bims-mitrat 2025-01-12 papers

bims-mitrat

Biomed News

on Mitochondrial transplantation and transfer

Issue of 2025–01–12
thirteen papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute

Enhancing fat graft survival: thymosin beta-4 facilitates mitochondrial transfer from ADSCs via tunneling nanotubes by upregulating the Rac/F-actin pathway.
[The impact of mitochondrial transfer on leukemia progression].
Safety and efficacy of mesenchymal stromal cells mitochondria transplantation as a cell-free therapy for osteoarthritis.
The adaptor protein Miro1 modulates horizontal transfer of mitochondria in mouse melanoma models.
Intravenous administration of mitochondria improves ovarian function by anti-apoptosis in the premature ovarian insufficiency model.
Mitochondrial diseases: from molecular mechanisms to therapeutic advances.
Mitochondria- and ER-associated actin are required for mitochondrial fusion.
Regulation of calcium homeostasis in endoplasmic reticulum-mitochondria crosstalk: implications for skeletal muscle atrophy.
MitoMAMMAL: a genome scale model of mammalian mitochondria predicts cardiac and BAT metabolism.
Inhibition of Mitochondrial Fission Protein Drp1 Ameliorates Myopathy in the D2-mdx Model of Duchenne Muscular Dystrophy.
E-cigarette-induced changes in cell stress and mitochondrial function.
BNIP3 Downregulation Ameliorates Muscle Atrophy in Cancer Cachexia.
The effect of exercise and physical activity on skeletal muscle epigenetics and metabolic adaptations.

Free Radic Biol Med. 2025 Jan 04. pii: S0891-5849(24)01170-5. [Epub ahead of print]

Enhancing fat graft survival: thymosin beta-4 facilitates mitochondrial transfer from ADSCs via tunneling nanotubes by upregulating the Rac/F-actin pathway.

Xiaoyu Zhang, Yan Lin, Haoran Li, Qian Wang, Dali Mu.

  Autologous fat grafting is a widely used technique in plastic and reconstructive surgery, but its efficacy is often limited by the poor survival rate of transplanted adipose tissue. This study aims to enhance the survival of fat grafts by investigating the role of thymosin beta-4 (Tβ4) in facilitating mitochondrial transfer from adipose-derived stem cells (ADSCs) to adipocytes and newly formed blood vessels within the grafts via tunneling nanotubes (TNTs). We demonstrate that Tβ4 upregulates the Rac/F-actin pathway, leading to an increased formation of TNTs and subsequent transfer of mitochondria from ADSCs. This process mitigates oxidative stress, reduces apoptosis, and promotes revascularization, thereby improving the quality and volume retention of fat grafts. Our findings provide a novel mechanistic insight into the enhancement of fat graft survival and suggest Tβ4 as a potential therapeutic agent to improve clinical outcomes in autologous fat transfer procedures.

Keywords:  Adipose-derived Stem Cells; Fat Grafting; Mitochondrial Transfer; Thymosin Beta-4; Tunneling Nanotubes

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.12.061
Sheng Li Xue Bao. 2024 Dec 25. 76(6): 943-952

[The impact of mitochondrial transfer on leukemia progression].

Wen-Jia Fang, Biao Zhang, Tao Cheng, Hui Cheng.

The objective of the present study was to investigate the role and mechanism of bone marrow microenvironmental cells in regulating the mitochondrial mass of leukemia cells, and to uncover the mechanism of leukemia progression at the metabolic level. A mouse model of acute myeloid leukemia (AML) induced by the overexpression of the MLL-AF9 (MA9) fusion protein was established, and the bone marrow cells of AML mice were transplanted into mitochondrial fluorescence reporter mice expressing the Dendra2 protein (mito-Dendra2 mice). The proportion of Dendra2+ cells in bone marrow leukemia cells at different stages of AML was quantified by flow cytometry. The effects of transferred mitochondria on leukemia cells were studied by fluorescence-activated cell sorting (FACS), followed by functional experiments and bulk RNA sequencing. Finally, components within the bone marrow niche, such as mesenchymal stromal cells (MSCs) and endothelial cells (ECs), were co-cultured with leukemia cells in vitro. The proportion of leukemia cells that underwent mitochondrial transfer and the apoptosis level of leukemia cells were then detected by flow cytometry. The results showed that mitochondria from bone marrow cells were transferred to leukemia cells in the AML mouse model, and the proportion of mitochondrial transfer decreased with AML progression. The proportion of mitochondria transferred to leukemia stem cells (LSCs) was lower than that of mature AML cells. In AML cells receiving Dendra2+ mitochondria, there was a significant increase in the levels of intracellular reactive oxygen species (ROS) and apoptosis, while the levels of protein translation and their colony-forming capacities were decreased. The transplantation of Dendra2+ AML cells resulted in an extension of the survival of mice. RNA sequencing analysis demonstrated a significant downregulation of pathways related to translation, aerobic respiration and mitochondrial organization in AML cells that had received mitochondria. In vitro co-culture experiments indicated that MSCs within the bone marrow niche tended to transfer their mitochondria to leukemia cells and promoted the apoptosis of leukemia cells. These results indicate that in the MA9-induced AML mouse model, bone marrow niche cells can transfer mitochondria to leukemia cells, resulting in a reduction in the overall survival and function of the leukemia cells. Mitochondrial transfer in the bone marrow microenvironment may serve as a self-defensive mechanism of the host bone marrow niche cells, inhibiting the progression of AML.
J Transl Med. 2025 Jan 07. 23(1): 26

Safety and efficacy of mesenchymal stromal cells mitochondria transplantation as a cell-free therapy for osteoarthritis.

Ana Maria Vega-Letter, Cynthia García-Guerrero, Liliana Yantén-Fuentes, Carolina Pradenas, Yeimi Herrera-Luna, Eliana Lara-Barba, Felipe A Bustamante-Barrientos, Masyelly Rojas, María Jesús Araya, Nicole Jeraldo, Constanza Aros, Francisca Troncoso, Daniela Poblete, Angela Court, Alexander Ortloff, Jose Barraza, Francesca Velarde, Carlos Farkas, Claudio Carril, Noymar Luque-Campos, Gonzalo Almarza, Maximiliano Barahona, Jose Matas, Lucas Cereceda, Rocío Lorca, Jorge Toledo, Karina Oyarce, Rolando Vernal, Andrés Caicedo, Andrea Del Campo, Yessia Hidalgo, Roberto Elizondo-Vega, Farida Djouad, Maroun Khoury, Fernando E Figueroa, Patricia Luz-Crawford.

   OBJECTIVE: The inflammatory responses from synovial fibroblasts and macrophages and the mitochondrial dysfunction in chondrocytes lead to oxidative stress, disrupt extracellular matrix (ECM) homeostasis, and accelerate the deterioration process of articular cartilage in osteoarthritis (OA). In recent years, it has been proposed that mesenchymal stromal cells (MSC) transfer their functional mitochondria to damaged cells in response to cellular stress, becoming one of the mechanisms underpinning their therapeutic effects. Therefore, we hypothesize that a novel cell-free treatment for OA could involve direct mitochondria transplantation, restoring both cellular and mitochondrial homeostasis.
METHODS: Mitochondria were isolated from Umbilical Cord (UC)-MSC (Mito-MSC) and characterized based on their morphology, phenotype, functions, and their ability to be internalized by different articular cells. Furthermore, the transcriptional changes following mitochondrial uptake by chondrocytes were evaluated using an Affymetrix analysis, Lastly, the dose dependence therapeutic efficacy, biodistribution and immunogenicity of Mito-MSC were assessed in vivo, through an intra-articular injection in male C57BL6 mice in a collagenase-induced OA (CIOA) model.
RESULTS: Our findings demonstrate the functional integrity of Mito-MSC and their ability to be efficiently transferred into chondrocytes, synovial macrophages, and synovial fibroblasts. Moreover, the transcriptomic analysis showed the upregulation of genes involved in stress such as DNA reparative machinery and inflammatory antiviral responses. Finally, Mito-MSC transplantation yielded significant reductions in joint mineralization, a hallmark of OA progression, as well as improvements in OA-related histological signs, with the lower dose exhibiting better therapeutic efficacy. Furthermore, Mito-MSC was detected within the knee joint for up to 24 h post-injection without eliciting an inflammatory response in CIOA mice.
CONCLUSION: Collectively, our results reveal that mitochondria derived from MSC are transferred to key articular cells and are retained in the joint without generating an inflammatory immune response mitigating articular cartilage degradation in OA, probably through a restorative effect triggered by the stress antiviral response within OA chondrocytes.

Keywords:  Biodistribution; Immuno-safety; Mesenchymal stromal cells; Mitochondria transplantation; Murine OA model; Osteoarthritis

DOI:  https://doi.org/10.1186/s12967-024-05945-7
Cell Rep. 2025 Jan 09. pii: S2211-1247(24)01505-5. [Epub ahead of print]44(1): 115154

The adaptor protein Miro1 modulates horizontal transfer of mitochondria in mouse melanoma models.

Jaromir Novak, Zuzana Nahacka, Gabriela L Oliveira, Petra Brisudova, Maria Dubisova, Sarka Dvorakova, Sona Miklovicova, Marketa Dalecka, Verena Puttrich, Lenka Grycova, Silvia Magalhaes-Novais, Catarina Mendes Correia, Jennifer Levoux, Ludek Stepanek, Jan Prochazka, David Svec, David Pajuelo Reguera, Guillermo Lopez-Domenech, Renata Zobalova, Radek Sedlacek, Mikkel G Terp, Payam A Gammage, Zdenek Lansky, Josef Kittler, Paulo J Oliveira, Henrik J Ditzel, Michael V Berridge, Anne-Marie Rodriguez, Stepana Boukalova, Jakub Rohlena, Jiri Neuzil.

  Recent research has shown that mtDNA-deficient cancer cells (ρ0 cells) acquire mitochondria from tumor stromal cells to restore respiration, facilitating tumor formation. We investigated the role of Miro1, an adaptor protein involved in movement of mitochondria along microtubules, in this phenomenon. Inducible Miro1 knockout (Miro1KO) mice markedly delayed tumor formation after grafting ρ0 cancer cells. Miro1KO mice with fluorescently labeled mitochondria revealed that this delay was due to hindered mitochondrial transfer from the tumor stromal cells to grafted B16 ρ0 cells, which impeded recovery of mitochondrial respiration and tumor growth. Miro1KO led to the perinuclear accumulation of mitochondria and impaired mobility of the mitochondrial network. In vitro experiments revealed decreased association of mitochondria with microtubules, compromising mitochondrial transfer via tunneling nanotubes (TNTs) in mesenchymal stromal cells. Here we show the role of Miro1 in horizontal mitochondrial transfer in mouse melanoma models in vivo and its involvement with TNTs.

Keywords:  CP: Cancer; CP: Cell biology; Miro1; RHOT1; cancer; horizontal transfer of mitochondria; melanoma; mitochondria; tunneling nanotubes

DOI:  https://doi.org/10.1016/j.celrep.2024.115154
Climacteric. 2025 Jan 10. 1-12

Intravenous administration of mitochondria improves ovarian function by anti-apoptosis in the premature ovarian insufficiency model.

Han-Lin Yang, Yuan-Mei Wang, Qing Li, Hao Luo, Jun Tan, Xing Zhao, Dan Zi.

   OBJECTIVE: For patients with contraindications to hormone therapy, the absence of effective treatments for ovarian dysfunction post chemotherapy represents a critical issue requiring resolution. Local administration of mitochondria may enhance ovarian function in premature ovarian insufficiency (POI) by ameliorating diminished mitochondrial activity. Nevertheless, there is a paucity of literature on the efficacy of mitochondrial transplantation through intravenous injection, a less invasive and more convenient method than local injection, for the improvement of ovarian function in POI following chemotherapy.
METHOD: Mitochondria were isolated from mouse livers, their activity and integrity were validated with MitoTracker Red and their localization was examined via confocal microscopy, real-time quantitative PCR and enzyme-linked immunosorbent assay post tail vein injection. An ovarian insufficiency animal model induced by chemotherapy was developed, and ovarian function was assessed through ovarian diameter, vaginal smear, body weight, sex hormone levels and histological analysis. The impact of mitochondrial transplantation on an ovarian cell model was examined through the assessment of mitochondrial function, apoptosis and levels of reactive oxygen species.
CONCLUSION: Tail vein injection of isolated mitochondria has the potential to enhance ovarian functions in an animal model of POI induced by cyclophosphamide, increase mitochondrial activity in impaired ovarian cells and decrease the rate of apoptosis.

Keywords:  Chemotherapy; apoptosis; isolated mitochondria; mitochondrial transplantation; premature ovarian insufficiency

DOI:  https://doi.org/10.1080/13697137.2024.2441248
Signal Transduct Target Ther. 2025 Jan 10. 10(1): 9

Mitochondrial diseases: from molecular mechanisms to therapeutic advances.

Haipeng Wen, Hui Deng, Bingyan Li, Junyu Chen, Junye Zhu, Xian Zhang, Shigeo Yoshida, Yedi Zhou.

Mitochondria are essential for cellular function and viability, serving as central hubs of metabolism and signaling. They possess various metabolic and quality control mechanisms crucial for maintaining normal cellular activities. Mitochondrial genetic disorders can arise from a wide range of mutations in either mitochondrial or nuclear DNA, which encode mitochondrial proteins or other contents. These genetic defects can lead to a breakdown of mitochondrial function and metabolism, such as the collapse of oxidative phosphorylation, one of the mitochondria's most critical functions. Mitochondrial diseases, a common group of genetic disorders, are characterized by significant phenotypic and genetic heterogeneity. Clinical symptoms can manifest in various systems and organs throughout the body, with differing degrees and forms of severity. The complexity of the relationship between mitochondria and mitochondrial diseases results in an inadequate understanding of the genotype-phenotype correlation of these diseases, historically making diagnosis and treatment challenging and often leading to unsatisfactory clinical outcomes. However, recent advancements in research and technology have significantly improved our understanding and management of these conditions. Clinical translations of mitochondria-related therapies are actively progressing. This review focuses on the physiological mechanisms of mitochondria, the pathogenesis of mitochondrial diseases, and potential diagnostic and therapeutic applications. Additionally, this review discusses future perspectives on mitochondrial genetic diseases.

DOI: https://doi.org/10.1038/s41392-024-02044-3
Nat Commun. 2025 Jan 07. 16(1): 451

Mitochondria- and ER-associated actin are required for mitochondrial fusion.

Priya Gatti, Cara Schiavon, Julien Cicero, Uri Manor, Marc Germain.

Mitochondria are crucial for cellular metabolism and signalling. Mitochondrial activity is modulated by mitochondrial fission and fusion, which are required to properly balance metabolic functions, transfer material between mitochondria, and remove defective mitochondria. Mitochondrial fission occurs at mitochondria-endoplasmic reticulum (ER) contact sites, and requires the formation of actin filaments that drive mitochondrial constriction and the recruitment of the fission protein DRP1. The role of actin in mitochondrial fusion remains entirely unexplored. Here we show that preventing actin polymerisation on either mitochondria or the ER disrupts both fission and fusion. We show that fusion but not fission is dependent on Arp2/3, whereas both fission and fusion require INF2 formin-dependent actin polymerization. We also show that mitochondria-associated actin marks fusion sites prior to the fusion protein MFN2. Together, our work introduces a method for perturbing organelle-associated actin and demonstrates a previously unknown role for actin in mitochondrial fusion.

DOI: https://doi.org/10.1038/s41467-024-55758-x
Cell Commun Signal. 2025 Jan 09. 23(1): 17

Regulation of calcium homeostasis in endoplasmic reticulum-mitochondria crosstalk: implications for skeletal muscle atrophy.

Xuexin Li, Xin Zhao, Zhengshan Qin, Jie Li, Bowen Sun, Li Liu.

  This review comprehensively explores the critical role of calcium as an essential small-molecule biomessenger in skeletal muscle function. Calcium is vital for both regulating muscle excitation-contraction coupling and for the development, maintenance, and regeneration of muscle cells. The orchestrated release of calcium from the endoplasmic reticulum (ER) is mediated by receptors such as the ryanodine receptor (RYR) and inositol 1,4,5-trisphosphate receptor (IP3R), which is crucial for skeletal muscle contraction. The sarcoendoplasmic reticulum calcium ATPase (SERCA) pump plays a key role in recapturing calcium, enabling the muscle to return to a relaxed state. A pivotal aspect of calcium homeostasis involves the dynamic interaction between mitochondria and the ER. This interaction includes local calcium signaling facilitated by RYRs and a "quasi-synaptic" mechanism formed by the IP3R-Grp75-VDAC/MCU axis, allowing rapid calcium uptake by mitochondria with minimal interference at the cytoplasmic level. Disruption of calcium transport can lead to mitochondrial calcium overload, triggering the opening of the mitochondrial permeability transition pore and subsequent release of reactive oxygen species and cytochrome C, ultimately resulting in muscle damage and atrophy. This review explores the complex relationship between the ER and mitochondria and how these organelles regulate calcium levels in skeletal muscle, aiming to provide valuable perspectives for future research on the pathogenesis of muscle diseases and the development of prevention strategies.

Keywords:  Atrophy; Calcium; Endoplasmic reticulum; Mitochondria; Skeletal muscle

DOI:  https://doi.org/10.1186/s12964-024-02014-w
Bioinform Adv. 2025 ;5(1): vbae172

MitoMAMMAL: a genome scale model of mammalian mitochondria predicts cardiac and BAT metabolism.

Stephen Chapman, Theo Brunet, Arnaud Mourier, Bianca H Habermann.

Motivation: Mitochondria are essential for cellular metabolism and are inherently flexible to allow correct function in a wide range of tissues. Consequently, dysregulated mitochondrial metabolism affects different tissues in different ways leading to challenges in understanding the pathology of mitochondrial diseases. System-level metabolic modelling is useful in studying tissue-specific mitochondrial metabolism, yet despite the mouse being a common model organism in research, no mouse specific mitochondrial metabolic model is currently available.
Results: Building upon the similarity between human and mouse mitochondrial metabolism, we present mitoMammal, a genome-scale metabolic model that contains human and mouse specific gene-product reaction rules. MitoMammal is able to model mouse and human mitochondrial metabolism. To demonstrate this, using an adapted E-Flux algorithm, we integrated proteomic data from mitochondria of isolated mouse cardiomyocytes and mouse brown adipocyte tissue, as well as transcriptomic data from in vitro differentiated human brown adipocytes and modelled the context specific metabolism using flux balance analysis. In all three simulations, mitoMammal made mostly accurate, and some novel predictions relating to energy metabolism in the context of cardiomyocytes and brown adipocytes. This demonstrates its usefulness in research in cardiac disease and diabetes in both mouse and human contexts.
Availability and implementation: The MitoMammal Jupyter Notebook is available at: https://gitlab.com/habermann_lab/mitomammal.

DOI: https://doi.org/10.1093/bioadv/vbae172
bioRxiv. 2024 Dec 26. pii: 2024.12.26.628172. [Epub ahead of print]

Inhibition of Mitochondrial Fission Protein Drp1 Ameliorates Myopathy in the D2-mdx Model of Duchenne Muscular Dystrophy.

H Grace Rosen, Nicolas J Berger, Shantel N Hodge, Atsutaro Fujishiro, Jared Lourie, Vrusti Kapadia, Melissa A Linden, Eunbin Jee, Jonghan Kim, Yuho Kim, Kai Zou.

Although current treatments for Duchenne Muscular Dystrophy (DMD) have proven to be effective in delaying myopathy, there remains a strong need to identify novel targets to develop additional therapies. Mitochondrial dysfunction is an early pathological feature of DMD. A fine balance of mitochondrial dynamics (fission and fusion) is crucial to maintain mitochondrial function and skeletal muscle health. Excessive activation of Dynamin-Related Protein 1 (Drp1)-mediated mitochondrial fission was reported in animal models of DMD. However, whether Drp1-mediated mitochondrial fission is a viable target for treating myopathy in DMD remains unknown. Here, we treated a D2-mdx model of DMD (9-10 weeks old) with Mdivi-1, a selective Drp1 inhibitor, every other day (i.p. injection) for 5 weeks. We demonstrated that Mdivi-1 effectively improved skeletal muscle strength and reduced serum creatine kinase concentration. Mdivi-1 treatment also effectively inhibited mitochondrial fission regulatory protein markers, Drp1(Ser616) phosphorylation and Fis1 in skeletal muscles from D2-mdx mice, which resulted in reduced content of damaged and fragmented mitochondria. Furthermore, Mdivi-1 treatment attenuated lipid peroxidation product, 4-HNE, in skeletal muscle from D2-mdx mice, which was inversely correlated with muscle grip strength. Finally, we revealed that Mdivi-1 treatment downregulated Alpha 1 Type I Collagen (Col1a1) protein expression, a marker of fibrosis, and Interleukin-6 (IL-6) mRNA expression, a marker of inflammation. In summary, these results demonstrate that inhibition of Drp1-mediated mitochondrial fission by Mdivi-1 is effective in improving muscle strength and alleviating muscle damage in D2-mdx mice. These improvements are associated with improved skeletal muscle mitochondrial integrity, leading to attenuated lipid peroxidation.

DOI: https://doi.org/10.1101/2024.12.26.628172
Free Radic Biol Med. 2025 Jan 03. pii: S0891-5849(25)00004-8. [Epub ahead of print]

E-cigarette-induced changes in cell stress and mitochondrial function.

Ramamurthy Chitteti, Juan Pablo Zuniga Hertz, Jorge A Masso-Silva, John Shin, Ingrid Niesman, Christine M Bojanowski, Avnee J Kumar, Mark Hepokoski, Laura E Crotty Alexander, Hemal H Patel, David M Roth.

  Inhaling aerosols from electronic nicotine delivery systems, such as e-cigarettes (e-cigs), may pose health risks beyond those caused by nicotine intake. Exposure to e-cig aerosols can lead to the release of exosomes and metabolites into the bloodstream, potentially affecting mitochondrial physiology across the body, leading to chronic inflammatory diseases. In this study we assessed the effects of e-cig use by young healthy human subjects on the circulating exosome profile and markers of cell stress, and also defined the effects of e-cig user plasma on mitochondrial function in endothelial cells (EA. Hy 926) and epithelial cells (A549) via adoptive transfer. E-cig users had altered plasma exosome profiles, with significantly increased levels of cell free mitochondrial DNA (mtDNA), protein carbonyls, and 4-HNE relative to non-users. Plasma from e-cig users decreased maximal mitochondrial respiration and spare capacity of cells, while also increasing metabolic stress, as evidenced by changes in mitochondrial phenotype from basal to stressed in both endothelial and epithelial cells, which was corroborated by electron microscopy demonstrating structural changes in mitochondria. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) levels significantly increased in e-cig plasma-subjected cells. Overall, we identified alterations in plasma exosome profiles and increased markers of mitochondrial stress in e-cig users and evidence that circulating factors within plasma from e-cig users drives metabolic stress in endothelial and epithelial cells. Our results imply that e-cig use adversely affects mitochondrial function, leading to stress and potentially chronic inflammation across the body.

Keywords:  Tobacco; electronic (e)-cigarette; endothelial cells; epithelial cells; metabolic stress; mitochondria; reactive oxygen species

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.01.004
Cancers (Basel). 2024 Dec 11. pii: 4133. [Epub ahead of print]16(24):

BNIP3 Downregulation Ameliorates Muscle Atrophy in Cancer Cachexia.

Claudia Fornelli, Marc Beltrà, Antonio Zorzano, Paola Costelli, David Sebastian, Fabio Penna.

   BACKGROUND AND AIMS: Cancer cachexia is a complex syndrome affecting most cancer patients and is directly responsible for about 20% of cancer-related deaths. Previous studies showed muscle proteolysis hyper-activation and mitophagy induction in tumor-bearing animals. While basal mitophagy is required for maintaining muscle mass and quality, excessive mitophagy promotes uncontrolled protein degradation, muscle loss and impaired function. BNIP3, a key mitophagy-related protein, is significantly increased in the muscles of both mice and human cancer hosts. This study aimed to define the potential of mitigating mitophagy via BNIP3 downregulation in preserving mitochondrial integrity, counteracting skeletal muscle loss in experimental cancer cachexia.
METHODS: Two in vivo gene delivery methods were performed to knock down muscle BNIP3: electroporation of a BNIP3-specific shRNA expression vector or adenovirus injection.
RESULTS: The electroporation effectively reduced muscle BNIP3 in healthy mice but was ineffective in C26 tumor-bearing mice. In contrast, adenovirus-mediated BNIP3 knockdown successfully decreased BNIP3 levels also in tumor hosts. Although BNIP3 knockdown did not impact overall on body or muscle mass, it improved muscle fiber size in C26-bearing miceh2, suggesting partial prevention of muscle atrophy. Mitochondrial respiratory chain complexes (OxPhos) and TOM20 protein levels were consistently rescued, indicating improvements in mitochondrial mass, while H2O2 levels were unchanged among the groups, suggesting that BNIP3 downregulation does not impair the endogenous control of oxidative balance.
CONCLUSIONS: These findings suggest that a fine balance between mitochondrial disposal and biogenesis is fundamental for preserving muscle homeostasis and highlight a potential role for BNIP3 modulation against cancer-induced muscle wasting.

Keywords:  BNIP3; cancer cachexia; mitochondria; mitophagy; muscle wasting

DOI:  https://doi.org/10.3390/cancers16244133
Eur J Appl Physiol. 2025 Jan 08.

The effect of exercise and physical activity on skeletal muscle epigenetics and metabolic adaptations.

Gregg Mallett.

  Physical activity (PA) and exercise elicit adaptations and physiological responses in skeletal muscle, which are advantageous for preserving health and minimizing chronic illnesses. The complicated atmosphere of the exercise response can be attributed to hereditary and environmental variables. The primary cause of these adaptations and physiological responses is the transcriptional reactions that follow exercise, whether endurance- (ET) or resistance- training (RT). As a result, the essential metabolic and regulatory pathways and myogenic genes associated with skeletal muscle alter in response to acute and chronic exercise. Epigenetics is the study of the relationship between genetics and the environment. Exercise evokes signaling pathways that strongly alter myofiber metabolism and skeletal muscle physiological and contractile properties. Epigenetic modifications have recently come to light as essential regulators of exercise adaptations. Research has shown various epigenetic markers linked to PA and exercise. The most critical epigenetic alterations in gene transcription identified are DNA methylation and histone modifications, which are associated with the transcriptional response of skeletal muscle to exercise and facilitate the modification to exercise. Other changes in the epigenetic markers are starting to emerge as essential processes for gene transcription, including acetylation as a new epigenetic modification, mediated changes by methylation, phosphorylation, and micro-RNA (miRNA). This review briefly introduces PA and exercise and associated benefits, provides a summary of epigenetic modifications, and a fundamental review of skeletal muscle physiology. The objectives of this review are 1) to discuss exercise-induced adaptations related to epigenetics and 2) to examine the interaction between exercise metabolism and epigenetics.

Keywords:  Chronic disease; Endurance training; Metabolism; Resistance training; Skeletal muscle epigenetics

DOI:  https://doi.org/10.1007/s00421-025-05704-6