bims-moremu 2024-03-10 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2024‒03‒10
29 papers selected by
Anna Vainshtein, Craft Science Inc.

Mustn1 is a smooth muscle cell-secreted microprotein that modulates skeletal muscle extracellular matrix composition.
Ectodysplasin A2 receptor signaling in skeletal muscle pathophysiology.
Exploiting the therapeutic potential of contracting skeletal muscle-released extracellular vesicles in cancer: Current insights and future directions.
Resistance exercise preconditioning prevents disuse muscle atrophy by inhibiting apoptosis and protein degradation via SESN2 in C57BL/6J mice.
Cancer-associated muscle weakness - From triggers to molecular mechanisms.
Reciprocal communication between FAPs and muscle cells via distinct extracellular vesicle miRNAs in muscle regeneration.
Postsynaptic β1 spectrin maintains Na+ channels at the neuromuscular junction.
After obesity drugs' success, companies rush to preserve skeletal muscle.
Psat1-generated α-ketoglutarate and glutamine promote muscle stem cell activation and regeneration.
Sex-based differences in Muscle Stem Cell Regulation Following Exercise.
p66Shc signaling and autophagy impact on C2C12 myoblast differentiation during senescence.
Beneficial effects of resistance training on both mild and severe mouse dystrophic muscle function as a preclinical option for Duchenne muscular dystrophy.
Mitochondrial calcium: An essential element for skeletal muscle performance and function.
Fat infiltration in skeletal muscle: Influential triggers and regulatory mechanism.
Liver-derived plasminogen mediates muscle stem cell expansion during caloric restriction through the plasminogen receptor Plg-RKT.
The effect of neuromuscular electrical stimulation on the human skeletal muscle transcriptome.
Celecoxib attenuates hindlimb unloading-induced muscle atrophy via suppressing inflammation, oxidative stress and ER stress by inhibiting STAT3.
FM19G11-loaded nanoparticles modulate energetic status and production of reactive oxygen species in myoblasts from ALS mice.
Childhood adverse life events and skeletal muscle mitochondrial function.
Effects of low-load resistance training with blood flow restriction on muscle fiber myofibrillar and extracellular area.
Motor neurons and endothelial cells additively promote development and fusion of human iPSC-derived skeletal myocytes.
Cadherin-dependent adhesion is required for muscle stem cell niche anchorage and maintenance.
Social jetlag impairs exercise volume and attenuates physiological and metabolic adaptations to voluntary exercise training.
Transcriptomic signature of cancer cachexia by integration of machine learning, literature mining and meta-analysis.
fhl2b mediates extraocular muscle protection in zebrafish models of muscular dystrophies and its ectopic expression ameliorates affected body muscles.
Locally applied heat stress during exercise training may promote adaptations to mitochondrial enzyme activities in skeletal muscle.
Muscle physiology and its relations to the whole body in health and disease.
The interplay between mitochondrial dynamics and autophagy: From a key homeostatic mechanism to a driver of pathology.
Bisphenol-A Abrogates Proliferation and Differentiation of C2C12 Mouse Myoblasts via Downregulation of Phospho-P65 NF-κB Signaling Pathway.

Mol Metab. 2024 Mar 06. pii: S2212-8778(24)00043-7. [Epub ahead of print] 101912

Mustn1 is a smooth muscle cell-secreted microprotein that modulates skeletal muscle extracellular matrix composition.

Serge Ducommun, Paulo R Jannig, Igor Cervenka, Marta Murgia, Melanie J Mittenbühler, Ekaterina Chernogubova, José M Dias, Baptiste Jude, Jorge C Correia, Jonathan G Van Vranken, Gabriel Ocana-Santero, Margareta Porsmyr-Palmertz, Sarah McCann Haworth, Vicente Martínez-Redondo, Zhengye Liu, Mattias Carlström, Matthias Mann, Johanna T Lanner, Ana I Teixeira, Lars Maegdefessel, Bruce M Spiegelman, Jorge L Ruas.

  OBJECTIVE: Skeletal muscle plasticity and remodeling are critical for adapting tissue function to use, disuse, and regeneration. The aim of this study was to identify genes and molecular pathways that regulate the transition from atrophy to compensatory hypertrophy or recovery from injury. Here, we have used a mouse model of hindlimb unloading and reloading, which causes skeletal muscle atrophy, and compensatory regeneration and hypertrophy, respectively.METHODS: We analyzed mouse skeletal muscle at the transition from hindlimb unloading to reloading for changes in transcriptome and extracellular fluid proteome. We then used qRT-PCR, immunohistochemistry, and bulk and single-cell RNA sequencing data to determine Mustn1 gene and protein expression, including changes in gene expression in mouse and human skeletal muscle with different challenges such as exercise and muscle injury. We generated Mustn1-deficient genetic mouse models and characterized them in vivo and ex vivo with regard to muscle function and whole-body metabolism. We isolated smooth muscle cells and functionally characterized them, and performed transcriptomics and proteomics analysis of skeletal muscle and aorta of Mustn1-deficient mice.
RESULTS: We show that Mustn1 (Musculoskeletal embryonic nuclear protein 1, also known as Mustang) is highly expressed in skeletal muscle during the early stages of hindlimb reloading. Mustn1 expression is transiently elevated in mouse and human skeletal muscle in response to intense exercise, resistance exercise, or injury. We find that Mustn1 expression is highest in smooth muscle-rich tissues, followed by skeletal muscle fibers. Muscle from heterozygous Mustn1-deficient mice exhibit differences in gene expression related to extracellular matrix and cell adhesion, compared to wild-type littermates. Mustn1-deficient mice have normal muscle and aorta function and whole-body glucose metabolism. Loss of Mustn1 in vascular smooth muscle cells does not affect their proliferative or migratory functions. We show that Mustn1 can be secreted from smooth muscle cells, and that it is present in arterioles of the muscle microvasculature and in muscle extracellular fluid, particularly during the hindlimb reloading phase. Proteomics analysis of muscle from Mustn1-deficient mice confirms differences in extracellular matrix composition, and female mice display higher collagen content after chemically induced muscle injury compared to wild-type littermates.
CONCLUSIONS: We show that, in addition to its previously reported intracellular localization, Mustn1 is a microprotein secreted from smooth muscle cells into the muscle extracellular space. We explore its role in muscle ECM deposition and remodeling in homeostasis and upon muscle injury. The role of Mustn1 in fibrosis and immune infiltration upon muscle injury and dystrophies remains to be investigated, as does its potential for therapeutic interventions.

Keywords:  Extracellular Matrix; Leiokine; Microprotein; Muscle regeneration; Mustn1; Smooth Muscle

DOI:  https://doi.org/10.1016/j.molmet.2024.101912
Trends Mol Med. 2024 Mar 04. pii: S1471-4914(24)00027-3. [Epub ahead of print]

Ectodysplasin A2 receptor signaling in skeletal muscle pathophysiology.

Sevgi Döndü Özen, Serkan Kir.

  Skeletal muscle is essential in generating mechanical force and regulating energy metabolism and body temperature. Pathologies associated with muscle tissue often lead to impaired physical activity and imbalanced metabolism. Recently, ectodysplasin A2 receptor (EDA2R) signaling has been shown to promote muscle loss and glucose intolerance. Upregulated EDA2R expression in muscle tissue was associated with aging, denervation, cancer cachexia, and muscular dystrophies. Here, we describe the roles of EDA2R signaling in muscle pathophysiology, including muscle atrophy, insulin resistance, and aging-related sarcopenia. We also discuss the EDA2R pathway, which involves EDA-A2 as the ligand and nuclear factor (NF)κB-inducing kinase (NIK) as a downstream mediator, and the therapeutic potential of targeting these proteins in the treatment of muscle wasting and metabolic dysfunction.

Keywords:  NFκB-inducing kinase; aging-related sarcopenia; ectodysplasin A2 receptor signaling; insulin resistance in muscle; skeletal muscle atrophy

DOI:  https://doi.org/10.1016/j.molmed.2024.02.002
J Mol Med (Berl). 2024 Mar 07.

Exploiting the therapeutic potential of contracting skeletal muscle-released extracellular vesicles in cancer: Current insights and future directions.

Ana Carolina Pinto, Patrícia Tavares, Bruno Neves, Pedro F Oliveira, Rui Vitorino, Daniel Moreira-Gonçalves, Rita Ferreira.

  The health benefits of exercise training in a cancer setting are increasingly acknowledged; however, the underlying molecular mechanisms remain poorly understood. It has been suggested that extracellular vesicles (EVs) released from contracting skeletal muscles play a key role in mediating the systemic benefits of exercise by transporting bioactive molecules, including myokines. Nevertheless, skeletal muscle-derived vesicles account for only about 5% of plasma EVs, with the immune cells making the largest contribution. Moreover, it remains unclear whether the contribution of skeletal muscle-derived EVs increases after physical exercise or how muscle contraction modulates the secretory activity of other tissues and thus influences the content and profile of circulating EVs. Furthermore, the destination of EVs after exercise is unknown, and it depends on their molecular composition, particularly adhesion proteins. The cargo of EVs is influenced by the training program, with acute training sessions having a greater impact than chronic adaptations. Indeed, there are numerous questions regarding the role of EVs in mediating the effects of exercise, the clarification of which is critical for tailoring exercise training prescriptions and designing exercise mimetics for patients unable to engage in exercise programs. This review critically analyzes the current knowledge on the effects of exercise on the content and molecular composition of circulating EVs and their impact on cancer progression.

Keywords:  Cancer; Exercise training; Extracellular vesicles; Proteome; miRNAs

DOI:  https://doi.org/10.1007/s00109-024-02427-7
Biochim Biophys Acta Mol Basis Dis. 2024 Mar 02. pii: S0925-4439(24)00100-5. [Epub ahead of print]1870(4): 167111

Resistance exercise preconditioning prevents disuse muscle atrophy by inhibiting apoptosis and protein degradation via SESN2 in C57BL/6J mice.

Yating Huang, Chenxin Jiang, Xiuru Li, Sujuan Liu, Yanmei Niu, Li Fu.

  AIM: To compare the effects of different exercise preconditioning in the context of skeletal muscle atrophy and to investigate the potential involvement of Sestrin2 (SESN2), a stress-inducible protein that can be regulated by exercise, in exercise preconditioning on preventing disuse muscle atrophy.METHODS: Eight-week-old male C57BL/6J mice were randomly assigned to sedentary groups (SD), aerobic exercise groups (AE), resistance exercise groups (RE), and combined exercise groups (CE) with or without 7 days of immobilization. The duration of the exercise intervention was 10 weeks. The effects of different exercise preconditioning to prevent muscle atrophy were analyzed by evaluating skeletal muscle function and mass. Additionally, to investigate the potential underlying mechanism of exercise-induced protection of skeletal muscle, wild-type and SESN2--/-- mice were randomly divided into sedentary group and resistance exercise preconditioning group. C2C12 cells were treated with SESN2 adenoviruses and MK2206 (an AKT inhibitor) for 48 h to elucidate the underlined mechanism.
RESULTS: RE was more effective in preserving skeletal muscle function, muscle mass and maintaining skeletal muscle protein homeostasis than AE and CE under immobilized condition. Importantly, exercise performance, muscle mass to body weight ratio, and the cross-sectional area of muscle fibers were significantly lower in SESN2-/- mice than wild-type mice after resistance exercise preconditioning. Mechanistically, the absence of SESN2 led to activation of the ubiquitin-proteasome system and induction of apoptosis. In vitro experiments showed that MK2206 treatment mitigated the regulatory effects of overexpression-SESN2 on protein hydrolysis and apoptosis.
CONCLUSION: RE was more effective than AE or CE in preventing disuse muscle atrophy. SESN2 mediated the protective effects of resistance exercise preconditioning on skeletal muscle atrophy.

Keywords:  Exercise preconditioning; Muscle atrophy; Resistance exercise; SESN2

DOI:  https://doi.org/10.1016/j.bbadis.2024.167111
Mol Aspects Med. 2024 Mar 07. pii: S0098-2997(24)00019-0. [Epub ahead of print]97 101260

Cancer-associated muscle weakness - From triggers to molecular mechanisms.

Emily Shorter, Viktor Engman, Johanna T Lanner.

Skeletal muscle weakness is a debilitating consequence of many malignancies. Muscle weakness has a negative impact on both patient wellbeing and outcome in a range of cancer types and can be the result of loss of muscle mass (i.e. muscle atrophy, cachexia) and occur independently of muscle atrophy or cachexia. There are multiple cancer specific triggers that can initiate the progression of muscle weakness, including the malignancy itself and the tumour environment, as well as chemotherapy, radiotherapy and malnutrition. This can induce weakness via different routes: 1) impaired intrinsic capacity (i.e., contractile dysfunction and intramuscular impairments in excitation-contraction coupling or crossbridge cycling), 2) neuromuscular disconnection and/or 3) muscle atrophy. The mechanisms that underlie these pathways are a complex interplay of inflammation, autophagy, disrupted protein synthesis/degradation, and mitochondrial dysfunction. The current lack of therapies to treat cancer-associated muscle weakness highlight the critical need for novel interventions (both pharmacological and non-pharmacological) and mechanistic insight. Moreover, most research in the field has placed emphasis on directly improving muscle mass to improve muscle strength. However, accumulating evidence suggests that loss of muscle function precedes atrophy. This review primarily focuses on cancer-associated muscle weakness, independent of cachexia, and provides a solid background on the underlying mechanisms, methodology, current interventions, gaps in knowledge, and limitations of research in the field. Moreover, we have performed a mini-systematic review of recent research into the mechanisms behind muscle weakness in specific cancer types, along with the main pathways implicated.

DOI: https://doi.org/10.1016/j.mam.2024.101260
Proc Natl Acad Sci U S A. 2024 Mar 12. 121(11): e2316544121

Reciprocal communication between FAPs and muscle cells via distinct extracellular vesicle miRNAs in muscle regeneration.

Yingying Yu, Yang Su, Guoxiao Wang, Miaomiao Lan, Jin Liu, Ruben Garcia Martin, Bruna Brasil Brandao, Marsel Lino, Lei Li, Chang Liu, C Ronald Kahn, Qingyong Meng.

  Muscle regeneration is a complex process relying on precise teamwork between multiple cell types, including muscle stem cells (MuSCs) and fibroadipogenic progenitors (FAPs). FAPs are also the main source of intramuscular adipose tissue (IMAT). Muscles without FAPs exhibit decreased IMAT infiltration but also deficient muscle regeneration, indicating the importance of FAPs in the repair process. Here, we demonstrate the presence of bidirectional crosstalk between FAPs and MuSCs via their secretion of extracellular vesicles (EVs) containing distinct clusters of miRNAs that is crucial for normal muscle regeneration. Thus, after acute muscle injury, there is activation of FAPs leading to a transient rise in IMAT. These FAPs also release EVs enriched with a selected group of miRNAs, a number of which come from an imprinted region on chromosome 12. The most abundant of these is miR-127-3p, which targets the sphingosine-1-phosphate receptor S1pr3 and activates myogenesis. Indeed, intramuscular injection of EVs from immortalized FAPs speeds regeneration of injured muscle. In late stages of muscle repair, in a feedback loop, MuSCs and their derived myoblasts/myotubes secrete EVs enriched in miR-206-3p and miR-27a/b-3p. The miRNAs repress FAP adipogenesis, allowing full muscle regeneration. Together, the reciprocal communication between FAPs and muscle cells via miRNAs in their secreted EVs plays a critical role in limiting IMAT infiltration while stimulating muscle regeneration, hence providing an important mechanism for skeletal muscle repair and homeostasis.

Keywords:  extracellular vesicles; fibroadipogenic progenitors; muscle injury/regeneration; muscle stem cell; tissue crosstalk

DOI:  https://doi.org/10.1073/pnas.2316544121
J Physiol. 2024 Mar 05.

Postsynaptic β1 spectrin maintains Na+ channels at the neuromuscular junction.

Ozlem Sert, Xiaoyun Ding, Chuansheng Zhang, Ruifa Mi, Ahmet Hoke, Matthew N Rasband.

  Spectrins function together with actin as obligatory subunits of the submembranous cytoskeleton. Spectrins maintain cell shape, resist mechanical forces, and stabilize ion channel and transporter protein complexes through binding to scaffolding proteins. Recently, pathogenic variants of SPTBN4 (β4 spectrin) were reported to cause both neuropathy and myopathy. Although the role of β4 spectrin in neurons is mostly understood, its function in skeletal muscle, another excitable tissue subject to large forces, is unknown. Here, using a muscle specific β4 spectrin conditional knockout mouse, we show that β4 spectrin does not contribute to muscle function. In addition, we show β4 spectrin is not present in muscle, indicating the previously reported myopathy associated with pathogenic SPTBN4 variants is neurogenic in origin. More broadly, we show that α2, β1 and β2 spectrins are found in skeletal muscle, with α2 and β1 spectrins being enriched at the postsynaptic neuromuscular junction (NMJ). Surprisingly, using muscle specific conditional knockout mice, we show that loss of α2 and β2 spectrins had no effect on muscle health, function or the enrichment of β1 spectrin at the NMJ. Muscle specific deletion of β1 spectrin also had no effect on muscle health, but, with increasing age, resulted in the loss of clustered NMJ Na+ channels. Together, our results suggest that muscle β1 spectrin functions independently of an associated α spectrin to maintain Na+ channel clustering at the postsynaptic NMJ. Furthermore, despite repeated exposure to strong forces and in contrast to neurons, muscles do not require spectrin cytoskeletons to maintain cell shape or integrity. KEY POINTS: The myopathy found in pathogenic human SPTBN4 variants (where SPTBN4 is the gene encoding β4 spectrin) is neurogenic in origin. β1 spectrin plays essential roles in maintaining the density of neuromuscular junction Nav1.4 Na+ channels. By contrast to the canonical view of spectrin organization and function, we show that β1 spectrin can function independently of an associated α spectrin. Despite the large mechanical forces experienced by muscle, we show that spectrins are not required for muscle cell integrity. This is in stark contrast to red blood cells and the axons of neurons.

Keywords:  axon injury; cytoskeleton; neuromuscular junction; regeneration; repair

DOI:  https://doi.org/10.1113/JP285894
Nat Biotechnol. 2024 Mar 05.

After obesity drugs' success, companies rush to preserve skeletal muscle.

Carrie Arnold.

DOI: https://doi.org/10.1038/s41587-024-02176-5
Genes Dev. 2024 Mar 07.

Psat1-generated α-ketoglutarate and glutamine promote muscle stem cell activation and regeneration.

Veronica Ciuffoli, Xuesong Feng, Kan Jiang, Natalia Acevedo-Luna, Kyung Dae Ko, A Hong Jun Wang, Giulia Riparini, Mamduh Khateb, Brian Glancy, Stefania Dell'Orso, Vittorio Sartorelli.

  By satisfying bioenergetic demands, generating biomass, and providing metabolites serving as cofactors for chromatin modifiers, metabolism regulates adult stem cell biology. Here, we report that a branch of glycolysis, the serine biosynthesis pathway (SBP), is activated in regenerating muscle stem cells (MuSCs). Gene inactivation and metabolomics revealed that Psat1, one of the three SBP enzymes, controls MuSC activation and expansion of myogenic progenitors through production of the metabolite α-ketoglutarate (α-KG) and α-KG-generated glutamine. Psat1 ablation resulted in defective expansion of MuSCs and impaired regeneration. Psat1, α-KG, and glutamine were reduced in MuSCs of old mice. α-KG or glutamine re-established appropriate muscle regeneration of adult conditional Psat1 -/- mice and of old mice. These findings contribute insights into the metabolic role of Psat1 during muscle regeneration and suggest α-KG and glutamine as potential therapeutic interventions to ameliorate muscle regeneration during aging.

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

DOI:  https://doi.org/10.1101/gad.351428.123
Exerc Sport Sci Rev. 2024 Mar 06.

Sex-based differences in Muscle Stem Cell Regulation Following Exercise.

Kayleigh Beaudry, Michael De Lisio.

ABSTRACT: Sexual dimorphism, driven by the sex hormones testosterone and estrogen, influences body composition, muscle fiber type, and inflammation. Research related to muscle stem cell (MuSC) responses to exercise has mainly focused on males. We propose a novel hypothesis that there are sex-based differences in MuSC regulation following exercise, such that males have more MuSCs while females demonstrate a greater capacity for regeneration.

DOI: https://doi.org/10.1249/JES.0000000000000337
Cell Death Dis. 2024 Mar 08. 15(3): 200

p66Shc signaling and autophagy impact on C2C12 myoblast differentiation during senescence.

Yaiza Potes, Juan C Bermejo-Millo, Catarina Mendes, José P Castelão-Baptista, Andrea Díaz-Luis, Zulema Pérez-Martínez, Juan J Solano, Vilma A Sardão, Paulo J Oliveira, Beatriz Caballero, Ana Coto-Montes, Ignacio Vega-Naredo.

During aging, muscle regenerative capacities decline, which is concomitant with the loss of satellite cells that enter in a state of irreversible senescence. However, what mechanisms are involved in myogenic senescence and differentiation are largely unknown. Here, we showed that early-passage or "young" C2C12 myoblasts activated the redox-sensitive p66Shc signaling pathway, exhibited a strong antioxidant protection and a bioenergetic profile relying predominantly on OXPHOS, responses that decrease progressively during differentiation. Furthermore, autophagy was increased in myotubes. Otherwise, late-passage or "senescent" myoblasts led to a highly metabolic profile, relying on both OXPHOS and glycolysis, that may be influenced by the loss of SQSTM1/p62 which tightly regulates the metabolic shift from aerobic glycolysis to OXPHOS. Furthermore, during differentiation of late-passage C2C12 cells, both p66Shc signaling and autophagy were impaired and this coincides with reduced myogenic capacity. Our findings recognized that the lack of p66Shc compromises the proliferation and the onset of the differentiation of C2C12 myoblasts. Moreover, the Atg7 silencing favored myoblasts growth, whereas interfered in the viability of differentiated myotubes. Then, our work demonstrates that the p66Shc signaling pathway, which highly influences cellular metabolic status and oxidative environment, is critical for the myogenic commitment and differentiation of C2C12 cells. Our findings also support that autophagy is essential for the metabolic switch observed during the differentiation of C2C12 myoblasts, confirming how its regulation determines cell fate. The regulatory roles of p66Shc and autophagy mechanisms on myogenesis require future attention as possible tools that could predict and measure the aging-related state of frailty and disability.

DOI: https://doi.org/10.1038/s41419-024-06582-0
PLoS One. 2024 ;19(3): e0295700

Beneficial effects of resistance training on both mild and severe mouse dystrophic muscle function as a preclinical option for Duchenne muscular dystrophy.

Medhi Hassani, Dylan Moutachi, Mégane Lemaitre, Alexis Boulinguiez, Denis Furling, Onnik Agbulut, Arnaud Ferry.

Mechanical overloading (OVL) resulting from the ablation of muscle agonists, a supra-physiological model of resistance training, reduces skeletal muscle fragility, i.e. the immediate maximal force drop following lengthening contractions, and increases maximal force production, in mdx mice, a murine model of Duchene muscular dystrophy (DMD). Here, we further analyzed these beneficial effects of OVL by determining whether they were blocked by cyclosporin, an inhibitor of the calcineurin pathway, and whether there were also observed in the D2-mdx mice, a more severe murine DMD model. We found that cyclosporin did not block the beneficial effect of 1-month OVL on plantaris muscle fragility in mdx mice, nor did it limit the increases in maximal force and muscle weight (an index of hypertrophy). Fragility and maximal force were also ameliorated by OVL in the plantaris muscle of D2-mdx mice. In addition, OVL increased the expression of utrophin, cytoplamic γ-actin, MyoD, and p-Akt in the D2-mdx mice, proteins playing an important role in fragility, maximal force gain and muscle growth. In conclusion, OVL reduced fragility and increased maximal force in the more frequently used mild mdx model but also in D2-mdx mice, a severe model of DMD, closer to human physiopathology. Moreover, these beneficial effects of OVL did not seem to be related to the activation of the calcineurin pathway. Thus, this preclinical study suggests that resistance training could have a potential benefit in the improvement of the quality of life of DMD patients.

DOI: https://doi.org/10.1371/journal.pone.0295700
J Physiol. 2024 Mar 04.

Mitochondrial calcium: An essential element for skeletal muscle performance and function.

Jaydeep Sharma, Somnath Mondal, Mahima Kumari.



Keywords:  MCU; MICU; calcium; fibre type; mitochondria; skeletal muscle

DOI:  https://doi.org/10.1113/JP286218
iScience. 2024 Mar 15. 27(3): 109221

Fat infiltration in skeletal muscle: Influential triggers and regulatory mechanism.

Liyi Wang, Teresa G Valencak, Tizhong Shan.

  Fat infiltration in skeletal muscle (also known as myosteatosis) is now recognized as a distinct disease from sarcopenia and is directly related to declining muscle capacity. Hence, understanding the origins and regulatory mechanisms of fat infiltration is vital for maintaining skeletal muscle development and improving human health. In this article, we summarized the triggering factors such as aging, metabolic diseases and metabolic syndromes, nonmetabolic diseases, and muscle injury that all induce fat infiltration in skeletal muscle. We discussed recent advances on the cellular origins of fat infiltration and found several cell types including myogenic cells and non-myogenic cells that contribute to myosteatosis. Furthermore, we reviewed the molecular regulatory mechanism, detection methods, and intervention strategies of fat infiltration in skeletal muscle. Based on the current findings, our review will provide new insight into regulating function and lipid metabolism of skeletal muscle and treating muscle-related diseases.

Keywords:  Health sciences; Human metabolism; Physiology

DOI:  https://doi.org/10.1016/j.isci.2024.109221
Cell Rep. 2024 Mar 04. pii: S2211-1247(24)00209-2. [Epub ahead of print]43(3): 113881

Liver-derived plasminogen mediates muscle stem cell expansion during caloric restriction through the plasminogen receptor Plg-RKT.

Akshay Bareja, David E Lee, Tricia Ho, Greg Waitt, Lauren H McKay, Sarah A Hannou, Melissa C Orenduff, Kristen M McGreevy, Alexandra Binder, Calen P Ryan, Erik J Soderblom, Daniel W Belsky, Luigi Ferrucci, Jayanta Kumar Das, Nirad Banskota, Virginia B Kraus, Janet L Huebner, William E Kraus, Kim M Huffman, Gurpreet S Baht, Steve Horvath, Robert J Parmer, Lindsey A Miles, James P White.

  An intriguing effect of short-term caloric restriction (CR) is the expansion of certain stem cell populations, including muscle stem cells (satellite cells), which facilitate an accelerated regenerative program after injury. Here, we utilized the MetRSL274G (MetRS) transgenic mouse to identify liver-secreted plasminogen as a candidate for regulating satellite cell expansion during short-term CR. Knockdown of circulating plasminogen prevents satellite cell expansion during short-term CR. Furthermore, loss of the plasminogen receptor KT (Plg-RKT) is also sufficient to prevent CR-related satellite cell expansion, consistent with direct signaling of plasminogen through the plasminogen receptor Plg-RKT/ERK kinase to promote proliferation of satellite cells. Importantly, we are able to replicate many of these findings in human participants from the CALERIE trial. Our results demonstrate that CR enhances liver protein secretion of plasminogen, which signals directly to the muscle satellite cell through Plg-RKT to promote proliferation and subsequent muscle resilience during CR.

Keywords:  CALERIE; CP: Metabolism; CP: Stem cell research; MetRS; PAI-1; caloric restriction; liver; muscle; plasminogen; satellite cell; secretome; stem cell

DOI:  https://doi.org/10.1016/j.celrep.2024.113881
Acta Physiol (Oxf). 2024 Mar 08. e14129

The effect of neuromuscular electrical stimulation on the human skeletal muscle transcriptome.

Johanna Flodin, Stefan M Reitzner, Eric B Emanuelsson, Carl Johan Sundberg, Paul Ackermann.

  AIM: The influence on acute skeletal muscle transcriptomics of neuromuscular electrical stimulation (NMES), as compared to established exercises, is poorly understood. We aimed to investigate the effects on global mRNA-expression in the quadriceps muscle early after a single NMES-session, compared to the effects of voluntary knee extension exercise (EX), and to explore the discomfort level.METHODS: Global vastus lateralis muscle gene expression was assessed (RNA-sequencing) in 30 healthy participants, before and 3 h after a 30-min session of NMES and/or EX. The NMES-treatment was applied using textile electrodes integrated in pants and set to 20% of each participant's pre-tested MVC mean (±SD) 200 (±80) Nm. Discomfort was assessed using Visual Analogue Scale (VAS, 0-10). The EX-protocol was performed at 80% of 1-repetition-maximum.
RESULTS: NMES at 20% of MVC resulted in VAS below 4 and induced 4448 differentially expressed genes (DEGs) with 80%-overlap of the 2571 DEGs of EX. Genes well-known to be up-regulated following exercise, for example, PPARGC1A, ABRA, VEGFA, and GDNF, were also up-regulated by NMES. Gene set enrichment analysis demonstrated many common pathways after EX and NMES. Also, some pathways were exclusive to either EX, for example, muscle tissue proliferation, or to NMES, for example, neurite outgrowth and connective tissue proliferation.
CONCLUSION: A 30-min NMES-session at 20% of MVC with NMES-pants, which can be applied with an acceptable level of discomfort, induces over 4000 DEGs, of which 80%-overlap with DEGs of EX. NMES can induce exercise-like molecular effects, that potentially can lead to health and performance benefits in individuals who are unable to perform resistance exercise.

Keywords:  RNA sequencing; electrical stimulation therapy; gene expression; muscle stimulation; resistance exercise; skeletal muscles; smart textiles

DOI:  https://doi.org/10.1111/apha.14129
Inflammopharmacology. 2024 Mar 07.

Celecoxib attenuates hindlimb unloading-induced muscle atrophy via suppressing inflammation, oxidative stress and ER stress by inhibiting STAT3.

Yanan Ji, Junfei Lin, Ruiqi Liu, Kexin Wang, Mengyuan Chang, Zihui Gao, Boya Liu, Yuntian Shen, Jianwei Zhu, Xinlei Yao, Lei Qi, Hualin Sun.

  Improving inflammation may serve as useful therapeutic interventions for the hindlimb unloading-induced disuse muscle atrophy. Celecoxib is a selective non-steroidal anti-inflammatory drug. We aimed to determine the role and mechanism of celecoxib in hindlimb unloading-induced disuse muscle atrophy. Celecoxib significantly attenuated the decrease in soleus muscle mass, hindlimb muscle function and the shift from slow- to fast-twitch muscle fibers caused by hindlimb unloading in rats. Importantly, celecoxib inhibited the increased expression of inflammatory factors, macrophage infiltration in damaged soleus muscle. Mechanistically, Celecoxib could significantly reduce oxidative stress and endoplasmic reticulum stress in soleus muscle of unloaded rats. Furthermore, celecoxib inhibited muscle proteolysis by reducing the levels of MAFbx, MuRF1, and autophagy related proteins maybe by inhibiting the activation of pro-inflammatory STAT3 pathway in vivo and in vitro. This study is the first to demonstrate that celecoxib can attenuate disuse muscle atrophy caused by hindlimb unloading via suppressing inflammation, oxidative stress and endoplasmic reticulum stress probably, improving target muscle function and reversing the shift of muscle fiber types by inhibiting STAT3 pathways-mediated inflammatory cascade. This study not only enriches the potential molecular regulatory mechanisms, but also provides new potential therapeutic targets for disuse muscle atrophy.

Keywords:  Celecoxib; Hindlimb unloading; Inflammation; Muscle atrophy; Proteolysis

DOI:  https://doi.org/10.1007/s10787-024-01454-7
Biomed Pharmacother. 2024 Mar 05. pii: S0753-3322(24)00264-6. [Epub ahead of print]173 116380

FM19G11-loaded nanoparticles modulate energetic status and production of reactive oxygen species in myoblasts from ALS mice.

Claudia Malacarne, Eleonora Giagnorio, Cristina Chirizzi, Marco Cattaneo, Fulvia Saraceno, Paola Cavalcante, Silvia Bonanno, Renato Mantegazza, Victoria Moreno-Manzano, Giuseppe Lauria, Pierangelo Metrangolo, Francesca Baldelli Bombelli, Stefania Marcuzzo.

  Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. Considerable evidence indicates that early skeletal muscle atrophy plays a crucial role in the disease pathogenesis, leading to an altered muscle-motor neuron crosstalk that, in turn, may contribute to motor neuron degeneration. Currently, there is no effective treatment for ALS, highlighting the need to dig deeper into the pathological mechanisms for developing innovative therapeutic strategies. FM19G11 is a novel drug able to modulate the global cellular metabolism, but its effects on ALS skeletal muscle atrophy and mitochondrial metabolism have never been evaluated, yet. This study investigated whether FM19G11-loaded nanoparticles (NPs) may affect the bioenergetic status in myoblasts isolated from G93A-SOD1 mice at different disease stages. We found that FM19G1-loaded NP treatment was able to increase transcriptional levels of Akt1, Akt3, Mef2a, Mef2c and Ucp2, which are key genes associated with cell proliferation (Akt1, Akt3), muscle differentiation (Mef2c), and mitochondrial activity (Ucp2), in G93A-SOD1 myoblasts. These cells also showed a significant reduction of mitochondrial area and networks, in addition to decreased ROS production after treatment with FM19G11-loaded NPs, suggesting a ROS clearance upon the amelioration of mitochondrial dynamics. Our overall findings demonstrate a significant impact of FM19G11-loaded NPs on muscle cell function and bioenergetic status in G93A-SOD1 myoblasts, thus promising to open new avenues towards possible adoption of FM19G11-based nanotherapies to slow muscle degeneration in the frame of ALS and muscle disorders.

Keywords:  Amyotrophic lateral sclerosis; FM19G11; G93A-SOD1 mouse model; Muscle; Nanomedicine

DOI:  https://doi.org/10.1016/j.biopha.2024.116380
Sci Adv. 2024 Mar 08. 10(10): eadj6411

Childhood adverse life events and skeletal muscle mitochondrial function.

Kate A Duchowny, David J Marcinek, Theresa Mau, L Grisell Diaz-Ramierz, Li-Yung Lui, Frederico G S Toledo, Peggy M Cawthon, Russell T Hepple, Philip A Kramer, Anne B Newman, Stephen B Kritchevsky, Steven R Cummings, Paul M Coen, Anthony J A Molina.

Social stress experienced in childhood is associated with adverse health later in life. Mitochondrial function has been implicated as a mechanism for how stressful life events "get under the skin" to influence physical well-being. Using data from the Study of Muscle, Mobility, and Aging (n = 879, 59% women), linear models examined whether adverse childhood events (i.e., physical abuse) were associated with two measures of skeletal muscle mitochondrial energetics in older adults: (i) maximal adenosine triphosphate production (ATPmax) and (ii) maximal state 3 respiration (Max OXPHOS). Forty-five percent of the sample reported experiencing one or more adverse childhood events. After adjustment, each additional event was associated with -0.08 SD (95% confidence interval = -0.13, -0.02) lower ATPmax. No association was observed with Max OXPHOS. Adverse childhood events are associated with lower ATP production in later life. Findings indicate that mitochondrial function may be a mechanism for understanding how early social stress influences health in later life.

DOI: https://doi.org/10.1126/sciadv.adj6411
Front Physiol. 2024 ;15 1368646

Effects of low-load resistance training with blood flow restriction on muscle fiber myofibrillar and extracellular area.

Cleiton A Libardi, Joshua S Godwin, Tanner M Reece, Carlos Ugrinowitsch, Trent J Herda, Michael D Roberts.

  Blood flow restriction applied during low-load resistance training (LL-BFR) induces a similar increase in the cross-sectional area of muscle fibers (fCSA) compared to traditional high-load resistance training (HL-RT). However, it is unclear whether LL-BFR leads to differential changes in myofibrillar spacing in muscle fibers and/or extracellular area compared to HL-RT. Therefore, this study aimed to investigate whether the hypertrophy of type I and II fibers induced by LL-BFR or HL-RT is accompanied by differential changes in myofibrillar and non-myofibrillar areas. In addition, we examined if extracellular spacing was differentially affected between these two training protocols. Twenty recreationally active participants were assigned to LL-BFR or HL-RT groups and underwent a 6-week training program. Muscle biopsies were taken before and after the training period. The fCSA of type I and II fibers, the area occupied by myofibrillar and non-myofibrillar components, and extracellular spacing were analyzed using immunohistochemistry techniques. Despite the significant increase in type II and mean (type I + II) fCSA (p < 0.05), there were no significant changes in the proportionality of the myofibrillar and non-myofibrillar areas [∼86% and ∼14%, respectively (p > 0.05)], indicating that initial adaptations to LL-BFR are primarily characterized by conventional hypertrophy rather than disproportionate non-myofibrillar expansion. Additionally, extracellular spacing was not significantly altered between protocols. In summary, our study reveals that LL-BFR, like HL-RT, induces skeletal muscle hypertrophy with proportional changes in the areas occupied by myofibrillar, non-myofibrillar, and extracellular components.

Keywords:  exercise; extracellular matrix; myofibers; myofibrils; vascular occlusion

DOI:  https://doi.org/10.3389/fphys.2024.1368646
Skelet Muscle. 2024 Mar 07. 14(1): 5

Motor neurons and endothelial cells additively promote development and fusion of human iPSC-derived skeletal myocytes.

Suradip Das, Melanie C Hilman, Feikun Yang, Foteini Mourkioti, Wenli Yang, D Kacy Cullen.

BACKGROUND: Neurovascular cells have wide-ranging implications on skeletal muscle biology regulating myogenesis, maturation, and regeneration. Although several in vitro studies have investigated how motor neurons and endothelial cells interact with skeletal myocytes independently, there is limited knowledge about the combined effect of neural and vascular cells on muscle maturation and development.METHODS: Here, we report a triculture system comprising human-induced pluripotent stem cell (iPSC)-derived skeletal myocytes, human iPSC-derived motor neurons, and primary human endothelial cells maintained under controlled media conditions. Briefly, iPSCs were differentiated to generate skeletal muscle progenitor cells (SMPCs). These SMPCs were seeded at a density of 5 × 104 cells/well in 12-well plates and allowed to differentiate for 7 days before adding iPSC-derived motor neurons at a concentration of 0.5 × 104 cells/well. The neuromuscular coculture was maintained for another 7 days in coculture media before addition of primary human umbilical vein endothelial cells (HUVEC) also at 0.5 × 104 cells/well. The triculture was maintained for another 7 days in triculture media comprising equal portions of muscle differentiation media, coculture media, and vascular media. Extensive morphological, genetic, and molecular characterization was performed to understand the combined and individual effects of neural and vascular cells on skeletal muscle maturation.
RESULTS: We observed that motor neurons independently promoted myofiber fusion, upregulated neuromuscular junction genes, and maintained a molecular niche supportive of muscle maturation. Endothelial cells independently did not support myofiber fusion and downregulated expression of LRP4 but did promote expression of type II specific myosin isoforms. However, neurovascular cells in combination exhibited additive increases in myofiber fusion and length, enhanced production of Agrin, along with upregulation of several key genes like MUSK, RAPSYN, DOK-7, and SLC2A4. Interestingly, more divergent effects were observed in expression of genes like MYH8, MYH1, MYH2, MYH4, and LRP4 and secretion of key molecular factors like amphiregulin and IGFBP-4.
CONCLUSIONS: Neurovascular cells when cultured in combination with skeletal myocytes promoted myocyte fusion with concomitant increase in expression of various neuromuscular genes. This triculture system may be used to gain a deeper understanding of the effects of the neurovascular niche on skeletal muscle biology and pathophysiology.

DOI: https://doi.org/10.1186/s13395-024-00336-4
Development. 2024 Mar 08. pii: dev.202387. [Epub ahead of print]

Cadherin-dependent adhesion is required for muscle stem cell niche anchorage and maintenance.

Margaret Hung, Hsiao-Fan Lo, Aviva G Beckmann, Deniz Demircioglu, Gargi Damle, Dan Hasson, Glenn L Radice, Robert S Krauss.

  Adhesion between stem cells and their niche provides stable anchorage and signaling cues to sustain properties such as quiescence. Skeletal muscle stem cells (MuSCs) adhere to an adjacent myofiber via cadherin-catenin complexes. Previous studies on N- and M-cadherin in MuSCs revealed that while N-cadherin is required for quiescence, they are collectively dispensable for MuSC niche localization and regenerative activity. Although additional cadherins are expressed at low levels, these findings raise the possibility that cadherins are unnecessary for MuSC anchorage to the niche. To address this question, we conditionally removed from MuSCs b- and g-catenin and, separately, aE- and aT-catenin, factors essential for cadherin-dependent adhesion. Catenin-deficient MuSCs break quiescence similarly to N-/M-cadherin-deficient MuSCs, but exit the niche, and are depleted. Combined in vivo, ex vivo, and single cell RNA sequencing approaches reveal that MuSC attrition occurs via precocious differentiation, reentry to the niche, and fusion to myofibers. These findings indicate that cadherin-catenin-dependent adhesion is required for anchorage of MuSCs to their niche and preservation of the stem cell compartment. Furthermore, separable, cadherin-regulated functions govern niche localization, quiescence, and MuSC maintenance.

Keywords:  Cell adhesion; Cell signaling; Muscle stem cell; Quiescence; Stem cell niche

DOI:  https://doi.org/10.1242/dev.202387
J Appl Physiol (1985). 2024 Mar 07.

Social jetlag impairs exercise volume and attenuates physiological and metabolic adaptations to voluntary exercise training.

Michael B Dial, Elias M Malek, Austin R Cooper, Greco A Neblina, Nikoleta I Vasileva, Dustin J Hines, Graham R McGinnis.

  Social jetlag (SJL) is a misalignment between sleep and wake times on workdays and free days. SJL leads to chronic circadian rhythm disruption and may affect nearly 70% of the general population, leading to increased risk for cardiometabolic diseases. This study investigated the effects of SJL on metabolic health, exercise performance, and exercise-induced skeletal muscle adaptations in mice. 10-week-old C57BL/6J mice (n=40) were allocated to four groups; control sedentary (CON-SED), control exercise (CON-EX), social jetlag sedentary (SJL-SED), and social jetlag exercise (SJL-EX). CON mice were housed under a 12hr light:dark cycle. SJL was simulated by implementing a 4-hour phase delay for three days to simulate 'weekends,' followed by a 4-hour phase advance back to 'weekdays,' for six weeks. EX mice had free access to a running wheel. Graded exercise tests (GXT) and glucose tolerance tests (GTT) were performed at baseline and post intervention to monitor the effects of exercise and social jetlag on cardiorespiratory and metabolic health, respectively. SJL led to alterations in activity and running patterns and clock gene expression in skeletal muscle, and decreased average running distance (p<0.05). SJL-SED mice gained significantly more weight compared to CON-SED and SJL-EX (p<0.01). SJL impaired fasting blood glucose and glucose tolerance compared to CON mice (p<0.05), which was partially restored by exercise in SJL-EX mice. SJL also blunted improvements in exercise performance and mitochondrial content in the quadriceps. These data suggest that SJL blunted some cardiometabolic adaptations to exercise, and that proper circadian hygiene is necessary for maintaining health and performance.

Keywords:  Cardiometabolic Disease; Circadian Rhythm Disruption; Exercise Performance; Glucose Tolerance; Social Jetlag

DOI:  https://doi.org/10.1152/japplphysiol.00632.2023
Comput Biol Med. 2024 Feb 28. pii: S0010-4825(24)00317-2. [Epub ahead of print]172 108233

Transcriptomic signature of cancer cachexia by integration of machine learning, literature mining and meta-analysis.

Kening Zhao, Esmaeil Ebrahimie, Manijeh Mohammadi-Dehcheshmeh, Mathew G Lewsey, Lei Zheng, Nick J Hoogenraad.

  BACKGROUND: Cancer cachexia is a severe metabolic syndrome marked by skeletal muscle atrophy. A successful clinical intervention for cancer cachexia is currently lacking. The study of cachexia mechanisms is largely based on preclinical animal models and the availability of high-throughput transcriptomic datasets of cachectic mouse muscles is increasing through the extensive use of next generation sequencing technologies.METHODS: Cachectic mouse muscle transcriptomic datasets of ten different studies were combined and mined by seven attribute weighting models, which analysed both categorical variables and numerical variables. The transcriptomic signature of cancer cachexia was identified by attribute weighting algorithms and was used to evaluate the performance of eleven pattern discovery models. The signature was employed to find the best combination of drugs (drug repurposing) for developing cancer cachexia treatment strategies, as well as to evaluate currently used cachexia drugs by literature mining.
RESULTS: Attribute weighting algorithms ranked 26 genes as the transcriptomic signature of muscle from mice with cancer cachexia. Deep Learning and Random Forest models performed better in differentiating cancer cachexia cases based on muscle transcriptomic data. Literature mining revealed that a combination of melatonin and infliximab has negative interactions with 2 key genes (Rorc and Fbxo32) upregulated in the transcriptomic signature of cancer cachexia in muscle.
CONCLUSIONS: The integration of machine learning, meta-analysis and literature mining was found to be an efficient approach to identifying a robust transcriptomic signature for cancer cachexia, with implications for improving clinical diagnosis and management of this condition.

Keywords:  Cancer cachexia; Drug discovery; Literature mining; Machine learning; Transcriptomics

DOI:  https://doi.org/10.1016/j.compbiomed.2024.108233
Nat Commun. 2024 Mar 02. 15(1): 1950

fhl2b mediates extraocular muscle protection in zebrafish models of muscular dystrophies and its ectopic expression ameliorates affected body muscles.

Nils Dennhag, Abraha Kahsay, Itzel Nissen, Hanna Nord, Maria Chermenina, Jiao Liu, Anders Arner, Jing-Xia Liu, Ludvig J Backman, Silvia Remeseiro, Jonas von Hofsten, Fatima Pedrosa Domellöf.

In muscular dystrophies, muscle fibers loose integrity and die, causing significant suffering and premature death. Strikingly, the extraocular muscles (EOMs) are spared, functioning well despite the disease progression. Although EOMs have been shown to differ from body musculature, the mechanisms underlying this inherent resistance to muscle dystrophies remain unknown. Here, we demonstrate important differences in gene expression as a response to muscle dystrophies between the EOMs and trunk muscles in zebrafish via transcriptomic profiling. We show that the LIM-protein Fhl2 is increased in response to the knockout of desmin, plectin and obscurin, cytoskeletal proteins whose knockout causes different muscle dystrophies, and contributes to disease protection of the EOMs. Moreover, we show that ectopic expression of fhl2b can partially rescue the muscle phenotype in the zebrafish Duchenne muscular dystrophy model sapje, significantly improving their survival. Therefore, Fhl2 is a protective agent and a candidate target gene for therapy of muscular dystrophies.

DOI: https://doi.org/10.1038/s41467-024-46187-x
Pflugers Arch. 2024 Mar 06.

Locally applied heat stress during exercise training may promote adaptations to mitochondrial enzyme activities in skeletal muscle.

Ed Maunder, Andrew King, Jeffrey A Rothschild, Matthew J Brick, Warren B Leigh, Christopher P Hedges, Troy L Merry, Andrew E Kilding.

  There is some evidence for temperature-dependent stimulation of mitochondrial biogenesis; however, the role of elevated muscle temperature during exercise in mitochondrial adaptation to training has not been studied in humans in vivo. The purpose of this study was to determine the role of elevating muscle temperature during exercise in temperate conditions through the application of mild, local heat stress on mitochondrial adaptations to endurance training. Eight endurance-trained males undertook 3 weeks of supervised cycling training, during which mild (~ 40 °C) heat stress was applied locally to the upper-leg musculature of one leg during all training sessions (HEAT), with the contralateral leg serving as the non-heated, exercising control (CON). Vastus lateralis microbiopsies were obtained from both legs before and after the training period. Training-induced increases in complex I (fold-change, 1.24 ± 0.33 vs. 1.01 ± 0.49, P = 0.029) and II (fold-change, 1.24 ± 0.33 vs. 1.01 ± 0.49, P = 0.029) activities were significantly larger in HEAT than CON. No significant effects of training, or interactions between local heat stress application and training, were observed for complex I-V or HSP70 protein expressions. Our data provides partial evidence to support the hypothesis that elevating local muscle temperature during exercise augments training-induced adaptations to mitochondrial enzyme activity.

Keywords:  Exercise; Heat; Mitochondria; Muscle

DOI:  https://doi.org/10.1007/s00424-024-02939-8
Acta Physiol (Oxf). 2024 Mar 08. e14131

Muscle physiology and its relations to the whole body in health and disease.

Kathrin Groeneveld.

  Over the past years, researchers increased awareness of the connection of muscle tissue to the rest of the human body and of the possibilities to tweak the muscles' metabolism in order to gain positive effects on whole body metabolism, energy balance, and immune system. Physiotherapists and doctors aim to find practical exercise guidelines for patients to follow for ideal treatment. To do so, much research is happening to understand the complexity of muscle-body balance. This article reviews the most recent research in this topic that was published by ActaPhysiologica.

Keywords:  muscle physiology; skeletal muscle tissue

DOI:  https://doi.org/10.1111/apha.14131
Semin Cell Dev Biol. 2024 Mar 01. pii: S1084-9521(24)00022-3. [Epub ahead of print]161-162 1-19

The interplay between mitochondrial dynamics and autophagy: From a key homeostatic mechanism to a driver of pathology.

Alice Lacombe, Luca Scorrano.

  The complex relationship between mitochondrial dynamics and autophagy illustrates how two cellular housekeeping processes are intimately linked, illuminating fundamental principles of cellular homeostasis and shedding light on disparate pathological conditions including several neurodegenerative disorders. Here we review the basic tenets of mitochondrial dynamics i.e., the concerted balance between fusion and fission of the organelle, and its interplay with macroautophagy and selective mitochondrial autophagy, also dubbed mitophagy, in the maintenance of mitochondrial quality control and ultimately in cell viability. We illustrate how conditions of altered mitochondrial dynamics reverberate on autophagy and vice versa. Finally, we illustrate how altered interplay between these two key cellular processes participates in the pathogenesis of human disorders affecting multiple organs and systems.

Keywords:  Mitochondria; autophagy; diseases; fusion-fission; mitophagy

DOI:  https://doi.org/10.1016/j.semcdb.2024.02.001
J Toxicol. 2024 ;2024 3840950

Bisphenol-A Abrogates Proliferation and Differentiation of C2C12 Mouse Myoblasts via Downregulation of Phospho-P65 NF-κB Signaling Pathway.

Chittipong Tipbunjong, Thanvarin Thitiphatphuvanon, Chumpol Pholpramool, Piyaporn Surinlert.

Previous studies showed that bisphenol-A (BPA), a monomer of polycarbonate plastic, is leached out and contaminated in foods and beverages. This study aimed to investigate the effects of BPA on the myogenesis of adult muscle stem cells. C2C12 myoblasts were treated with BPA in both proliferation and differentiation conditions. Cytotoxicity, cell proliferation and differentiation, antioxidant activity, apoptosis, myogenic regulatory factors (MRFs) gene expression, and mechanism of BPA on myogenesis were examined. C2C12 myoblasts exposed to 25-50 µM BPA showed abnormal morphology, expressing numerous and long cytoplasmic extensions. Cell proliferation was inhibited and was accumulated in subG1 and S phases of the cell cycle, subsequently leading to apoptosis confirmed by nuclear condensation and the expression of apoptosis markers, cleaved caspase-9 and caspase-3. In addition, the activity of antioxidant enzymes, catalase, superoxide dismutase, and glutathione peroxidase was significantly decreased. Meanwhile, BPA suppressed myoblast differentiation by decreasing the number and size of multinucleated myotubes via the modulation of MRF gene expression. Moreover, BPA significantly inhibited the phosphorylation of P65 NF-κB in both proliferation and differentiation conditions. Altogether, the results revealed the adverse effects of BPA on myogenesis leading to abnormal growth and development via the inhibition of phospho-P65 NF-κB.

DOI: https://doi.org/10.1155/2024/3840950