo on metabolism and its adaptation to physical exercise in insulin resistance and type 2 diabetes.
The worsening of skeletal muscle atrophy induced by immobilization at the early stage of remobilization correlates with BNIP3-dependent mitophagy.
A transcriptome-based single-cell biological age model and resource for tissue-specific aging measures.
Skeletal muscle mitochondrial function predicts cognitive impairment and is associated with biomarkers of Alzheimer's disease and neurodegeneration.
Identification of a novel immune-related transcriptional regulatory network in sarcopenia.

Nat Commun. 2023 Aug 04. 14(1): 4675

Myonectin protects against skeletal muscle dysfunction in male mice through activation of AMPK/PGC1α pathway.

Yuta Ozaki, Koji Ohashi, Naoya Otaka, Hiroshi Kawanishi, Tomonobu Takikawa, Lixin Fang, Kunihiko Takahara, Minako Tatsumi, Sohta Ishihama, Mikito Takefuji, Katsuhiro Kato, Yuuki Shimizu, Yasuko K Bando, Aiko Inoue, Masafumi Kuzuya, Shinji Miura, Toyoaki Murohara, Noriyuki Ouchi.

To maintain and restore skeletal muscle mass and function is essential for healthy aging. We have found that myonectin acts as a cardioprotective myokine. Here, we investigate the effect of myonectin on skeletal muscle atrophy in various male mouse models of muscle dysfunction. Disruption of myonectin exacerbates skeletal muscle atrophy in age-associated, sciatic denervation-induced or dexamethasone (DEX)-induced muscle atrophy models. Myonectin deficiency also contributes to exacerbated mitochondrial dysfunction and reduces expression of mitochondrial biogenesis-associated genes including PGC1α in denervated muscle. Myonectin supplementation attenuates denervation-induced muscle atrophy via activation of AMPK. Myonectin also reverses DEX-induced atrophy of cultured myotubes through the AMPK/PGC1α signaling. Furthermore, myonectin treatment suppresses muscle atrophy in senescence-accelerated mouse prone (SAMP) 8 mouse model of accelerated aging or mdx mouse model of Duchenne muscular dystrophy. These data indicate that myonectin can ameliorate skeletal muscle dysfunction through AMPK/PGC1α-dependent mechanisms, suggesting that myonectin could represent a therapeutic target of muscle atrophy.

DOI: https://doi.org/10.1038/s41467-023-40435-2
FASEB J. 2023 09;37(9): e23107

Kinetics of skeletal muscle regeneration after mild and severe muscle damage induced by electrically-evoked lengthening contractions.

Clara Bernard, Charline Jomard, Bénédicte Chazaud, Julien Gondin.

  Post-injury skeletal muscle regeneration requires interactions between myogenic and non-myogenic cells. Our knowledge on the regeneration process is mainly based on models using toxic, chemical, or physical (e.g., based on either muscle freezing or crushing) injury. Strikingly, the time course and magnitude of changes in the number of cells involved in muscle regeneration have been poorly described in relation to mild and severe muscle damage induced by electrically-evoked lengthening contractions. We investigated for the first time the kinetics and magnitude of changes in mononuclear cells in relation to the extent of muscle damage. Mild and severe injury were induced in vivo in the mouse gastrocnemius muscle by 1 and 30 electrically-evoked lengthening contractions, respectively. Several days after muscle damage, functional analysis of maximal torque production and histological investigations were performed to assess the related cellular changes. Torque recovery was faster after mild injury than after severe muscle damage. More necrotic and regenerating myofibers were observed after severe muscle damage as compared with mild injury, illustrating an association between functional and histological alterations. The kinetics of changes in muscle stem cells (total, proliferating, and differentiating), endothelial cells, fibro-adipogenic progenitors (FAPs), and macrophages in the regenerating muscle was similar in mild and severe models. However, the magnitude of changes in the number of differentiating muscle stem cells, hematopoietic cells, among which macrophages, and FAPs was higher in severe muscle damage. Collectively, our results show that the amount of myogenic and non-myogenic cells varies according to the extent of skeletal muscle injury to ensure efficient skeletal muscle regeneration while the kinetics of changes is independent of muscle tissue alterations. The possibility to experimentally modulate the extent of muscle damage will be useful to further investigate the cellular and molecular events involved in muscle regeneration.

Keywords:  fibro-adipogenic progenitors; lengthening contraction; macrophages; muscle stem cells; skeletal muscle regeneration

DOI:  https://doi.org/10.1096/fj.202201708RR
J Physiol. 2023 Aug 02.

SIRT1 induction in the skeletal muscle of male mice partially preserves limb muscle mass but not contractile force in response to androgen deprivation.

Bradley S Gordon, Patrick K Burns, Grant R Laskin, Kirsten R Dunlap, Jake R Boykin, Michael L Rossetti, David H Fukuda, Jennifer L Steiner.

  In males, the factors that decrease limb muscle mass and strength in response to androgen deprivation are largely unknown. Sirtuin1 (SIRT1) protein levels are lower in the limb muscle of male mice subjected to androgen deprivation. The present study aimed to assess whether SIRT1 induction preserved limb muscle mass and force production in response to androgen deprivation. Physically mature male mice containing an inducible muscle-specific SIRT1 transgene were subjected to a sham or castration surgery and compared to sham and castrated male mice where the SIRT1 transgene was not induced. SIRT1 induction partially preserved whole-body lean mass, tibialis anterior (TA) mass and triceps surae muscle mass in response to castration. Further analysis of the TA muscle showed that muscle-specific SIRT1 induction partially preserved limb muscle soluble protein content and fibre cross-sectional area. Unilateral AAV9-mediated SIRT1 induction in the TA muscle showed that SIRT1 partially preserved mass by acting directly in the muscle. Despite those positive outcomes to limb muscle morphology, muscle-specific SIRT1 induction did not preserve the force generating capacity of the TA or triceps surae muscles. Interestingly, SIRT1 induction in females did not alter limb muscle mass or limb muscle strength even though females have naturally low androgen levels. SIRT1 also did not alter the androgen-mediated increase in limb muscle mass or strength in females. In all, these data suggest that decreases in SIRT1 protein in the limb muscle of males may partially contribute to the loss of limb muscle mass in response to androgen deprivation. KEY POINTS: SIRT1 induction in skeletal muscle of male mice subjected to androgen deprivation partially preserved limb muscle mass and fibre cross-sectional area. SIRT1 induction in skeletal muscle of male mice subjected to androgen deprivation did not prevent preserve limb muscle force generating capacity. SIRT1 induction in skeletal muscle of females did not alter baseline limb muscle mass, nor did it affect the androgen-mediated increase in limb muscle mass.

Keywords:  hypogonadism; muscle atrophy; muscle force; testosterone

DOI:  https://doi.org/10.1113/JP284869
J Appl Physiol (1985). 2023 Aug 03.

Females Display Relatively Preserved Muscle Quality Compared to Males During the Onset and Early Stages of C26-induced Cancer-Cachexia.

Ana Regina Cabrera, J William Deaver, Seongkyun Lim, Francielly Morena da Silva, Eleanor R Schrems, Landen W Saling, Stavroula Tsitkanou, Megan E Rosa-Caldwell, Michael P Wiggs, Tyrone A Washington, Nicholas P Greene.

  BACKGROUND: Cancer-cachexia is clinically defined by involuntary weight loss >5% in <6 months, primarily affecting skeletal muscle. Here, we aimed to identify sex differences in the onset of colorectal cancer-cachexia with specific consideration to skeletal muscle contractile and metabolic functions.METHODS: Eight-weeks old BALB/c mice (69 male, 59 female) received subcutaneous C26 allografts or PBS vehicle. Tumors developed for 10-, 15-, 20-, or 25-days. Muscles and organs were collected, in vivo muscle contractility, protein synthesis rate, mitochondrial function, and protein turnover markers were assessed. One-way ANOVA within sex and trend analysis between sexes were performed, p<0.05.
RESULTS: Gastrocnemius and TA muscles became atrophic in male mice at 25-days, while female mice exhibited no significant differences in muscle weights at endpoints despite presenting hallmarks of cancer-cachexia (fat loss, hepatosplenomegaly). We observed lowered muscle contractility and protein synthesis concomitantly to muscle mass decay in males, with higher proteolytic markers in muscles of both sexes. mRNA of Opa1 was lower in TA, while Bnip3 was higher in gastrocnemius after 25-days in male mice, with no significance effect in female mice.
CONCLUSIONS: Our data suggest relative protections to skeletal muscle in females compared to males despite other canonical signs of cancer-cachexia and increased protein degradation markers; suggesting we should place onus upon non-muscle tissues during early-stages of cancer-cachexia in females. We noted potential protective mechanisms relating to skeletal muscle contractile and mitochondrial functions. Our findings, underline possible heterogeneity in onset of cancer-cachexia between biological sexes, suggesting the need for sex-specific approaches to treat cancer-cachexia.

Keywords:  Mitochondrial function; Muscle atrophy; Muscle contractility; Protein turnover; Skeletal muscle

DOI:  https://doi.org/10.1152/japplphysiol.00196.2023
FEBS J. 2023 Jul 31.

Skeletal muscle-enriched miRNAs are highly unstable in vivo and may be regulated in a Dicer-independent manner.

Satoshi Oikawa, Shuaibang Yuan, Yoshio Kato, Takayuki Akimoto.

  MicroRNAs (miRNAs) are small noncoding RNAs that control essential cellular processes. For several decades, the molecular mechanisms underlying the functions and biogenesis of miRNAs have been clarified, whereas the molecular dynamics of miRNAs are poorly understood. We recently found that muscle-enriched miRNAs were reduced by only 20~50% in the skeletal muscles even 4 weeks after the suppression of miRNA processing through an inducible depletion of Dicer1 gene. These data suggest that miRNAs are stably expressed in skeletal muscle. In this study, we investigated the half-lives of those miRNAs in adult skeletal muscle with an in vivo metabolic labeling strategy and a genetic mouse model. In contrast to the hypothesis, in vivo metabolic labeling revealed that the half-lives of skeletal-muscle-enriched miRNAs were approximately 11-20 hours. Furthermore, the levels of mature miR-23a decreased rapidly in the skeletal muscle of mice lacking miR-23 clusters in a tamoxifen-inducible manner. These data suggest that skeletal-muscle-enriched miRNAs are not highly stable in vivo. We also observed that the transfer of miR-150 into Dicer1-deficient muscle increased the miR-150 level to the same as that in control muscle. Taken together, our data demonstrate that miRNAs are degraded within a few days in adult skeletal muscle and that a Dicer-independent biogenetic pathway may produce mature miRNAs.

Keywords:  Dicer; MicroRNAs; RNA degradation; RNA stability; Skeletal muscle

DOI:  https://doi.org/10.1111/febs.16917
Autophagy. 2023 Aug 01. 1-9

Sustained oral spermidine supplementation rescues functional and structural defects in COL6-deficient myopathic mice.

Lisa Gambarotto, Samuele Metti, Matteo Corpetti, Martina Baraldo, Patrizia Sabatelli, Silvia Castagnaro, Matilde Cescon, Bert Blaauw, Paolo Bonaldo.

  COL6 (collagen type VI)-related myopathies (COL6-RM) are a distinct group of inherited muscle disorders caused by mutations of COL6 genes and characterized by early-onset muscle weakness, for which no cure is available yet. Key pathophysiological features of COL6-deficient muscles involve impaired macroautophagy/autophagy, mitochondrial dysfunction, neuromuscular junction fragmentation and myofiber apoptosis. Targeting autophagy by dietary means elicited beneficial effects in both col6a1 null (col6a1-/-) mice and COL6-RM patients. We previously demonstrated that one-month per os administration of the nutraceutical spermidine reactivates autophagy and ameliorates myofiber defects in col6a1-/- mice but does not elicit functional improvement. Here we show that a 100-day-long spermidine regimen is able to rescue muscle strength in col6a1-/- mice, with also a beneficial impact on mitochondria and neuromuscular junction integrity, without any noticeable side effects. Altogether, these data provide a rationale for the application of spermidine in prospective clinical trials for COL6-RM.Abbreviations: AChR: acetylcholine receptor; BTX: bungarotoxin; CNF: centrally nucleated fibers; Colch: colchicine; COL6: collagen type VI; COL6-RM: COL6-related myopathies; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; NMJ: neuromuscular junction; Spd: spermidine; SQSTM1/p62: sequestosome 1; TA: tibialis anterior; TOMM20: translocase of outer mitochondrial membrane 20; TUNEL: terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling.

Keywords:  Autophagy; collagen VI; nutraceutical; skeletal muscle; spermidine

DOI:  https://doi.org/10.1080/15548627.2023.2241125
Geroscience. 2023 Aug 03.

Sex-specific preservation of neuromuscular function and metabolism following systemic transplantation of multipotent adult stem cells in a murine model of progeria.

Seth D Thompson, Kelsey L Barrett, Chelsea L Rugel, Robin Redmond, Alexia Rudofski, Jacob Kurian, Jodi L Curtin, Sudarshan Dayanidhi, Mitra Lavasani.

  Onset and rates of sarcopenia, a disease characterized by a loss of muscle mass and function with age, vary greatly between sexes. Currently, no clinical interventions successfully arrest age-related muscle impairments since the decline is frequently multifactorial. Previously, we found that systemic transplantation of our unique adult multipotent muscle-derived stem/progenitor cells (MDSPCs) isolated from young mice-but not old-extends the health-span in DNA damage mouse models of progeria, a disease of accelerated aging. Additionally, induced neovascularization in the muscles and brain-where no transplanted cells were detected-strongly suggests a systemic therapeutic mechanism, possibly activated through circulating secreted factors. Herein, we used ZMPSTE24-deficient mice, a lamin A defect progeria model, to investigate the ability of young MDSPCs to preserve neuromuscular tissue structure and function. We show that progeroid ZMPST24-deficient mice faithfully exhibit sarcopenia and age-related metabolic dysfunction. However, systemic transplantation of young MDSPCs into ZMPSTE24-deficient progeroid mice sustained healthy function and histopathology of muscular tissues throughout their 6-month life span in a sex-specific manner. Indeed, female-but not male-mice systemically transplanted with young MDSPCs demonstrated significant preservation of muscle endurance, muscle fiber size, mitochondrial respirometry, and neuromuscular junction morphometrics. These novel findings strongly suggest that young MDSPCs modulate the systemic environment of aged animals by secreted rejuvenating factors to maintain a healthy homeostasis in a sex-specific manner and that the female muscle microenvironment remains responsive to exogenous regenerative cues in older age. This work highlights the age- and sex-related differences in neuromuscular tissue degeneration and the future prospect of preserving health in older adults with systemic regenerative treatments.

Keywords:  Aging; Cell therapy; Metabolism; Muscle fatigue; Neuromuscular tissues; Progeria; Regeneration; Sex differences; Skeletal muscle

DOI:  https://doi.org/10.1007/s11357-023-00892-5
JCI Insight. 2023 Aug 03. pii: e170387. [Epub ahead of print]

Muscle specific ER-associated degradation maintains postnatal muscle hypertrophy and systemic energy metabolism.

Benedict Abdon, Yusheng Liang, Débora da Luz Scheffer, Mauricio Torres, Neha Shrestha, Rachel B Reinert, You Lu, Brent Pederson, Amara Bugarin-Lapuz, Sander Kersten, Ling Qi.

  The growth of skeletal muscle relies on a delicate equilibrium between protein synthesis and degradation; however, how proteostasis is managed in the endoplasmic reticulum is largely unknown. Here, we report that the SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD) complex, the primary molecular machinery that degrades misfolded proteins in the ER is vital to maintain postnatal muscle growth and systemic energy balance. Myocyte-specific SEL1L deletion blunts the hypertrophic phase of muscle growth, resulting in a net zero gain of muscle mass during this developmental period and a 30% reduction in overall body growth. In addition, myocyte-specific SEL1L deletion triggered a systemic reprogramming of metabolism characterized by improved glucose sensitivity, enhanced beiging of adipocytes, and resistance to diet induced obesity. These effects were partially mediated by the upregulation of the myokine FGF21. These findings highlight the pivotal role of SEL1L-HRD1 ERAD activity in skeletal myocytes for postnatal muscle growth, and its physiological integration in maintaining whole-body energy balance.

Keywords:  Cell Biology; Cell stress; Muscle Biology; Protein misfolding; Skeletal muscle

DOI:  https://doi.org/10.1172/jci.insight.170387
Front Biosci (Landmark Ed). 2023 Jul 13. 28(7): 136

ER Stress is Activated and Involved in Disuse-Induced Muscle Atrophy.

Lu Wang, Xiangsheng Pang, Shiming Li, Wenjiong Li, Xiaoping Chen, Peng Zhang.

  BACKGROUND: Muscle atrophy resulting wholly or partially from disuse represents a serious medical complication that decreases quality of life and increases morbidity and mortality. The accumulation of misfolded/unfolded proteins disrupts endoplasmic reticulum (ER) homeostasis and thus causes ER stress. Growing evidence indicates that ER stress plays an essential role in skeletal muscle remodeling under various physiological or pathophysiological conditions. However, whether ER stress is involved in disuse-induced muscle atrophy remains unclear.METHODS: To induce muscle atrophy, 8-week-old C57BL/6JNifdc male mice were subjected to 3, 7, or 14 days of hindlimb unloading (HU), and rhesus macaques (Macaca mulatta) were subjected to 10∘ head-down tilted bed rest (HDBR) for 6 weeks. Tauroursodeoxycholic acid (TUDCA) (500 mg/kg/d) was orally administered to mice during HU to inhibit ER stress. Quantitative PCR, Western blotting, and immunohistochemistry were conducted to evaluate gene, protein, and structural changes, respectively.
RESULTS: ER stress marker genes were rapidly induced by HU in a similar trend to that observed with atrophy-related genes such as Atrogin-1, muscle RING finger 1 (MuRF1), and muscle ubiquitin ligase of SCF complex in atrophy-1 (MUSA1). Inhibition of ER stress with TUDCA, a pan-ER stress inhibitor, attenuated HU-induced muscle atrophy and the upregulation of ubiquitin ligases via the AKT/forkhead box O3a pathway. In addition, the oxidative-to-glycolytic myofiber type transition caused by HU was also inhibited by TUDCA treatment. ER stress activation was also confirmed in HDBR-induced rhesus soleus muscle atrophy.
CONCLUSIONS: The strong positive correlation between ER stress activation and both HU- and HDBR-induced muscle atrophy indicates that ER stress activation is ubiquitously involved in disuse-induced muscle atrophy, regardless of species. Thus, inhibiting ER stress may be an effective therapeutic strategy to prevent muscle atrophy during disuse.

Keywords:  ER stress; disuse; head-down tilted bed rest; hindlimb unloading; muscle atrophy

DOI:  https://doi.org/10.31083/j.fbl2807136
J Neuromuscul Dis. 2023 Jul 28.

Induced pluripotent stem cells for modeling physiological and pathological striated muscle complexity.

Leslie Caron, Stefano Testa, Frédérique Magdinier.

  Neuromuscular disorders (NMDs) are a large group of diseases associated with either alterations of skeletal muscle fibers, motor neurons or neuromuscular junctions. Most of these diseases is characterized with muscle weakness or wasting and greatly alter the life of patients. Animal models do not always recapitulate the phenotype of patients. The development of innovative and representative human preclinical models is thus strongly needed for modeling the wide diversity of NMDs, characterization of disease-associated variants, investigation of novel genes function, or the development of therapies. Over the last decade, the use of patient's derived induced pluripotent stem cells (hiPSC) has resulted in tremendous progress in biomedical research, including for NMDs. Skeletal muscle is a complex tissue with multinucleated muscle fibers supported by a dense extracellular matrix and multiple cell types including motor neurons required for the contractile activity. Major challenges need now to be tackled by the scientific community to increase maturation of muscle fibers in vitro, in particular for modeling adult-onset diseases affecting this tissue (neuromuscular disorders, cachexia, sarcopenia) and the evaluation of therapeutic strategies. In the near future, rapidly evolving bioengineering approaches applied to hiPSC will undoubtedly become highly instrumental for investigating muscle pathophysiology and the development of therapeutic strategies.

Keywords:  3D culture; Induced pluripotent stem cells; motor neurons; myoblasts; myotubes; neuromuscular disorders; neuromuscular junctions; satellite cells; therapy

DOI:  https://doi.org/10.3233/JND-230076
Exp Physiol. 2023 Aug 01.

Resistance wheel running improves contractile strength, but not metabolic capacity, in a murine model of volumetric muscle loss injury.

Albino G Schifino, Christiana J Raymond-Pope, Junwon Heo, Jennifer McFaline-Figueroa, Jarrod A Call, Sarah M Greising.

  The primary objective of this study was to determine if low- or high-resistance voluntary wheel running leads to functional improvements in muscle strength (i.e., isometric and isokinetic torque) and metabolic function (i.e., permeabilized fiber bundle mitochondrial respiration) after a volumetric muscle loss (VML) injury. C57BL/6J mice were randomized into one of four experimental groups at age 12 weeks: Uninjured control, VML untreated (VML), low-resistance wheel running (VML-LR), and high-resistance wheel running (VML-HR). All mice, excluding the Uninjured, were subject to a unilateral VML injury to the plantar flexor muscles and wheel running began 3-days post-VML. At 8-weeks post-VML, peak-isometric torque was greater in Uninjured compared to all VML-injured groups, but both VML-LR and VML-HR had greater (∼32%) peak-isometric torque compared to VML. All VML-injured groups had less isokinetic torque compared to Uninjured, and there was no statistical difference among VML, VML-LR, and VML-HR. No differences in cumulative running distance were observed between VML-LR and VML-HR groups. Because adaptations in VML-HR peak-isometric torque were attributed to greater gastrocnemius muscle mass, atrophy- and hypertrophy-related protein content and post-translational modifications were explored via immunoblot; however, results were inconclusive. Permeabilized fiber bundle mitochondrial oxygen consumption was 22% greater in Uninjured compared to VML, but there was no statistical difference among VML, VML-LR, and VML-HR. Furthermore, neither wheel running group demonstrated a change in the relative protein content of the mitochondrial biogenesis transcription factor, PGC-1α. These results indicate that resistance wheel running alone only has modest benefit in the VML-injured muscle. NEW FINDINGS: What is the central question of the study? If initiation of a resistance wheel running regimen following VML improves the functional capacity of skeletal muscle? What is the main finding and its importance? Resistance wheel running led to greater muscle mass and strength in mice with a VML injury but did not result in a full recovery. Neither low- nor high-resistance wheel running was associated with a change in permeabilized muscle fiber respiration despite runners having greater whole-body treadmill endurance capacity, suggesting a resilience to metabolic adaptations in VML-injured muscle. Resistance wheel running may be a suitable adjuvant rehabilitation strategy, but alone does not fully mitigate VML pathology. This article is protected by copyright. All rights reserved.

Keywords:  CK clamp; neuromusculoskeletal injury; rehabilitation; skeletal muscle injury

DOI:  https://doi.org/10.1113/EP091284
Cell. 2023 Aug 03. pii: S0092-8674(23)00732-8. [Epub ahead of print]186(16): 3520

Enveloped viruses pseudotyped with mammalian myogenic cell fusogens target skeletal muscle for gene delivery.

Sajedah M Hindi, Michael J Petrany, Elena Greenfeld, Leah C Focke, Alyssa A W Cramer, Michael A Whitt, Ramzi J Khairallah, Christopher W Ward, Jeffrey S Chamberlain, Vikram Prasad, Benjamin Podbilewicz, Douglas P Millay.

DOI: https://doi.org/10.1016/j.cell.2023.06.025
Stem Cell Res Ther. 2023 Aug 04. 14(1): 195

Mesenchymal stem cells alleviate dexamethasone-induced muscle atrophy in mice and the involvement of ERK1/2 signalling pathway.

Belle Yu-Hsuan Wang, Allen Wei-Ting Hsiao, Hoi Ting Shiu, Nicodemus Wong, Amanda Yu-Fan Wang, Chien-Wei Lee, Oscar Kuang-Sheng Lee, Wayne Yuk-Wai Lee.

  BACKGROUND: High dosage of dexamethasone (Dex) is an effective treatment for multiple diseases; however, it is often associated with severe side effects including muscle atrophy, resulting in higher risk of falls and poorer life quality of patients. Cell therapy with mesenchymal stem cells (MSCs) holds promise for regenerative medicine. In this study, we aimed to investigate the therapeutic efficacy of systemic administration of adipose-derived mesenchymal stem cells (ADSCs) in mitigating the loss of muscle mass and strength in mouse model of DEX-induced muscle atrophy.METHODS: 3-month-old female C57BL/6 mice were treated with Dex (20 mg/kg body weight, i.p.) for 10 days to induce muscle atrophy, then subjected to intravenous injection of a single dose of ADSCs ([Formula: see text] cells/kg body weight) or vehicle control. The mice were killed 7 days after ADSCs treatment. Body compositions were measured by animal DXA, gastrocnemius muscle was isolated for ex vivo muscle functional test, histological assessment and Western blot, while tibialis anterior muscles were isolated for RNA-sequencing and qPCR. For in vitro study, C2C12 myoblast cells were cultured under myogenic differentiation medium for 5 days following 100 [Formula: see text]M Dex treatment with or without ADSC-conditioned medium for another 4 days. Samples were collected for qPCR analysis and Western blot analysis. Myotube morphology was measured by myosin heavy chain immunofluorescence staining.
RESULTS: ADSC treatment significantly increased body lean mass (10-20%), muscle wet weight (15-30%) and cross-sectional area (CSA) (~ 33%) in DEX-induced muscle atrophy mice model and down-regulated muscle atrophy-associated genes expression (45-65%). Hindlimb grip strength (~ 37%) and forelimb ex vivo muscle contraction property were significantly improved (~ 57%) in the treatment group. Significant increase in type I fibres (~ 77%) was found after ADSC injection. RNA-sequencing results suggested that ERK1/2 signalling pathway might be playing important role underlying the beneficial effect of ADSC treatment, which was confirmed by ERK1/2 inhibitor both in vitro and in vivo.
CONCLUSIONS: ADSCs restore the pathogenesis of Dex-induced muscle atrophy with an increased number of type I fibres, stronger muscle strength, faster recovery rate and more anti-fatigue ability via ERK1/2 signalling pathway. The inhibition of muscle atrophy-associated genes by ADSCs offered this treatment as an intervention option for muscle-associated diseases. Taken together, our findings suggested that adipose-derived mesenchymal stem cell therapy could be a new treatment option for patient with Dex-induced muscle atrophy.

Keywords:  Cell therapy; Dexamethasone; Mesenchymal stem cell; Muscle atrophy

DOI:  https://doi.org/10.1186/s13287-023-03418-0
Eur J Transl Myol. 2023 Jul 28.

Autophagy increase in Merosin-Deficient Congenital Muscular Dystrophy type 1A.

Mariangela Mastrapasqua, Roberta Rossi, Lucrezia De Cosmo, Annalisa Resta, Mariella Errede, Antonella Bizzoca, Stefania Zampatti, Nicoletta Resta, Emiliano Giardina, Maddalena Ruggieri, Daniela Virgintino, Tiziana Annese, Nicola Laforgia, Francesco Girolamo.

The autophagy process recycles dysfunctional cellular components and protein aggregates by sequestering them in autophagosomes directed to lysosomes for enzymatic degradation. A basal level of autophagy is essential for skeletal muscle maintenance. Increased autophagy occurs in several forms of muscular dystrophy and in the merosin-deficient congenital muscular dystrophy 1A mouse model (dy3k/dy3k) lacking the laminin-α2 chain. This pilot study aimed to compare autophagy marker expression and autophagosomes presence using light and electron microscopes and western blotting in diagnostic muscle biopsies from newborns affected by different congenital muscular myopathies and dystrophies. Morphological examination showed dystrophic muscle features, predominance of type 2A myofibers, accumulation of autophagosomes in the subsarcolemmal areas, increased number of autophagosomes overexpressing LC3b, Beclin-1 and ATG5, in the merosin-deficient newborn suggesting an increased autophagy. In Duchenne muscular dystrophy, nemaline myopathy, and spinal muscular atrophy the predominant accumulation of p62+ puncta rather suggests an autophagy impairment.

DOI: https://doi.org/10.4081/ejtm.2023.11501
iScience. 2023 Jul 21. 26(7): 107161

Vamorolone improves Becker muscular dystrophy and increases dystrophin protein in bmx model mice.

Nikki M McCormack, Nhu Y Nguyen, Christopher B Tully, Trinitee Oliver, Alyson A Fiorillo, Christopher R Heier.

  There is no approved therapy for Becker muscular dystrophy (BMD), a genetic muscle disease caused by in-frame dystrophin deletions. We previously developed the dissociative corticosteroid vamorolone for treatment of the allelic, dystrophin-null disease Duchenne muscular dystrophy. We hypothesize vamorolone can treat BMD by safely reducing inflammatory signaling in muscle and through a novel mechanism of increasing dystrophin protein via suppression of dystrophin-targeting miRNAs. Here, we test this in the bmx mouse model of BMD. Daily oral treatment with vamorolone or prednisolone improves bmx grip strength and hang time phenotypes. Both drugs reduce myofiber size and decrease the percentage of centrally nucleated fibers. Vamorolone shows improved safety versus prednisolone by avoiding or reducing key side effects to behavior and growth. Intriguingly, vamorolone increases dystrophin protein in both heart and skeletal muscle. These data indicate that vamorolone, nearing approval for Duchenne, shows efficacy in bmx mice and therefore warrants clinical investigation in BMD.

Keywords:  Biological sciences; Neuroscience; Pharmacology

DOI:  https://doi.org/10.1016/j.isci.2023.107161
J Clin Biochem Nutr. 2023 Jul;73(1): 34-42

Mitophagy-mediated inflammation and oxidative stress contribute to muscle wasting in cancer cachexia.

Zhige Zhang, Shanjun Tan, Shuhao Li, Yuxi Cheng, Junjie Wang, Hao Liu, Mingyue Yan, Guohao Wu.

  Cancer cachexia is commonly seen in patients with malignant tumors, which usually leads to poor life quality and negatively affects long-term prognosis and survival. Mitochondria dysfunction and enhanced autophagy are well-established to play an important role in skeletal muscle wasting. However, whether mitophagy is engaged in the pathogenesis of cancer cachexia requires further investigation. This study comprised a clinical study and animal experimentation. Clinical data such as CT images and laboratory results were obtained and analyzed. Then mice model of cancer cachexia and mitophagy inhibition were established. Data including skeletal muscle mass and function, mitochondria structure and function, inflammatory factors as well as ROS concentration. Mitophagy was enhanced in cancer cachexia patients with increased inflammatory factors. Greater disruption of skeletal muscle fiber and mitochondria structure were seen in cancer cachexia, with a higher level of inflammatory factors and ROS expression in skeletal muscle. Meanwhile, ATP production was undermined, indicating a close relationship with mitophagy, inflammation, and oxidative stress in the skeletal muscle of cancer cachexia mice models. In conclusion, mitophagy is activated in cancer cachexia and may play a role in skeletal muscle atrophy, and inflammation and oxidative stress might participate in mitophagy-related skeletal muscle injury.

Keywords:  cancer cachexia; inflammation; mitophagy; oxidative stress; skeletal muscle wasting

DOI:  https://doi.org/10.3164/jcbn.23-1
Nutrition. 2023 Jun 05. pii: S0899-9007(23)00146-6. [Epub ahead of print]115 112117

Locomotor function of skeletal muscle is regulated by vitamin D via adenosine triphosphate metabolism.

Risako Mori, Megumi Mae, Hitoki Yamanaka, Shigeaki Kato, Ritsuko Masuyama.

  OBJECTIVES: During musculoskeletal development, the vitamin D endocrine system is crucial, because vitamin D-dependent calcium absorption is a major regulator of bone growth. Because exercise regimens depend on bone mass, the direct action of active vitamin D (1,25-dihydroxyvitamin D3 [1,25(OH)2D3]) on musculoskeletal performance should be determined.METHODS: To evaluate the effect of 1,25(OH)2D3 on muscle tissue, the vitamin D receptor (Vdr) gene was genetically inactivated in mouse skeletal muscle and the role of 1,25(OH)2D3-VDR signaling on locomotor function was assessed. The direct action of 1,25(OH)2D3 on muscle development was determined using cultured C2C12 cells with myogenic differentiation.
RESULTS: The lack of Vdr activity in skeletal muscle decreased spontaneous locomotor activity, suggesting that the skeletal muscle performance depended on 1,25(OH)2D3-VDR signaling. Bone phenotypes, reduced femoral bone mineral density, and accelerated osteoclast bone resorption were confirmed in mice lacking skeletal muscle Vdr activity. In vitro study revealed that the treatment with 1,25(OH)2D3 decreased the cellular adenosine triphosphate (ATP)-to-adenosine monophosphate ratio without reducing ATP production. Remarkably, protein expressions of connexin 43, an ATP releaser to extracellular space, and ATP metabolizing enzyme ectonucleotide pyrophosphatase phosphodiesterase 1 were increased responding to 1,25(OH)2D3 treatment. Furthermore, the concentration of pyrophosphate in the culture medium, which inhibits tissue calcification, was increased with 1,25(OH)2D3 treatment. In the presence of 1,25(OH)2D3-VDR signaling, calcium accumulation was suppressed in both muscle samples isolated from mice and in cultured C2C12 cells.
CONCLUSIONS: This study dissected the physiological functions of 1,25(OH)2D3-VDR signaling in muscle and revealed that regulation of ATP dynamics is involved in sustaining locomotor function.

Keywords:  ATP dynamics; Calcium accumulation; Locomotor function; Skeletal muscle; Vitamin D

DOI:  https://doi.org/10.1016/j.nut.2023.112117
J Cell Mol Med. 2023 Jul 30.

Histological characteristics of exercise-induced skeletal muscle remodelling.

Qihang Su, Jie Li, Jingbiao Huang, Qiuchen Cai, Chao Xue, Chenglong Huang, Liyang Chen, Jun Li, Dandan Li, Hengan Ge, Biao Cheng.

  This study aims to analyse the pathological features of skeletal muscle injury repair by using rats to model responses to different exercise intensities. Eighty-four rats were randomly divided into five groups for treadmill exercise. The short-term control, low-intensity, medium-intensity and high-intensity groups underwent gastrocnemius muscle sampling after 6, 8 and 12 weeks of exercise. The long-term high-intensity group underwent optical coherence tomography angiography and sampling after 18 weeks of exercise. RNA sequencing was performed on the muscle samples, followed by the corresponding histological staining. Differentially expressed genes were generally elevated at 6 weeks in the early exercise stage, followed by a decreasing trend. Meanwhile, the study demonstrated a negative correlation between time and the gene modules involved in vascular regulation. The modules associated with muscle remodelling were positively correlated with exercise intensity. Although the expression of many genes associated with common angiogenesis was downregulated at 8, 12 and 18 weeks, we found that muscle tissue microvessels were still increased, which may be closely associated with elevated sFRP2 and YAP1. During muscle injury-remodelling, angiogenesis is characterized by significant exercise time and exercise intensity dependence. We find significant differences in the spatial distribution of angiogenesis during muscle injury-remodelling, which be helpful for the future achievement of spatially targeted treatments for exercise-induced muscle injuries.

Keywords:  angiogenesis; exercise-induced muscle injury; load exercise; skeletal muscle remodelling; temporal regulation

DOI:  https://doi.org/10.1111/jcmm.17879
Front Aging Neurosci. 2023 ;15 1213057

Myokines as mediators of exercise-induced cognitive changes in older adults: protocol for a comprehensive living systematic review and meta-analysis.

Wouter A J Vints, Evrim Gökçe, Antoine Langeard, Iuliia Pavlova, Özge Selin Çevik, Mohammad Mosaferi Ziaaldini, Jasemin Todri, Orges Lena, Giorgos K Sakkas, Suzanne Jak, Ioanna Zorba Zormpa, Christina Karatzaferi, Oron Levin, Nerijus Masiulis, Yael Netz.

  Background: The world's population is aging, but life expectancy has risen more than healthy life expectancy (HALE). With respect to brain and cognition, the prevalence of neurodegenerative disorders increases with age, affecting health and quality of life, and imposing significant healthcare costs. Although the effects of physical exercise on cognition in advanced age have been widely explored, in-depth fundamental knowledge of the underlying mechanisms of the exercise-induced cognitive improvements is lacking. Recent research suggests that myokines, factors released into the blood circulation by contracting skeletal muscle, may play a role in mediating the beneficial effect of exercise on cognition. Our goal in this ongoing (living) review is to continuously map the rapidly accumulating knowledge on pathways between acute or chronic exercise-induced myokines and cognitive domains enhanced by exercise.Method: Randomized controlled studies will be systematically collected at baseline and every 6 months for at least 5 years. Literature search will be performed online in PubMed, EMBASE, PsycINFO, Web of Science, SportDiscus, LILACS, IBECS, CINAHL, SCOPUS, ICTRP, and ClinicalTrials.gov. Risk of bias will be assessed using the Revised Cochrane Risk of Bias tool (ROB 2). A random effects meta-analysis with mediation analysis using meta-analytic structural equation modeling (MASEM) will be performed. The primary research question is to what extent exercise-induced myokines serve as mediators of cognitive function. Secondarily, the pooled effect size of specific exercise characteristics (e.g., mode of exercise) or specific older adults' populations (e.g., cognitively impaired) on the relationship between exercise, myokines, and cognition will be assessed. The review protocol was registered in PROSPERO (CRD42023416996).
Discussion: Understanding the triad relationship between exercise, myokines and cognition will expand the knowledge on multiple integrated network systems communicating between skeletal muscles and other organs such as the brain, thus mediating the beneficial effects of exercise on health and performance. It may also have practical implications, e.g., if a certain myokine is found to be a mediator between exercise and cognition, the optimal exercise characteristics for inducing this myokine can be prescribed. The living review is expected to improve our state of knowledge and refine exercise regimes for enhancing cognitive functioning in diverse older adults' populations.
Registration: Systematic review and meta-analysis protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on the 24th of April 2023 (registration number CRD42023416996).

Keywords:  aged; biomarker; brain; cognition; exercise; muscle; myokine; physical activity

DOI:  https://doi.org/10.3389/fnagi.2023.1213057
Stem Cell Res Ther. 2023 07 31. 14(1): 190

Targeted screening and identification of chlorhexidine as a pro-myogenic circadian clock activator.

Tali Kiperman, Weini Li, Xuekai Xiong, Hongzhi Li, David Horne, Ke Ma.

  BACKGROUND: The circadian clock is an evolutionarily conserved mechanism that exerts pervasive temporal control in stem cell behavior. This time-keeping machinery is required for orchestrating myogenic progenitor properties in regenerative myogenesis that ameliorates muscular dystrophy. Here we report a screening platform to discover circadian clock modulators that promote myogenesis and identify chlorhexidine (CHX) as a clock-activating molecule with pro-myogenic activities.METHODS: A high-throughput molecular docking pipeline was applied to identify compounds with a structural fit for a hydrophobic pocket within the key circadian transcription factor protein, Circadian Locomotor Output Cycles Kaput (CLOCK). These identified molecules were further screened for clock-modulatory activities and functional validations for pro-myogenic properties.
RESULTS: CHX was identified as a clock activator that promotes distinct aspects of myogenesis. CHX activated circadian clock that reduced cycling period length and augmented amplitude. This action was mediated by the targeted CLOCK structure via augmented interaction with heterodimer partner Bmal1, leading to enhanced CLOCK/Bmal1-controlled transcription with upregulation of core clock genes. Consistent with its clock-activating function, CHX displayed robust effects on stimulating myogenic differentiation in a clock-dependent manner. In addition, CHX augmented the proliferative and migratory activities of myoblasts.
CONCLUSION: Our findings demonstrate the feasibility of a screening platform to discover clock modulators with myogenic regulatory activities. Discovery of CHX as a pro-myogenic molecule could be applicable to promote regenerative capacities in ameliorating dystrophic or degenerative muscle diseases.

Keywords:  Circadian clock; Drug screening; Muscle stem cell; Myoblast differentiation; Myogenesis; Myogenic progenitor; Small molecule

DOI:  https://doi.org/10.1186/s13287-023-03424-2
Proteomics. 2023 Jul 31. e2300078

The effects of extracellular vesicles and their cargo on metabolism and its adaptation to physical exercise in insulin resistance and type 2 diabetes.

Lucia Mastrototaro, Michael Roden.

  Lifestyle modification represents the first-line strategy for the prevention and treatment of type 2 diabetes mellitus (T2DM), which is frequently associated with obesity and characterized by defective pancreatic insulin secretion and/or insulin resistance. Exercise training is an essential component of lifestyle modification and has been shown to ameliorate insulin resistance by reducing body fat mass and by enhancing skeletal muscle mitochondrial biogenesis and insulin-independent glucose uptake. Additionally, exercising stimulates the release of exerkines such as metabolites or cytokines, but also long non-coding RNA, microRNAs, cell-free DNA (cf-DNA), and extracellular vesicles (EVs), which contribute to inter-tissue communication. There is emerging evidence that EV number and content are altered in obesity and T2DM and may be involved in several metabolic processes, specifically either worsening or improving insulin resistance. This review summarizes the current knowledge on the metabolic effects of exercise training and on the potential role of humoral factors and EV as new biomarkers for early diagnosis and tailored treatment of T2DM.

Keywords:  diabetes mellitus; exercise; exerkines; extracellular vesicles; organ crosstalk

DOI:  https://doi.org/10.1002/pmic.202300078
BMC Musculoskelet Disord. 2023 Aug 04. 24(1): 632

The worsening of skeletal muscle atrophy induced by immobilization at the early stage of remobilization correlates with BNIP3-dependent mitophagy.

Feng Wang, Ting Zhou, Chen Xu Zhou, Quan Bing Zhang, Hua Wang, Yun Zhou.

  BACKGROUND: Recent studies have shown that immobilization enhances reactive oxygen species (ROS) production and mitophagy activity in atrophic skeletal muscle. However, there are relatively few studies examining the biological changes and underlying mechanisms of skeletal muscle during remobilization. In this study, we aimed to investigate the effects of remobilization on skeletal muscle and explore the role of BNIP3-dependent mitophagy in this process.METHODS: Thirty rats were randomly divided into six groups based on immobilization and remobilization time: control (C), immobilization for two weeks (I-2w), and remobilization for one day (R-1d), three days (R-3d), seven days (R-7d), and two weeks (R-2w). At the end of the experimental period, the rectus femoris muscles were removed and weighed, and the measurements were expressed as the ratio of muscle wet weight to body weight (MWW/BW). Sirius Red staining was performed to calculate the values of cross-sectional area (CSA) of rectus femoris. Oxidative fluorescent dihydroethidium was used to evaluate the production of ROS, and the levels of superoxide dismutase (SOD) were also detected. The morphological changes of mitochondria and the formation of mitophagosomes in rectus femoris were examined and evaluated by transmission electron microscope. Immunofluorescence was employed to detect the co-localization of BNIP3 and LC3B, while Western blot analysis was performed to quantify the levels of proteins associated with mitophagy and mitochondrial biogenesis. The total ATP content of the rectus femoris was determined to assess mitochondrial function.
RESULTS: Within the first three days of remobilization, the rats demonstrated decreased MWW/BW, CSA, and ATP concentration, along with increased ROS production and HIF-1α protein levels in the rectus femoris. Results also indicated that remobilization triggered BNIP3-dependent mitophagy, supported by the accumulation of mitophagosomes, the degradation of mitochondrial proteins (including HSP60 and COX IV), the elevation of BNIP3-dependent mitophagy protein markers (including BNIP3, LC3B-II/LC3B-I, and Beclin-1), and the accumulation of puncta representing co-localization of BNIP3 with LC3B. Additionally, PGC-1α, which is involved in the regulation of mitochondrial biogenesis, was upregulated within the first seven days of remobilization to counteract this adverse effect.
CONCLUSION: Our findings suggested that BNIP3-denpendent mitophagy was sustained activated at the early stages of remobilization, and it might contribute to the worsening of skeletal muscle atrophy.

Keywords:  BNIP3-denpendent mitophagy; HIF-1α; Muscle atrophy; ROS; Remobilization

DOI:  https://doi.org/10.1186/s12891-023-06759-2
Genome Res. 2023 Jul 31. pii: gr.277491.122. [Epub ahead of print]

A transcriptome-based single-cell biological age model and resource for tissue-specific aging measures.

Shulin Mao, Jiayu Su, Longteng Wang, Xiaochen Bo, Cheng Li, Hebing Chen.

Accurately measuring biological age is crucial for improving healthcare for the elderly population. However, the complexity of aging biology poses challenges in how to robustly estimate aging and in how to interpret the biological significance of the traits used for estimation. Here we present SCALE, a statistical pipeline that quantifies biological aging in different tissues using explainable features learned from literature and single-cell transcriptomic data. Applying SCALE to the "Mouse Aging Cell Atlas" (Tabula Muris Senis) data, we identified tissue-level transcriptomic aging programs for over 20 murine tissues and created a multi-tissue resource of mouse quantitative aging-associated genes. We observe that SCALE correlates well with other age indicators, such as the accumulation of somatic mutations, and can distinguish subtle differences in aging even in cells of the same chronological age. We further compared SCALE with other transcriptomic and methylation 'clocks' in data of aging muscle stem cells, Alzheimer's disease, and heterochronic parabiosis. Our results confirm that SCALE is more generalizable and reliable in assessing biological aging in aging-related diseases and rejuvenating interventions. Overall, SCALE represents a valuable advancement in our ability to measure aging accurately, robustly, and interpretably in single cells.

DOI: https://doi.org/10.1101/gr.277491.122
Alzheimers Dement. 2023 Aug 02.

Skeletal muscle mitochondrial function predicts cognitive impairment and is associated with biomarkers of Alzheimer's disease and neurodegeneration.

Qu Tian, Murat Bilgel, Keenan A Walker, Abhay R Moghekar, Kenneth W Fishbein, Richard G Spencer, Susan M Resnick, Luigi Ferrucci.

  INTRODUCTION: Mitochondrial dysfunction is implicated in the pathophysiology of many chronic diseases. Whether it is related to cognitive impairment and pathological markers is unknown.METHODS: We examined the associations of in vivo skeletal muscle mitochondrial function (post-exercise recovery rate of phosphocreatine [kPCr] via magnetic resonance [MR] spectroscopy with future mild cognitive impairment (MCI) or dementia, and with positron emission tomography (PET) and blood biomarkers of Alzheimer's disease [AD] and neurodegeneration (i.e., Pittsburgh Compound-B [PiB] distribution volume ratio [DVR] for amyloid beta [Aβ], flortaucipir (FTP) standardized uptake value ratio [SUVR] for tau, Aβ42 /40 ratio, phosphorylated tau 181 [p-tau181], neurofilament light chain [NfL], and glial fibrillary acidic protein [GFAP]).
RESULTS: After covariate adjustment, each standard deviation (SD) higher kPCr level was associated with 52% lower hazards of developing MCI/dementia, and with 59% lower odds of being PiB positive with specific associations in DVR of frontal, parietal, and temporal regions, and cingulate cortex and pallidum. Higher kPCr level was also associated with lower plasma GFAP.
DISCUSSION: In aging, mitochondrial dysfunction may play a vital role in AD pathological changes and neuroinflammation. Highlights Higher in vivo mitochondrial function is related to lower risk of mild cognitive impairment (MCI)/dementia. Higher in vivo mitochondrial function is related to lower amyloid tracer uptake. Higher in vivo mitochondrial function is related to lower plasma neuroinflammation. Mitochondrial dysfunction may play a key role in Alzheimer's disease (AD) and neurodegeneration.

Keywords:  GFAP; PET biomarkers; aging; amyloid; dementia; mitochondrial function; tau

DOI:  https://doi.org/10.1002/alz.13388
BMC Geriatr. 2023 07 31. 23(1): 463

Identification of a novel immune-related transcriptional regulatory network in sarcopenia.

Xianzhong Zhang, Guanglou Zhu, Fengmin Zhang, Dingye Yu, Xuyang Jia, Bingwei Ma, Weizhe Chen, Xinyu Cai, Lingzhou Mao, Chengle Zhuang, Zhen Yu.

  BACKGROUND: Sarcopenia is highly prevalent in elderly individuals and has a significant adverse effect on their physical health and quality of life, but the mechanisms remain unclear. Studies have indicated that transcription factors (TFs) and the immune microenvironment play a vital role in skeletal muscle atrophy.METHODS: RNA-seq data of 40 muscle samples were downloaded from the GEO database. Then, differentially expressed genes (DEGs), TFs(DETFs), pathways(DEPs), and the expression of immune gene sets were identified with limma, edgeR, GO, KEGG, ORA, GSVA, and ssGSEA. Furthermore, the results above were integrated into coexpression analysis by Pearson correlation analysis (PCA). Significant coexpression patterns were used to construct the immune-related transcriptional regulatory network by Cytoscape and potential medicine targeting the network was screened by Connectivity Map. Finally, the regulatory mechanisms and RNA expression of DEGs and DETFs were identified by multiple online databases and RT‒qPCR.
RESULTS: We screened 808 DEGs (log2 fold change (FC) > 1 or < - 1, p < 0.05), 4 DETFs (log2FC > 0.7 or < - 0.7, p < 0.05), 304 DEPs (enrichment scores (ES) > 1 or < - 1, p < 0.05), and 1208 differentially expressed immune genes sets (DEIGSs) (p < 0.01). Based on the results of PCA (correlation coefficient (CC) > 0.4 or < - 0.4, p < 0.01), we then structured an immune-related network with 4 DETFs, 9 final DEGs, 11 final DEPs, and 6 final DEIGSs. Combining the results of online databases and in vitro experiments, we found that PAX5-SERPINA5-PI3K/Akt (CC ≤ 0.444, p ≤ 0.004) was a potential transcriptional regulation axis, and B cells (R = 0.437, p = 0.005) may play a vital role in this signal transduction. Finally, the compound of trichostatin A (enrichment = -0.365, specificity = 0.4257, p < 0.0001) might be a potential medicine for sarcopenia based on the PubChem database and the result of the literature review.
CONCLUSIONS: We first identified immune-related transcriptional regulatory network with high-throughput RNA-seq data in sarcopenia. We hypothesized that PAX5-SERPIAN5-PI3K/Akt axis is a potential mechanism in sarcopenia and that B cells may play a vital role in this signal transduction. In addition, trichostatin A might be a potential medicine for sarcopenia.

Keywords:  Immune gene sets; RNA-seq; Regulatory network; Sarcopenia; Transcription factors

DOI:  https://doi.org/10.1186/s12877-023-04152-1