bims-askmum 2026-11-15 papers

bims-askmum

Biomed News

on Aging skeletal muscle and mitochondria

Issue of 2026–11–15
twenty-two papers selected by
Victoria Sanfrancesco, York University

Mitochondrial Unfolded Protein Response Under Hypoxic Conditions.
Age-related disruption of endoplasmic reticulum homeostasis in leydig cells: Mechanisms of declining testosterone biosynthesis and potential therapeutic strategies.
The integration of protein and organelle degradation systems and its pathophysiological functions.
Lipid mediated ER stress contributes to the pathogenesis of mitochondrial myopathies.
Mitochondrial translation and coordinated cytosolic translation in metabolic homeostasis and disease.
Mitochondrial Biogenesis in Human Skeletal Muscle: High-Intensity Interval Training Versus Moderate-Intensity Continuous Training.
Factors determining time to exhaustion during constant-power exercise of identical absolute and relative intensity in skeletal muscle: Implications for aging.
The Lactate-Mitokine Axis in Exercise Adaptation: Linking Glycolytic and Mitochondrial Stress Signaling.
Mitochondrial LONP1: Linking structure and function to context‑dependent roles in disease (Review).
Excessive COX-Prostaglandin Signaling Promotes Cellular Senescence and Impaired Skeletal Muscle Recovery in Aging.
LSP Methylation in Skeletal Muscle and Cross-Tissue Candidate NUMT Signals Reveal Complementary Features of Mitonuclear Aging in Mice.
Satellite cell attrition and skeletal muscle aging.
Exercise Reprograms the Epigenetic-Mitochondrial Axis: Mechanisms of Healthy Aging across Muscle, Brain, and Heart.
Dynamics of Mitochondrial Structure, Biogenesis and Function in Skeletal Muscle of Critically Ill Patients.
Chronobiology of Aging: Interactions Between Circadian Rhythms, Oxidative Stress, and Inflammation.
Elucidating lysosomal dysfunction in cardiac fibrosis progression: Molecular understanding and pharmacological targeting strategies.
Dietary Ursolic Acid Supplementation Induces Beneficial Changes in Skeletal Muscle mRNA Expression and Improves Functional Mobility in Older Cats with Sarcopenia: A Proof-of-Concept Study.
Molecular targets for the treatment of sarcopenia: a geroscience approach.
Olanzapine induces Mdivi-1-resistant disruption of insulin signaling in skeletal muscle cells.
Exercise monitoring from a Network Physiology approach.
Developmental epigenetic circuits and their epigenetic drift in skeletal muscle ageing.
A natural small molecule Hdj-15 coordinates the ER and lysosomes to induce ferroptosis by targeting TrxR1.

Cureus. 2026 Oct;18(10): e117584

Mitochondrial Unfolded Protein Response Under Hypoxic Conditions.

Gamze Bilgili, Fevzi Sökmen, Yunus Emre Cavlak, Hasan H Kazan, Ahmet Caglar Ozketen.

  Hypoxia is a critical condition affecting the physiological and pathophysiological processes in the cellular environment due to depleted oxygen levels. Under hypoxic conditions, cells undergo a series of changes to adapt to the lack of oxygen that is vital for cellular metabolism in higher organisms. Importantly, hypoxia may induce organelle-specific molecular alterations, including misfolded/unfolded proteins. As a fundamental response to these changes, the unfolded protein response (UPR) is triggered by organelles, including the endoplasmic reticulum (ER) and mitochondria. UPR in mitochondria (UPRmt) is a mitochondrial stress-adaptation pathway that communicates mitochondrial dysfunction to the nucleus to induce response genes such as chaperones and proteases, distinct from UPR in the endoplasmic reticulum (UPRer). Although UPR in the ER under hypoxic conditions has been well documented, the association of UPRmt has not been clearly evaluated. Given the fact that mitochondria are one of the pivotal organelles where oxygen consumption carries utmost importance, understanding the underlying mechanisms is crucial to overcoming hypoxic pathology and maintaining mitochondrial homeostasis. In this study, we reviewed the literature to dissect studies combining UPRmt under hypoxia in various physiological and pathophysiological conditions, including the regulation of tissue barrier homeostasis in diverse organisms, to present a comprehensive perspective. Accumulatively, the studies have revealed the protective effects of UPRmt under hypoxic conditions; yet some of them have reported that the association between hypoxia and UPRmt could be organism-specific. Even so, the number of studies is limited to systematically conclude the involvement of UPRmt in hypoxia. Therefore, further molecular studies are still needed.

Keywords:  hypoxia; hypoxic pathology; mitochondria; proteostasis; unfolded protein response

DOI:  https://doi.org/10.7759/cureus.117584
Ageing Res Rev. 2026 Nov 07. pii: S1568-1637(26)00433-2. [Epub ahead of print]123 103441

Age-related disruption of endoplasmic reticulum homeostasis in leydig cells: Mechanisms of declining testosterone biosynthesis and potential therapeutic strategies.

Meng Yuhao, Ning Gang, Wu Hui, Wang Haoyu, Liu Wei, Yang Chun, Yang Yang, Li Bonan, Jian Mintao, Zhou Xing.

  A progressive decline in testosterone levels is a hallmark of male reproductive aging and is closely associated with impaired Leydig cell function. Leydig cell function relies on intracellular homeostasis, with endoplasmic reticulum (ER) homeostasis playing a particularly important role in steroidogenesis. The ER supports steroidogenesis by regulating protein quality control, lipid and cholesterol metabolism, calcium homeostasis, and interactions between organelles. With advancing age, the capacity to maintain ER homeostasis and adapt to cellular stress diminishes. These changes interact with other age-associated alterations, contributing to impaired steroidogenesis in Leydig cells. This review synthesizes current evidence on how disrupted ER homeostasis may compromise testosterone biosynthesis in Leydig cells through alterations in the unfolded protein response (UPR) and integrated stress response (ISR), impaired autophagy and cholesterol utilization, mitochondrial dysfunction and altered interorganelle interactions, oxidative stress, inflammation, and apoptosis. We also discuss the influence of metabolic factors and exogenous exposures, along with potential therapeutic strategies aimed at restoring ER homeostasis and improving testosterone biosynthesis in aging Leydig cells. Collectively, this review establishes a mechanistic framework linking disrupted ER homeostasis to Leydig cell aging and declining testosterone biosynthesis, providing insights into the pathophysiology and potential treatment approaches for late-onset hypogonadism and related disorders.

Keywords:  Aging; Endoplasmic reticulum homeostasis; Leydig cells; Steroidogenesis; Testosterone

DOI:  https://doi.org/10.1016/j.arr.2026.103441
Nat Rev Mol Cell Biol. 2026 Nov 09.

The integration of protein and organelle degradation systems and its pathophysiological functions.

Florian Wilfling, Ivan Dikic.

Timely removal of defective or superfluous cellular components, including misfolded proteins, aberrant protein complexes and damaged organelles, is essential for maintaining cellular homeostasis and adaptation to stress. This process is controlled by an intricate interplay between two principal degradation systems, the ubiquitin-proteasome system and autophagy, which together mediate the recognition, selection and elimination of diverse substrates. In this Review, we discuss how proteins and organelles are dynamically partitioned between these catabolic pathways in response to physiological demands, cellular stress and damage. We highlight the mechanisms of substrate sequestration, the spatial and temporal organization of the degradation machineries and the compensatory responses that preserve proteostasis when one pathway is compromised, including the coordination with the unfolded protein response. We also examine how selective pathways such as endoplasmic reticulum phagy and mitophagy remodel or eliminate damaged organelles. Recent advances in electron tomography have revealed the ultrastructural basis of these networks, providing insights into their architecture and dynamics. Finally, we discuss how defects in these degradation systems contribute to ageing, cancer, neurodegeneration and other pathologies.

DOI: https://doi.org/10.1038/s41580-026-01037-0
Mol Metab. 2026 Nov 11. pii: S2212-8778(26)00156-0. [Epub ahead of print] 102472

Lipid mediated ER stress contributes to the pathogenesis of mitochondrial myopathies.

Inaya Laubach, Guido Primiano, Nneka Southwell, Nicola Rizzardi, Belem Yoval-Sánchez, Christian Bergamini, Serenella Servidei, Alexander Galkin, Giovanni Manfredi, Qiuying Chen, Marilena D'Aurelio.

  Mitochondrial diseases are a heterogeneous group of genetic disorders caused by impaired oxidative phosphorylation (OxPhos). When skeletal muscle is predominantly affected, they are defined as primary mitochondrial myopathies. Although the genetic causes of mitochondrial myopathies and the resulting bioenergetic impairments are well established, the metabolic drivers behind progressive muscle dysfunction remain poorly defined. This gap in knowledge may contribute to the lack of effective treatments for these disorders. OxPhos defective muscle initiates a metabolic response coordinated by systemic signals which results in muscle and adipose tissue wasting. Here, we show ectopic muscle lipid accumulation in a COX10 KO mouse model of mitochondrial myopathy due to inability to oxidize fatty acids in muscle. In both the mouse model and in mitochondrial patients, we find an increase in ceramides, which is mechanistically linked to chronic ER stress, phosphorylation of eIF2α, and activation of ATF4 signaling. We propose that Ph-eIF2α-mediated attenuation of global protein synthesis and ATF4-initiated atrophy pathways contribute to muscle wasting and weakness. Importantly, inhibition of de novo synthesis of ceramides with myriocin reduces ER stress and ATF4 signaling and improves muscle proteostasis, body weight, and motor functions in the COX10 KO mouse. Together, these findings highlight the role of lipid metabolism as a contributor to mitochondrial myopathy and identify lipid-mediated stress pathways that can be targeted therapeutically.

Keywords:  COX10; ER stress; ceramides; lipid metabolism; mitochondrial myopathy; muscle wasting

DOI:  https://doi.org/10.1016/j.molmet.2026.102472
FEBS Lett. 2026 Nov 09.

Mitochondrial translation and coordinated cytosolic translation in metabolic homeostasis and disease.

Boseon Kim, Thi Thanh Mai Tran, Nakyung Kang, Min-Woo Lee, Mihye Lee.

  Mitochondria are essential organelles that regulate cellular metabolism, signaling, and stress responses. Their function depends on coordinated protein synthesis from the mitochondrial and nuclear genomes, together with mechanisms that preserve mitochondrial proteostasis. Translation of both nuclear- and mitochondrial-encoded transcripts is dynamically regulated in response to developmental, metabolic, and environmental cues, allowing mitochondria to remodel their proteome and adapt to changing physiological demands. Disruption of these processes impairs respiratory complex assembly, mitochondrial function, and protein homeostasis, contributing to a wide range of metabolic, cardiovascular, muscular, neurodegenerative, and immune disorders. In this review, we summarize the evolutionary specialization of the mitochondrial translational machinery and the molecular mechanisms that regulate mitochondrial protein synthesis. We discuss recent advances in cytosolic translational control of nuclear-encoded mitochondrial proteins, mito-nuclear coordination, tissue-specific regulation of mitochondrial proteostasis, and their implications for human disease. Finally, we highlight emerging challenges and future directions in the translational regulation of mitochondrial protein synthesis and its relevance to mitochondrial biology and disease.

Keywords:  RNA localization; metabolism; mitochondrial dysfunction; mitochondrial protein; mito‐nuclear coordination; translational control

DOI:  https://doi.org/10.1002/1873-3468.70502
Int J Mol Sci. 2026 Oct 25. pii: 9537. [Epub ahead of print]27(21):

Mitochondrial Biogenesis in Human Skeletal Muscle: High-Intensity Interval Training Versus Moderate-Intensity Continuous Training.

Kevin Bischof.

  Mitochondrial biogenesis is a hallmark adaptation to endurance exercise with broad implications for metabolic health and athletic performance. High-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) both stimulate mitochondrial remodeling in human skeletal muscle, yet whether exercise intensity or total work performed is the principal determinant remains contested. This mini review synthesizes current evidence on the intensity-dependent activation of AMP-activated protein kinase (AMPK), p38 mitogen-activated protein kinase (p38 MAPK), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)-a central transcriptional coactivator in mitochondrial biogenesis. The author critically examines the distinction between mitochondrial content and respiratory function, discusses how study design-particularly work-matched versus time-matched protocols-shapes comparative conclusions, and identifies key unresolved questions including sex-based differences, fiber-type specificity, and the role of mitochondrial dynamics. The evidence indicates that both modalities are effective but operate through overlapping yet intensity-sensitive mechanisms; the metabolic-stress hypothesis provides a testable explanatory framework. Practical implications for exercise prescription are discussed. The review further considers the coordination of mitochondrial translation and turnover, mitochondrial Ca2+ handling, sex-specific evidence limitations, and translational outcomes in cardiometabolic disease.

Keywords:  AMPK; HIIT; MICT; PGC-1α; exercise intensity; mitochondrial biogenesis; skeletal muscle

DOI:  https://doi.org/10.3390/ijms27219537
Respir Physiol Neurobiol. 2026 Nov 10. pii: S1569-9048(26)00133-3. [Epub ahead of print]347 104674

Factors determining time to exhaustion during constant-power exercise of identical absolute and relative intensity in skeletal muscle: Implications for aging.

Bernard Korzeniewski.

  The sensitivities and large-scale responses related to aging of time to exhaustion (tlim) during constant-power exercise to various factors/parameters of the skeletal muscle bioenergetic system in humans are investigated. A dynamic computer model of the system is used. tlim is highly positively sensitive to Pipeak (peak Pi at which exercise is terminated because of fatigue), kOX (OXPHOS activity) and AOXmax (each-step activation (ESA) intensity) and moderately positively sensitive to Picrit (critical Pi at which the additional ATP usage is initiated). tlim is strongly negatively sensitive to tCaP (total creatine and accessible phosphate pool) and AUT (work intensity), and moderately negatively sensitive to kadd (activity of the additional ATP usage). Generally, the sensitivity of tlim to factors/parameters is much higher at lower work intensities above critical power (CP) and thus longer tlims than at higher work intensities/shorter tlims. The same relative decrease in power output (PO) and OXPHOS activity to 70% has essentially no impact on tlim. The decrease in only kOX to 70% related to aging at the same absolute PO dramatically reduces tlim. This effect can be partly compensated by an aging-related increase in Pipeak. A potential decrease in tCaP would lengthen tlim. The drop in kOX to 70% at a somewhat lower PO can bring exercise from the heavy to severe intensity domain. Physical activity/training, no or cautious creatine supplementation if advisable for other reasons and avoiding of high-phosphate diet can improve muscle performance during endurance constant-power exercise and thus elevate life quality in old people.

Keywords:  absolute work intensity; computer model; constant-power exercise; limit of tolerance; old individuals; power-duration relationship; relative work intensity; skeletal muscle; task failure

DOI:  https://doi.org/10.1016/j.resp.2026.104674
Int J Mol Sci. 2026 Nov 04. pii: 9871. [Epub ahead of print]27(21):

The Lactate-Mitokine Axis in Exercise Adaptation: Linking Glycolytic and Mitochondrial Stress Signaling.

Amelia Tero-Vescan, Ruxandra Ștefănescu, Bianca Eugenia Ősz, Mădălina Buț, Amalia Pușcaș, Mark Slevin.

  Exercise induces coordinated metabolic and mitochondrial stress responses that extend beyond ATP production to regulate cellular and systemic adaptation. Lactate, traditionally viewed as a glycolytic product, is now recognized as an oxidative substrate, interorgan carbon shuttle, and signaling metabolite, whereas mitochondrial stress promotes adaptive signaling and the release of mitokines and mitochondrial-derived peptides. This narrative review proposes the lactate-mitokine axis as a conceptual framework integrating these two exercise-responsive systems, while distinguishing experimentally established mechanisms from potential interactions that remain to be functionally validated. Repeated exercise promotes mitochondrial remodeling and increases oxidative capacity, which in turn reshapes the lactate response to subsequent exercise, as reflected by lower post-exercise lactate concentrations and enhanced lactate clearance after training. Conversely, increased lactate flux may influence mitochondrial adaptation through metabolic, redox, and receptor-dependent signaling, supporting a potentially bidirectional relationship between lactate handling and mitochondrial remodeling. The relative contribution of these interconnected responses appears exercise modality-dependent, with high-intensity, prolonged endurance, and resistance exercise generating distinct combinations of glycolytic and mitochondrial stress. Although lactate metabolism and mitochondrial stress signaling share several regulatory pathways, direct causal interactions between lactate signaling and mitokine expression or secretion during exercise remain insufficiently established. Thus, the proposed lactate-mitokine axis should be regarded as a hypothesis-generating framework requiring further experimental validation.

Keywords:  FGF21; GDF15; MOTS-c; exercise; humanin; lactate; mitochondrial adaptation; mitochondrial stress; mitokines

DOI:  https://doi.org/10.3390/ijms27219871
Mol Med Rep. 2027 Jan;pii: 10. [Epub ahead of print]35(1):

Mitochondrial LONP1: Linking structure and function to context‑dependent roles in disease (Review).

Du Chen, Qifeng Li, Yuanxi Zhang, Zehua Zhang, Dengqiu Xu.

  Mitochondrial proteostasis is essential for maintaining organellar integrity, metabolic adaptation and cellular survival under physiological and stress conditions. Among mitochondrial quality control mechanisms, Lon peptidase 1 (LONP1) is an ATP‑dependent AAA+ serine protease localized predominantly in the mitochondrial matrix and plays a central role in the recognition and degradation of damaged or misfolded proteins. Recent structural, molecular and multi‑omics studies have expanded our understanding of LONP1 beyond proteolysis, implicating it in protein quality control, mitochondrial DNA maintenance, metabolic regulation and responses to oxidative and cellular stress. Increasing evidence also indicates that LONP1 functions are highly dependent on cellular and disease context, with both loss and gain of LONP1 activity associated with distinct pathological outcomes. The present review integrated recent structural and functional advances to establish a structure‑function framework for understanding how LONP1 coordinates proteolytic and chaperone‑like activities and how these functions are shaped by cellular and disease context. The present review further examined its roles in metabolic, neurodegenerative, reproductive, cardiovascular and malignant diseases, with particular emphasis on the context‑dependent consequences of LONP1 dysregulation and its emerging therapeutic potential. Finally, the present review highlighted unresolved questions concerning substrate recognition and specificity, the relative contributions of protease and chaperone‑like functions, disease‑specific directionality and the safety and feasibility of therapeutic modulation. These challenges need to be addressed to establish the functional and translational boundaries of LONP1.

Keywords:  Lon peptidase 1; diseases1; mitochondrial quality control; oxidative stress; proteostasis

DOI:  https://doi.org/10.3892/mmr.2026.14068
Aging Cell. 2026 Nov;pii: e70843. [Epub ahead of print]25(11):

Excessive COX-Prostaglandin Signaling Promotes Cellular Senescence and Impaired Skeletal Muscle Recovery in Aging.

Paul-Emile Bourrant, Zachary J Fennel, Elena M Yee, Robert J Castro, Patrick J Ferrara, Acintya Sai Yoganath, Chad M Skiles, Katsuhiko Funai, Micah J Drummond.

  The ability to recover skeletal muscle after periods of disuse declines with age leading to persistent deficits in strength and function that extend beyond muscle mass loss. Here, we investigated whether age-related alterations in lipid remodeling contribute to impairment in skeletal muscle recovery following disuse. Lipidomic and oxylipin profiling revealed that aged mouse muscle is characterized by sustained phosphatidylcholine and omega-6-dependent COX-prostaglandin signaling during early recovery from disuse atrophy. This persistent lipid mediator response was associated with increased senescence burden, fibrosis, and impaired functional recovery. Pharmacological suppression of COX signaling during reloading in aged mice reduced senescence markers, limited fibrosis, and improved muscle function independent of improved muscle size. Mechanistically, senescent induced macrophages produced COX-2-dependent PGE2 and impaired myotube size and fusion through paracrine signaling. Activation of EP2 signaling was sufficient to induce a senescent macrophage phenotype. Importantly, a similar age-associated dysregulation of oxylipin content was observed in older adults after limb immobilization, supporting the translational relevance of these findings. Together, our results identify sustained COX-prostaglandin signaling as a key feature of impaired skeletal muscle recovery with aging and suggest that targeted modulation of this pathway may improve muscle recovery in older individuals. Trial Registration: ClinicalTrials.gov identifier: NCT04416191.

Keywords:  aging; cellular senescence; cyclooxygenase; disuse atrophy; skeletal muscle; skeletal muscle recovery

DOI:  https://doi.org/10.1111/acel.70843
Biology (Basel). 2026 Nov 02. pii: 1971. [Epub ahead of print]15(21):

LSP Methylation in Skeletal Muscle and Cross-Tissue Candidate NUMT Signals Reveal Complementary Features of Mitonuclear Aging in Mice.

Xijia Wang, Wenpeng Li, Xingbo Zhao.

  Aging disrupts communication between mitochondria and the nucleus, but compact molecular readouts of this interface remain limited. Here, we examined mitochondrial DNA light-strand promoter (LSP) methylation signals in skeletal muscle across natural-aging and mitochondrial-background models, and independently profiled candidate nuclear mitochondrial DNA insertion (NUMT) junction signals in brain and skeletal muscle across age groups. Natural aging was associated with reduced motor performance, altered skeletal-muscle mitochondrial status, and lower LSP methylation signals. Reciprocal F1 crosses and conplastic mice showed coordinated associations among mitochondrial background, LSP methylation signals, bioenergetic parameters, nuclear mitochondrial-gene expression, and physical performance. In parallel, short-read whole-genome sequencing revealed a non-monotonic candidate NUMT signal pattern, with the highest mean signal at 12 months. A Ptprc-associated candidate mitochondrial-nuclear junction was supported by split-read inference and junction-specific droplet digital PCR in a candidate-positive sample. Together, these findings identify LSP methylation signals and candidate NUMT junction signals as complementary but independently measured molecular features of mitonuclear aging.

Keywords:  LSP methylation; NUMT; Ptprc; aging; mitochondrial-nuclear crosstalk

DOI:  https://doi.org/10.3390/biology15211971
Bone Res. 2026 Nov 13. pii: 109. [Epub ahead of print]14(1):

Satellite cell attrition and skeletal muscle aging.

Yujia Teng, Ying Yao, Zhihang Zuo, Yuwei Li, Binxu Yin, Qian Wang, Kun Zhang.

Skeletal muscle aging involves the progressive decline in mass and function of muscle tissue, significantly impacting mobility and quality of life in older adults. Central to this process is the functional deterioration of SCs, the primary muscle stem cells responsible for regeneration. Aging impairs SC self-renewal, activation, proliferation, and differentiation through mechanisms including telomere attrition, mitochondrial dysfunction, epigenetic dysregulation, and aberrant signaling pathways such as Notch/Wnt and TGF-β. Additionally, the aged microenvironment-marked by chronic inflammation, oxidative stress, fibro-adipogenic infiltration, immune dysregulation, and vascular decline-further suppresses SC activity. Recent advances in multidisciplinary research, encompassing single-cell genomics, epigenetics, and bioengineering, have deepened our understanding of these mechanisms. Emerging interventions, such as nutritional strategies, exercise, pharmacological agents, cell therapy, and gene editing, offer promising avenues for restoring SC function and rejuvenating muscle regeneration. Future efforts should focus on integrated, personalized approaches to combat sarcopenia and improve healthspan.

DOI: https://doi.org/10.1038/s41413-026-00596-4
Dev Neurobiol. 2027 Jan;pii: e70069. [Epub ahead of print]87(1):

Exercise Reprograms the Epigenetic-Mitochondrial Axis: Mechanisms of Healthy Aging across Muscle, Brain, and Heart.

Yuwen Wan, Biao He.

  Aging manifests as a progressive, multi-hallmark deterioration involving epigenetic dysregulation, mitochondrial impairment, proteostatic collapse, and persistent inflammaging. Accumulating evidence positions habitual physical exercise as one of the most effective non-pharmacological geroprotectors, capable of inducing beneficial, partially reversible epigenetic reprogramming across multiple tissues. This comprehensive review synthesizes current understanding of how different exercise modalitiesendurance, resistance, and high-intensity interval trainingelicit targeted changes in DNA methylation, histone posttranslational modifications, and microRNA (miRNA) networks, collectively restoring mitochondrial biogenesis, dynamics, mitophagy, and redox homeostasis in aging skeletal muscle, brain, and heart. Special emphasis is placed on the dual role of reactive oxygen species (ROS): physiological, exercise-induced ROS pulses function as pivotal redox signals that interface with AMPK-SIRT1-PGC-1α signaling, TET-mediated demethylation, Class IIa HDAC nuclear export, and miRNA maturation, thereby driving adaptive mitochondrial and proteostatic responses rather than oxidative damage. Circulating exerkines and myokines (irisin, IL-6, BDNF, apelin) further orchestrate interorgan communication, linking muscle-derived signals to hippocampal neuroplasticity and cardiac metabolic resilience. Sex-specific epigenetic patterns and differential responsiveness to exercise intensity are highlighted, revealing important sources of individual variability in geroprotective outcomes. By integrating acute versus chronic adaptive signatures and tissue-specific mechanisms, this synthesis underscores exercise as a powerful, systems-level modulator of the epigenetic-mitochondrial axis. These insights pave the way for precision exercise prescriptions and mechanistically informed mimetic strategies aimed at extending healthspan, compressing morbidity, and attenuating major age-related pathologies in heterogeneous aging populations.

Keywords:  DNA methylation; aging; epigenetics; exercise; histone modifications; microRNAs (miRNAs)

DOI:  https://doi.org/10.1002/dneu.70069
Crit Care Med. 2026 Nov 13.

Dynamics of Mitochondrial Structure, Biogenesis and Function in Skeletal Muscle of Critically Ill Patients.

Anika Wickert, Julius J Grunow, Tobias Wollersheim, Lilian Jo Engelhardt, Stefan Groß, Sara Timm, Matthias Ochs, Jenny Meinhardt, Werner Stenzel, Michael Boschmann, Steffen Weber-Carstens, Jens Fielitz.

   OBJECTIVES: To define the timing and phenotype of mitochondrial ultrastructural remodeling and electron transport chain (ETC) function in skeletal muscle during early critical illness.
DESIGN: Secondary analysis of a prospective observational study with serial muscle biopsies.
SETTING: Adult ICU.
PATIENTS: Thirty-three mechanically ventilated ICU patients (median age, 49 yr; 27% women) with Sequential Organ Failure Assessment greater than or equal to 9 on three consecutive days; skeletal muscle biopsies of the vastus lateralis muscle at ICU day 5 (n = 29) and day 15 (n = 22). Healthy subjects served as controls.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: Vastus lateralis biopsies were analyzed by electron microscopy with stereology, quantitative real-time PCR (qRT-PCR), Western blotting, and spectrophotometric ETC enzyme assays (reported per tissue weight and normalized to citrate synthase [CS]). Intact mitochondrial profiles were reduced vs. controls (fold change vs. controls: day 5, 0.24 [0.18-0.34]; p = 0.039 and day 15, 0.20 [0.16-0.33]; p = 0.011) and disturbed profiles increased (day 5, 5.62 [3.20-7.17]; p < 0.001 and day 15, 5.20 [3.67-6.36]; p = 0.001), with reduced volume density of intact mitochondria (day 5, 0.33 [0.20-0.49]; p = 0.009 and day 15, 0.32 [0.21-0.50]; p = 0.005). Inner mitochondrial membrane surface-to-volume ratio was reduced at day 5 (0.69 [0.49-0.89]; p = 0.022) and remained unchanged at day 15. Complex III tissue activity was reduced at day 5 (85.6 [22.1-133.3] vs. 151.4 [100.5-205.0]; p = 0.015) and day 15 (50.5 [36.0-69.8]; p = 0.001), remaining reduced after CS normalization (day 5, 0.83 [0.34-1.49]; p = 0.040 and day 15, 0.87 [0.65-0.93]; p = 0.007). Complex IV activity remained reduced before and after CS normalization at both time points (all p < 0.001). CS activity declined by day 15 (56.3 [52.7-65.1] vs. 95.6 [80.1-133.0]; p = 0.001 and day 15 vs. day 5; p = 0.041). qRT-PCR and Western blot supported reduced ETC components and altered biogenesis signaling.
CONCLUSIONS: Skeletal muscle mitochondrial ultrastructure is altered by ICU day 5 and remains abnormal at day 15, with persistent complex III/IV dysfunction after CS normalization. These findings define an early sustained mitochondrial remodeling phenotype in skeletal muscle during critical illness.

Keywords:  critical illness; electron transport chain complex proteins; mitochondria; muscle; oxidative phosphorylation; skeletal

DOI:  https://doi.org/10.1097/CCM.0000000000007433
J Gerontol A Biol Sci Med Sci. 2026 Nov 12. pii: glag257. [Epub ahead of print]

Chronobiology of Aging: Interactions Between Circadian Rhythms, Oxidative Stress, and Inflammation.

Bharti Chauhan, Ishanka Singh, Pawan Kumar Maurya.

  Chronodisruption is increasingly recognised as a fundamental driver of biological aging rather than merely a consequence of advancing age. Although substantial evidence links circadian dysfunction with individual age-related diseases, the mechanistic integration of chronodisruption across the hallmarks of aging and its therapeutic implications remains fragmented. This review provides a comprehensive synthesis of current evidence describing how age-associated deterioration of the circadian timing system interacts with established hallmarks of aging, including genomic instability, epigenetic alterations, mitochondrial dysfunction, dysregulated nutrient sensing, impaired proteostasis, chronic inflammation, and cellular senescence. This article also incorporates how these interconnected mechanisms contribute to the development and progression of major age-related disorders, including neurodegenerative, cardiovascular, metabolic diseases, and cancer, highlighting shared molecular regulators such as BMAL1, CLOCK, PER, CRY, REV-ERBs, SIRT1, AMPK, and mTOR. Although several reviews exist that focus on individual diseases or isolated circadian mechanisms, this review integrates molecular, cellular, and translational evidence into a unified framework linking chronodisruption to systemic aging. This article discusses emerging chronotherapeutic strategies including chrono-phototherapy, chrono-nutrition, chrono-exercise, natural chrono-modulators, chrono-pharmacology, and precision geromedicine that aim to restore circadian homeostasis and improve healthy aging. Collectively, this review identifies circadian rhythm restoration as a promising systems-level therapeutic approach and outlines future directions for integrating chronobiology into precision interventions for age-related diseases.

Keywords:  Aging; Cellular senescence; Chronic inflammation; Chronodisruption; Chronotherapy; Circadian rhythm; Oxidative stress

DOI:  https://doi.org/10.1093/gerona/glag257
Eur J Pharmacol. 2026 Nov 10. pii: S0014-2999(26)01019-8. [Epub ahead of print]1040 179537

Elucidating lysosomal dysfunction in cardiac fibrosis progression: Molecular understanding and pharmacological targeting strategies.

Sangita Ghosh, Mansi Vinodkumar Trivedi, Anil Bhanudas Gaikwad.

  Cardiac fibrosis is a critical pathological condition characterized by an excessive accumulation of extracellular matrix components resulting from persistent cellular stress, inflammation, oxidative stress, and organelle dysfunction. These insoluble fibers form a 3D matrix that is evident in numerous heart-related conditions, including myocardial infarction, heart failure, cardiomyopathies, and hypertension. Cardiomyocytes, unlike fibroblasts and endothelial cells, are post-mitotic and rely heavily on cellular quality-control systems to sustain their workload. Lysosomes, a single-lipid-bilayered membrane-bound organelle, are one of the important organelles that maintain cellular homeostasis by degrading and recycling cellular debris. Autophagy is one of the catabolic processes that is heavily reliant on lysosomes to form autolysosomes, which help degrade and recycle cellular components, proteins, and lipids, and maintain cellular homeostasis. Recently, lysosomal dysfunction has been found to play a critical contributing role in modulating cardiac fibrosis. The involvement of lysosomal dysfunction in mediating cardiac fibrosis progression involves several intriguing mechanisms that regulate lysosomal integrity, including V-ATPase, transcription factor EB (TFEB), lysosomal-associated membrane protein-2 (LAMP-2), cathepsin B, and chaperone-mediated autophagy, among others. The subsequent review, therefore, demonstrates the role of lysosomes in physiological and pathological heart conditions, with a particular emphasis on cardiac fibrosis, the central mechanism underlying the most aggressive stages of cardiac disease. The correlation between lysosomal dysfunction and cardiac fibrosis, as well as the interconnections and cellular pathways linking them, is discussed, along with emerging preclinical and clinical investigations that could be pursued to elucidate the role of lysosomal dysfunction in cardiac fibrosis progression.

Keywords:  ATB2005A; Autophagy; Cardiac fibrosis; Corosolic acid; Lysosome; Transcription factor EB

DOI:  https://doi.org/10.1016/j.ejphar.2026.179537
Animals (Basel). 2026 Oct 26. pii: 3377. [Epub ahead of print]16(21):

Dietary Ursolic Acid Supplementation Induces Beneficial Changes in Skeletal Muscle mRNA Expression and Improves Functional Mobility in Older Cats with Sarcopenia: A Proof-of-Concept Study.

Scott M Ebert, Celine S Nicolas, Andrew R Judge, Jaime G Lopez, Alan T Taylor, Kotha Sekharam, John J Talley, Christophe A Rème, Christopher M Adams.

  Cats frequently lose mobility when they become older, ill, or injured, leading to additional impairments in health and quality of life. To help address this problem, a dietary supplement for cats containing ursolic acid was tested. Ursolic acid is a natural dietary compound that promotes muscle health and mobility in several non-feline species. A 60-day proof-of-concept efficacy study of ursolic acid dietary supplementation was conducted in older domestic shorthair cats with sarcopenia (age-related skeletal muscle atrophy). In feline skeletal muscle, 12 mg of ursolic acid per day generated beneficial changes in skeletal muscle mRNA expression, including repression of mRNAs that promote muscle atrophy and weakness and induction of mRNAs that promote muscle health. Furthermore, ursolic acid generated significant improvements in several important measures of feline mobility, including jumping, playing with toys, rising from a resting position, and transitioning from a standing position to a sitting or lying position. These findings identify ursolic acid supplementation as a new nutritional approach for promoting beneficial molecular and functional mobility outcomes in cats.

Keywords:  Ursolic acid; Ursolyx; cachexia; dietary supplement; exercise; feline; mobility; mobility improvement; muscle atrophy; muscle health; sarcopenia

DOI:  https://doi.org/10.3390/ani16213377
Expert Opin Ther Targets. 2026 Nov 11. 1-11

Molecular targets for the treatment of sarcopenia: a geroscience approach.

Anna Picca, Riccardo Calvani, Hélio José Coelho-Júnior, Stefano Cacciatore, Rola S Zeidan, Matteo Tosato, Francesco Landi, Emanuele Marzetti.

   INTRODUCTION: Sarcopenia is increasingly recognized as a multisystem geroscience condition. The limited efficacy of first-generation anabolic therapies has challenged the paradigm that increasing muscle mass is sufficient to restore physical performance, highlighting the need for therapeutic strategies that address the biological complexity of muscle aging.
AREAS COVERED: This review examines the evolution of molecular targets for sarcopenia, from anabolic pathways to emerging geroscience-based targets. We discuss mechanistic and clinical evidence supporting these approaches, emphasizing the distinction between molecular target engagement and functional efficacy, and examine how biological context, patient stratification, and multicomponent interventions influence therapeutic outcomes. The literature was identified through a comprehensive PubMed search, with emphasis on mechanistic studies, clinical trials, and recent advances in geroscience.
EXPERT OPINION: The future of therapeutics against sarcopenia will likely depend less on identifying anabolic agents than on matching molecular targets to the dominant biological mechanisms limiting muscle function in individual patients. Biomarkers of target engagement, deep phenotyping, and mechanism-informed combination strategies integrating pharmacological, nutritional, and exercise interventions will be essential to improve patient stratification and translate molecular target modulation into meaningful functional benefit.

Keywords:  Aging; biomarker; cytokine; inflammation; metabolism; mitochondria; physical function; skeletal muscle

DOI:  https://doi.org/10.1080/14728222.2026.2761684
Front Pharmacol. 2026 ;17 1920978

Olanzapine induces Mdivi-1-resistant disruption of insulin signaling in skeletal muscle cells.

Pablo Arias, Catalina Salamanca, Fernanda Briones-Manriquez, Lucas Oyaneder, Andrea Marimán, Gonzalo Almarza, Edson Yañez, Juan Rodriguez, Rodrigo Troncoso, Leonel E Rojo, Carlos F Lagos, Roberto Bravo-Sagua, Andrea Del Campo.

   Introduction: Second-generation antipsychotics such as olanzapine (OLZ) are widely prescribed because they produce fewer extrapyramidal adverse effects than first-generation agents. However, OLZ is strongly associated with metabolic dysfunction, and alterations in mitochondrial dynamics have been proposed to contribute to these effects. We investigated whether OLZ-induced mitochondrial dysfunction is linked to impaired insulin signaling in skeletal muscle cells and explored a potential interaction with the mitochondrial fission regulator dynamin-related protein 1 (DRP1).
Methods: L6 skeletal myoblasts were treated with OLZ, alone or in combination with the mitochondrial fission inhibitor Mdivi-1. Insulin signaling, glucose uptake, mitochondrial morphology, and insulin-stimulated mitochondrial bioenergetics were evaluated. In parallel, molecular dynamics simulations and MM/PBSA calculations were performed using a common DRP1/Mg2 + receptor model to compare the interactions of protonated OLZ and Mdivi-1 within the DRP1 GTPase domain.
Results: OLZ reduced insulin-mediated signaling and glucose uptake, promoted mitochondrial fragmentation, and impaired the insulin-induced increase in mitochondrial bioenergetic activity. Co-treatment with Mdivi-1 partially rescued OLZ-induced mitochondrial fragmentation but did not restore insulin responsiveness. Molecular simulations showed that protonated OLZ and Mdivi-1 remained within the same hydrophobic region of the DRP1 GTPase domain and shared an anchoring interaction involving Ile252. Their calculated MM/PBSA interaction free energies were similar (-22.26 ± 1.7 and -24.50 ± 0.5 kcal mol- 1, respectively), supporting compatible occupancy of a shared binding region but not demonstrating high-affinity or GTP-competitive binding.
Discussion: These findings indicate that OLZ disrupts mitochondrial dynamics and bioenergetics while decreasing insulin sensitivity in skeletal muscle cells. However, the dissociation between recovery of mitochondrial morphology and persistence of insulin resistance suggests that excessive mitochondrial fission alone does not account for OLZ-induced metabolic dysfunction. The computational results are compatible with an interaction of OLZ with the DRP1 GTPase domain but do not establish DRP1 as its primary pharmacological target. OLZ-associated insulin resistance therefore likely involves additional, potentially extramitochondrial mechanisms.

Keywords:  Mdivi-1; insulin resistance; mitochondria; olanzapine; skeletal muscle

DOI:  https://doi.org/10.3389/fphar.2026.1920978
Front Netw Physiol. 2026 ;6 1745246

Exercise monitoring from a Network Physiology approach.

Lluc Montull, Sergi Garcia-Retortillo, Óscar Abenza, Yaopeng J X Ma, Robert Hristovski, Plamen Ch Ivanov, Natàlia Balagué.

  Advancements in big data, artificial intelligence and related technology are shaping the future of exercise monitoring, yet current monitoring strategies may not fully capture the physiological complexity of athletes' health and performance. The multidisciplinary field of Network Physiology provides a conceptual and analytical framework to investigate the dynamic interactions, coordination and network integration among physiological systems in athletes during exercise, and thus, opens new directions in Exercise Physiology. This article aims to summarize the current advances, vision and perspectives within this framework, focusing on how investigations of the inter-organ dynamic networks (cardio-respiratory, cardio-muscular, cortico-cardiac, cortico-muscular, inter-muscular, etc.) can lead to valuable insights into athletes' performance, exercise monitoring, the underlying regulatory mechanisms of systems adaptation and coordination in response to exercise-induced stress, and to identify a novel class of network-based biomarkers related to training, levels of fitness, fatigue, and recovery.

Keywords:  complex adaptive systems; exercise; inter-muscular networks; inter-organs networks; intra-individual variability; network physiology; nonlinear dynamics; sports science

DOI:  https://doi.org/10.3389/fnetp.2026.1745246
Philos Trans R Soc Lond B Biol Sci. 2026 Nov 12. pii: 20250342. [Epub ahead of print]381(1963):

Developmental epigenetic circuits and their epigenetic drift in skeletal muscle ageing.

Laurent Schaeffer, Liudmila Afanaseva, Edwige Belotti.

  Development and ageing are two deeply intertwined processes, but it remains unclear how programmes established during early development influence the long-term stability of post-mitotic tissues. Skeletal muscle provides a model of choice to study the connection between these processes. Myofibres are long-lived, multinucleated syncytia whose identity and homeostasis rely on transcriptional, metabolic and epigenetic states established during embryonic and postnatal development. Throughout life, these states are further reinforced by satellite cell-derived inputs. In this review, we discuss how early specification cues, chromatin architecture and metabolic wiring establish durable regulatory circuits preserving myofibre integrity but also limiting its plasticity across the lifespan. These developmental features, combined with decades of physiological strain, progressively challenge genomic integrity and destabilize the maintenance of epigenetic information. Over time, this instability causes an epigenetic drift, encompassing alterations in DNA methylation, changes in histone landscapes and disruption in higher-order chromatin organization. Such alterations erode transcriptional fidelity and contribute to the appearance of hallmarks of the ageing phenotype. By integrating developmental and epigenetic perspectives, we argue that myofibre ageing reflects not only cumulative damage but also the long-term consequences of how these exceptionally long-lived cells were originally built. This article is part of the theme issue 'Developmental circuits in ageing'.

Keywords:  ageing; epigenetics; genome integrity; long-lived cells; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1098/rstb.2025.0342
Acta Pharmacol Sin. 2026 Nov 10.

A natural small molecule Hdj-15 coordinates the ER and lysosomes to induce ferroptosis by targeting TrxR1.

Yue-Qin Zhao, Fang-Jiao Zhou, Xian-le Duan, Ai-Ying Huang, Zheng-Rui Xiang, Yu-Han Zhao, Xiao Ding, Xiao-Jiang Hao.

  Ferroptosis, a type of regulated cell death characterized by lipid peroxide accumulation, has emerged as a promising subroutine of cell death capable of sensitizing chemoresistant cancer cells. To identify novel ferroptosis inducers, a natural product library of 1023 compounds was screened, leading to the identification of Hdj-15. Hdj-15 elicited oxidative stress, the unfolded protein response (UPR), lysosomal biogenesis, and massive lipid peroxidation to trigger ferroptosis. Mechanistically, Hdj-15 directly targeted TrxR1, leading to oxidative stress and ER stress. Knockdown of TXNRD1 (which encodes TrxR1) further sensitized cells to Hdj-15, and reconstitution with wild-type, but not U498C mutant, TXNRD1 reversed this effect. The IRE1α branch of the UPR was activated upon Hdj-15 treatment, which in turn enabled X-box binding protein 1 (XBP1) to directly transactivate transcription factor E3 (TFE3) and transcription factor EB (TFEB), thereby triggering lysosomal biogenesis. Chromatin immunoprecipitation (ChIP) revealed that XBP1s directly occupied the -735 to -631 and the -493 to -365 sites of the TFE3 and TFEB promoters. Hdj-15-induced lysosomal biogenesis further facilitated lysosomal GPX4 degradation via chaperone-mediated autophagy (CMA), sensitizing cancer cells to ferroptosis. Furthermore, drug-resistant cancer cells (Taxol-resistant A549 cells and gefitinib-resistant PC9 cells), including both p53-proficient and p53-deficient cells, were vulnerable to Hdj-15-mediated GPX4 inhibition. In xenograft tumor models, Hdj-15 suppressed tumor growth in vivo. In summary, elucidating the molecular mechanisms of the novel ferroptosis inducer Hdj-15 demonstrated that the interplay between the ER and lysosomes plays a critical role in shaping ferroptotic cell death, which in turn sensitizes drug-resistant cancer cells.

Keywords:  GPX4; TrxR1; chemoresistance; ferroptosis; lysosome; p53

DOI:  https://doi.org/10.1038/s41401-026-01938-y