bims-musmir 2026-09-27 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–09–27
fifteen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Mitochondrial permeability transition in skeletal muscle phenocopies muscle alterations seen in cancer cachexia and other wasting conditions.
Pancreatic Cancer Disrupts Circadian Patterns of Gene Expression in Cardiorespiratory Muscles.
Reassessing the Role of Progenitor Cells in Muscle Wasting in Cancer Cachexia.
High-resolution spatial transcriptomic atlas of mouse soleus muscle: Unveiling single cell and subcellular heterogeneity in health and denervation.
Tumor-derived MG53 aggravates gastrointestinal cancer cachexia related muscle atrophy by inhibiting the TLR4/PI3K/AKT/FOXO3a signaling pathway.
An iron-regulated methionine redox axis governs adipose browning and cancer cachexia.
Mitochondrial Quality Control Impairment Is a Hallmark of TDP-43G376D ALS Patient-Derived Fibroblasts.
Combinatorial targeting of the miR-379/miR-410 cluster normalizes glucose and lipid homeostasis in male models of diabetes and obesity.
Lysosomal function and homeostasis: From cellular adaptation to disease pathogenesis.
MA-5 attenuates disease-associated transcriptomic aging and pathological microglial states in Gaucher disease.
Chronic Contractile Activity Remediates Lysosomal Dysfunction in a Muscle Cell Lysosomal Disease Model.
Context-Dependent modulation of astrocytic Ca2+ signals by mitochondria: a computational study.
Design, Synthesis, and Biological Evaluation of Novel ML-167 Analogues as Therapeutic Candidates Against Sarcopenia-Induced Muscle Wasting.
Sarcopenia Is Associated With Severe Treatment Toxicity and Mortality in Older Adults With Advanced Cancer: A Secondary Analysis.
Lysosomal Expression Profile in Plasma Associates with Disease Severity in Parkinson's Disease.

J Physiol. 2026 Sep 24.

Mitochondrial permeability transition in skeletal muscle phenocopies muscle alterations seen in cancer cachexia and other wasting conditions.

Maya Semel, Cole Lukasiewicz, Sarah Skinner, Mark R Viggars, Sung Gi Noh, Martin Picard, Abbey-Gale Mannings, Michael S Cohen, Dennis W Wolan, Terence E Ryan, Russell T Hepple.

  Skeletal muscle in wasting conditions often exhibits atrophy, mitochondrial respiratory dysfunction and fragmentation of the acetylcholine receptor (AChR) cluster at the endplate. The accompanying alterations in mitochondrial morphology suggest that mitochondria may be involved in muscle pathology in these conditions. To address this gap, we tested an established pathological mechanism in ischaemia-reperfusion injury and neurodegeneration but poorly studied in skeletal muscle: mitochondrial permeability transition (mPT). We tested if mPT recapitulated phenotypes common in wasting conditions, whether tumour-conditioned media (TCM) could promote mPT and compared differentially expressed genes (DEGs) induced by mPT with DEGs observed in a mouse model of pancreatic cancer cachexia. Inducing mPT in mouse skeletal muscle bundles progressively altered mitochondrial cristae morphology, culminating in a breach of the outer mitochondrial membrane. Inducing mPT in mouse muscle fibres increased mitochondrial reactive oxygen species (mROS) and caspase 3 activity and caused atrophy. Inducing mPT caused a complex I mitochondrial respiratory impairment, increased lysosome-mitochondrion colocalization and fragmented the AChR cluster at the muscle endplate. The Ca2+ threshold for mPT, mitochondrial calcein colocalization and mitochondrial membrane potential were reduced by TCM in skeletal muscle or C2C12 myoblasts, respectively. Knockout of the mPT-regulating protein CypD attenuated the reduction in Ca2+ threshold for mPT by TCM. Inhibitors of mPT attenuated atrophy with TCM in C2C12 and human primary myotubes. Finally, there was overlap between the DEGs of mPT and diaphragm muscle in a mouse model of pancreatic cancer cachexia during the muscle-wasting phase. We conclude that mPT should be explored as a therapeutic target in muscle-wasting disorders. KEY POINTS: Mitochondrial permeability transition (mPT) induces marked alterations in mitochondrial morphology and muscle phenotypes that are common in wasting conditions. mPT is promoted by tumour-derived factors in a manner that depends in part on the mPT-regulating protein CypD. mPT generates transcriptional alterations that overlap with cachectic muscle in a mouse model of pancreatic cancer, particularly during the period of muscle wasting. Pharmacological targeting of mPT attenuates or prevents atrophy in C2C12 and human primary myotubes, respectively.

Keywords:  mitochondrial permeability transition; mitophagy; muscle atrophy; muscle wasting; neuromuscular junction

DOI:  https://doi.org/10.1113/JP291213
J Cachexia Sarcopenia Muscle. 2026 Oct;17(5): e70383

Pancreatic Cancer Disrupts Circadian Patterns of Gene Expression in Cardiorespiratory Muscles.

Jeremy B Ducharme, Martin M Schonk, Miguel A Gutierrez-Monreal, Leonardo F Ferreira, Karyn A Esser, Andrew R Judge, Sarah M Judge.

   BACKGROUND: Cancer cachexia, a debilitating syndrome characterized by muscle wasting, significantly impacts survival in gastrointestinal cancers like pancreatic cancer. Emerging evidence suggests a link between cancer cachexia and disrupted circadian rhythms in peripheral tissues, including locomotor muscles. However, circadian dysregulation in cardiorespiratory muscles-whose functional decline are suspected to contribute to increased morbidity and mortality in patients experiencing cachexia-remains largely unexplored.
METHODS: Herein, we investigated circadian gene expression patterns in cardiorespiratory muscles during cachexia using the orthotopic KPC pancreatic cancer model. To do this, circadian transcriptomes were generated from diaphragm and heart tissues collected from Sham and KPC mice every 4 h over 24 h, beginning on Day 12 postinoculation, which, based on our prior work, reflects the onset of cachexia in this model. Rhythmically expressed genes (REGs) (Pc < 0.01) were identified using the LR_rhythmicity R package, which evaluates the goodness-of-fit (R2) to a 24-h sinusoidal model of transcript oscillations. Differences in circadian patterns, including changes in amplitude, phase and basal expression, were assessed using the LR_diff R package with p < 0.05.
RESULTS: We found that ~60% of rhythmic genes lost their circadian rhythmicity in both tissues, with distinct shifts in gene networks. Diaphragm disruptions centred on repression in basal expression and/or amplitude of core clock components and rest-phase-dependent disruptions to gene networks governing lipid and oxidative programs of metabolism and proteostasis, which were linked to an upregulation and gain of rhythmicity in inflammatory networks that peaked during the rest phase. Circadian disruptions in the heart involved loss of rhythmicity in gene networks governing cardiac function, including beta-adrenergic and cAMP signalling, cellular responses to insulin and neurogenesis, with a similar, but more limited upregulation of inflammatory networks.
CONCLUSIONS: These findings demonstrate that pancreatic cancer cachexia is associated with widespread circadian dysregulation in cardiorespiratory muscles, potentially contributing to both muscle wasting and functional decline.

Keywords:  cancer cachexia; circadian rhythm; circadian transcriptome; diaphragm; heart; muscle atrophy

DOI:  https://doi.org/10.1002/jcsm.70383
Am J Physiol Cell Physiol. 2026 Sep 19.

Reassessing the Role of Progenitor Cells in Muscle Wasting in Cancer Cachexia.

Spencer G Miller, Abasi-Ama Udeme, Emma Funk, Carlos Alfaro-Quinde, Suganya Subramanian, Stefano Berto, Jian Ouyang, David J Wang, Michael C Ostrowski, Teresa A Zimmers, Denis C Guttridge.

  Skeletal muscles contain myogenic and non-myogenic progenitor cells that proliferate and differentiate after tissue damage to restore myofiber, connective tissue, and blood vessel homeostasis. We previously showed that cancer-induced muscle wasting involves myofiber damage and impaired differentiation of myogenic progenitors, coincident with the aberrant accumulation of mesenchymal progenitor cells expressing both myogenic (Pax7) and non-myogenic (Sca1, Pdgfrα) progenitor markers. Here, we combined lineage tracing and scRNA-seq to more deeply explore muscle resident progenitor cells during cancer cachexia. Colon-26 (C-26) carcinoma cells were injected into adult (≥12-weeks-old) Pax7-CreER; Rosa26-LSL-tdTomato mice, and tamoxifen was administered after tumors were established but prior to cachexia. At cachexia endpoint, scRNA-seq analysis was performed on muscle mononuclear cells. In both control and C-26 muscles, Pax7 and tdTomato transcripts were restricted to myogenic progenitors, whereas Sca1 and Pdgfrα were restricted to non-myogenic progenitors. These results were confirmed by flow cytometry and suggest that mesenchymal progenitor cells do not commit to a myogenic fate during cancer cachexia. However, consistent with earlier findings, our transcriptomic analyses validated that myogenic progenitors from tumor-bearing mice were impaired to differentiate. When we repeated Pax7-lineage tracing and scRNA-seq on young mice (6-week-old) still undergoing developmental muscle growth similar results were obtained, but interestingly, by flow cytometry we detected a small population of Sca1+; tdTomato+ cells, not present in adult muscles. Thus, non-myogenic progenitors might indeed be capable of adopting a myogenic fate during cancer cachexia, but this contributes to only a minor fraction of Pax7+ cells and likely to be age dependent.

Keywords:  Cancer cachexia; atrophy; mesenchymal progenitor cells; muscle stem cells; myogenesis; regeneration; skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00144.2026
FEBS J. 2026 Sep 21.

High-resolution spatial transcriptomic atlas of mouse soleus muscle: Unveiling single cell and subcellular heterogeneity in health and denervation.

Jer-En Hsu, Lloyd Ruiz, Yongha Hwang, Steve D Guzman, Chun-Seok Cho, Weiqiu Cheng, Yichen Si, Peter Macpherson, Angelo Anacleto, Qingyang Zhao, Xiaoya Zhao, Mitchell Schrank, Goo Jun, Hyun Min Kang, Myungjin Kim, Susan V Brooks, Jun Hee Lee.

  Skeletal muscle exhibits pronounced cellular and subcellular heterogeneity, but comprehensive spatial mapping has been constrained by cell/nuclei dissociation-based methods that lose tissue architecture and by spatial platforms with insufficient resolution or limited transcriptome coverage. Here, we present a high-resolution spatial transcriptomic atlas of mouse soleus muscle in longitudinal sections with unbiased whole-transcriptome coverage, enabling myofiber-resolved transcriptomes while preserving subcellular expression domains across the length of fibers. Combining histology-guided myofiber segmentation with unbiased grid-based mapping, we recover canonical fiber types and reveal widespread hybrid myofiber states in situ, including type IIb-associated signatures that are rare in soleus muscle and evident only when intramyofiber heterogeneity is assessed. At subcellular scale, we delineate the neuromuscular junction (NMJ) as a multicompartment niche comprising postsynaptic myonuclei and spatially distinct perisynaptic and myelinating Schwann cell-associated regions, each with characteristic gene programs. Applying this framework to denervation (3 and 7 days) identifies robust fiber-type-specific stress responses, coordinated remodeling of macrophage and fibroblast transcriptomes, and marked intramyofiber heterogeneity, including spatially nonuniform activation of damage-response genes along individual myofibers, with distinct transcriptional domains proximal and distal to the NMJ and associated degenerative histological features. Together, this atlas provides a high-resolution reference for muscle biology and clarifies how denervation reshapes myofiber, synaptic, and stromal-immune programs across cells and within cells in intact tissue.

Keywords:  Seq‐Scope; denervation; neuromuscular junction; skeletal muscle; spatial transcriptomics

DOI:  https://doi.org/10.1111/febs.70726
Front Oncol. 2026 ;16 1919475

Tumor-derived MG53 aggravates gastrointestinal cancer cachexia related muscle atrophy by inhibiting the TLR4/PI3K/AKT/FOXO3a signaling pathway.

Yong-Fei Wang, Yuan-Yuan Xin, Si-Yuan Wang, Zi-Yi An, Dong-Yang Qi, Wen- Li, Wei-Lin Jin, Wen-Zhen Yuan.

   Background: Cancer cachexia is a multisystem syndrome characterized by progressive skeletal muscle atrophy, anorexia, and weight loss, imposing a substantial global health burden. Gastrointestinal cancer cachexia is highly prevalent, yet its pathogenesis remains poorly understood, and there is currently a lack of effective diagnostic methods and therapeutic strategies specifically targeting muscle atrophy. Identifying diagnostic and therapeutic targets for gastrointestinal cancer cachexia-related muscle atrophy represents a critical challenge.
Methods: This study investigated the role of MG53 in gastrointestinal cancer cachexia. Serum MG53 levels were analyzed in patients, and experimental models examined tumor-derived MG53 effects on cancer cachexia-related muscle atrophy.
Results: Elevated serum MG53 levels were found in gastrointestinal cancer cachexia patients. Tumor-derived MG53 aggravates cancer cachexia-related muscle atrophy by inhibiting the TLR4/PI3K/AKT/FOXO3a signaling pathway in muscle.
Conclusions: MG53 is identified as a novel cancer cachexia factor driving gastrointestinal cancer cachexia-related muscle atrophy by inhibiting the TLR4/PI3K/AKT/FOXO3a signaling pathway in muscle. MG53 correlates with muscle atrophy, supporting its potential as a diagnostic biomarker and therapeutic target of gastrointestinal cancer cachexia.

Keywords:  E3 ubiquitin ligases; MG53; PI3K/AKT/FOXO3a signaling pathway; cancer cachexia; cancer cachexia factors; inter-organ communication; muscle atrophy; skeletal muscle index

DOI:  https://doi.org/10.3389/fonc.2026.1919475
Nat Cancer. 2026 Sep 22.

An iron-regulated methionine redox axis governs adipose browning and cancer cachexia.

Jung Seung Nam, Sung Shin Ahn, Yeonoh Shin, Ariana Vargas-Castillo, Maya S Dixon, Pardis Ahmadi, Kathrin Schilling, Fereshteh Zandkarimi, Alex Chen, Nal Ae Yoon, Harrison Cullen, Yanping Sun, Thomas C Caffrey, Kelsey A Klute, Benjamin J Swanson, Jordan Lu, Samuel Pan, Yuxuan Chen, Shu Ichimiya, Geena Kim, Jeanine M Genkinger, Kazuki Sugahara, Michael D Kluger, Paul Grandgenett, Michael A Hollingsworth, Luke Berchowitz, Anthony W Ferrante, Lori M Zeltser, Sabrina Diano, Iok In Christine Chio.

Adipose browning and atrophy are early events of cachexia, a lethal metabolic disorder affecting nearly half of the population with cancer. Here, using individual-derived specimens and mouse models, we identified an iron-dependent pathway that initiates adipose browning in both physiological and cachectic settings. Upon adrenergic stimulation of adipocytes, an influx of iron induces the activity of methionine sulfoxide reductase A (MSRA), an enzyme that reverses the oxidation of proteinaceous methionine residues. Mechanistically, iron coordination by the conserved iron-binding EXXH motif of two MSRA polypeptides serves to dimerize, stabilize and elevate its reductase activity. Iron-bound MSRA dimers in turn promote adipose browning by maintaining the reduced state of select substrates, including the catalytic subunit of protein kinase A. Remarkably, in mouse models, MsrA deletion impairs adipose browning, mitigates cachexia and prolongs the survival of tumor-bearing animals. Thus, as a key nexus of cancer-associated cachexia, the β3 adrenergic receptor-iron-MSRA axis is a promising target for clinical intervention.

DOI: https://doi.org/10.1038/s43018-026-01234-y
Antioxidants (Basel). 2026 Aug 22. pii: 1051. [Epub ahead of print]15(9):

Mitochondrial Quality Control Impairment Is a Hallmark of TDP-43G376D ALS Patient-Derived Fibroblasts.

Giuseppe Petito, Maria Ventriglia, Victoria Stefania Del Fiore, Arianna Cuomo, Federica Cioffi, Francesco Manfrevola, Flora Guerra, Lucia Bertuccini, Giulia Ricci, Gilda Cobellis, Antonia Lanni, Cecilia Bucci, Roberta Romano, Rosalba Senese.

  Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder strongly associated with mitochondrial dysfunction and impaired proteostasis. Mutations in TARDBP, encoding TAR DNA-binding protein 43 (TDP-43), contribute to disease pathogenesis through cytoplasmic mislocalization and aggregation. Among these, the ALS-linked TDP-43G376D mutation has been previously associated with oxidative stress, mitochondrial fragmentation, and impaired oxidative phosphorylation. Here, we investigated the impact of TDP-43G376D on Mitochondrial Quality Control (MQC) pathways using patient-derived dermal fibroblasts carrying the mutation at early and advanced disease stages, complemented by HEK293T and Neuro2a cellular models expressing mutant TDP-43. We show that TDP-43G376D impairs mitophagic flux, as evidenced by reduced delivery of damaged mitochondria to lysosomes. This was accompanied by pronounced disruption of mitochondrial cristae architecture and accumulation of mitochondrial DNA damage, indicating compromised mitochondrial genome integrity. Furthermore, TDP-43G376D induces sustained activation of the mitochondrial Unfolded Protein Response (UPRmt), consistent with persistent mitochondrial stress, while selectively impairing the sirtuin-dependent antioxidant branch. In parallel, activation of the Endoplasmic Reticulum UPR (UPRER) was observed, indicating a coordinated engagement of cellular stress pathways. Collectively, our findings identify coordinated alterations in multiple MQC pathways associated with TDP-43G376D rather than isolated mitochondrial defects, supporting further investigation of these pathways in larger and disease-relevant ALS models.

Keywords:  Amyotrophic Lateral Sclerosis (ALS); Endoplasmic Reticulum stress; Mitochondrial Quality Control (MQC); TDP-43; mitochondrial Unfolded Protein Response (UPRmt); mitochondrial dysfunction; mitophagy; oxidative stress

DOI:  https://doi.org/10.3390/antiox15091051
Nat Commun. 2026 Sep 21. pii: 10014. [Epub ahead of print]17(1):

Combinatorial targeting of the miR-379/miR-410 cluster normalizes glucose and lipid homeostasis in male models of diabetes and obesity.

Manuel Gil-Lozano, Estefanía Simoes, Moya Wu, Tobias Wiedemann, Yun Kwon, Revathi Sekar, Pauline Morigny, Maria Troullinaki, Juliane Merl-Pham, Michael Buettner, Annette Feuchtinger, Celine Jouffe, Adriano Maida, Daniela Hass, Daniel Samaga, Gretchen Wolff, Juliano Machado, Maude Giroud, Katarina Klepac, Carolyn L Cummins, Marcos Ríos García, Peter Weber, Anja Zeigerer, N Henriette Uhlenhaut, Julia Szendroedi, Matthias Blüher, Stephan Herzig.

Non-coding RNAs from the Dlk1-Dio3 locus are critical for the maturation of metabolic tissues in early stages of postnatal development; however, their role in the mature organs remains elusive. Herein, we show that microRNAs from the miR-379/miR-410 cluster are robustly upregulated in livers of subjects with obesity and various mouse models of metabolic dysfunction. Adult-onset, combinatorial inhibition of this miRNA cluster by hepatocyte-specific expression of a decoy sequence reduces triglyceride, total and LDL cholesterol circulating levels, decreases basal glycemia and improves glucose tolerance and insulin sensitivity irrespective of sex. Consistent with the decoy-triggered enhancement of PI3K/mTOR signaling in these mice, hepatocytes expressing the combinatorial decoy show augmented mitochondrial mass and function. Notably, decoy therapy also ameliorates glucose and lipid homeostasis in both type 1 diabetic and diet-induced, type 2 pre-diabetic, obese male animals. Collectively, our results demonstrate that microRNAs from the miR-379/miR-410 cluster are critical regulators of metabolic homeostasis in the mature liver. Given the preservation of miRNA dysfunction in human obesity, hepatocyte-specific combinatorial inhibition of a large miRNA cluster represents an approach towards multi-parameter improvements in diabetes and obesity.

DOI: https://doi.org/10.1038/s41467-026-77808-2
Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(26)00034-1. [Epub ahead of print]406 1-42

Lysosomal function and homeostasis: From cellular adaptation to disease pathogenesis.

Satoshi Minami, Maho Hamasaki.

  Lysosomes were once considered terminal degradative organelles responsible for disposing of cellular waste. However, recent studies have revealed that lysosomes serve as dynamic signalling and metabolic hubs at the center of diverse biological processes, including nutrient sensing, metabolic regulation, membrane trafficking, autophagy, inflammation, and cell death. To support this broad functional repertoire, lysosomes must possess robust mechanisms to maintain their integrity in the face of damage or stress. In response to lysosomal membrane damage, cells engage multilayered adaptive mechanisms that act in coordination-membrane repair (Repair), selective removal of damaged organelles (Removal), and de novo biogenesis of lysosomes (Regeneration). These processes are mediated by a range of molecular pathways, including the ESCRT complex, the PITT pathway, lysophagy, and TFEB-dependent lysosomal regeneration. Notably, recent findings highlight the noncanonical autophagy-like pathway known as ATG8ylation (conjugation of ATG8s on single membranes), which is activated via the STING-V-ATPase-ATG16L1 axis and functions as a critical hub connecting multiple arms of the lysosomal damage response. In this review, we systematically outline the molecular basis of lysosomal damage responses, including ATG8ylation, and explore how these networks are implicated in a broad spectrum of pathological conditions such as aging, neurodegeneration, cancer, obesity-related disorders, and immune dysfunction. Understanding these lysosomal quality control mechanisms not only sheds light on the fundamental principles of organelle homeostasis but also opens new avenues for therapeutic innovation.

Keywords:  Lysophagy; Lysosome; Organelle damage; Selective autophagy

DOI:  https://doi.org/10.1016/bs.ircmb.2026.04.002
Res Sq. 2026 Sep 14. pii: rs.3.rs-10994808. [Epub ahead of print]

MA-5 attenuates disease-associated transcriptomic aging and pathological microglial states in Gaucher disease.

Yoshiyasu Tongu, Tomoko Kasahara, Kohta Nakamura, Alexander Tyshkovskiy, Yoshitsugu Oikawa, Tetsuro Matsuhashi, Chikahiko Numakura, Risako Fujita, Yoshiteru Kagawa, Zhiqian Yu, Tomoyuki Furuyashiki, Rina Inoue, Daisuke Saigusa, Ryota Kujirai, Yotaro Matsumoto, Eiji Kakazu, Masaru Shimura, Yohei Sugiyama, Shun Watanabe, Yohei Honkura, Kuniyasu Niizuma, Hidenori Endo, Ko Hashimoto, Chiharu Kawabe, Hidetaka Tokuno, Koichi Kikuchi, Chitose Suzuki, Naoyuki Matsumoto, Junken Aoki, Kei Murayama, Hiroaki Tomita, Yuji Owada, Yukio Katori, Tomoyoshi Soga, Yoshihisa Tomioka, Takeya Sato, Takehiro Suzuki, Takafumi Toyohara, Yasushi Okazaki, Paul Anderson, Vadim N Gladyshev, Takaaki Abe.

  Chronic inflammation and mitochondrial dysfunction are hallmarks of neurodegeneration and aging, yet how mitochondrial damage contributes to inflammatory and aging-like cellular programs remains poorly understood. Gaucher disease (GD) is a lysosomal storage disorder caused by GBA1 mutations, which also represent a major genetic risk factor for Parkinson's disease. In a GD mouse model, we identified marked mitochondrial cristae disorganization accompanied by mitochondrial DNA release, activation of the cGAS-STING and NLRP3 inflammasome pathways, and subsequent inflammatory microglial activation. Circulating galectin-3 was also elevated in both model mice and patients with GD, supporting its potential relevance as a systemic marker of disease-associated inflammation. Mitochonic acid-5 (MA-5) is a mitochondria-targeting compound that interacts with mitofilin/MIC60 in the mitochondrial inner membrane and enhances ATP production. In a GD mouse model and patient-derived iPSC microglia, MA-5 increased ATP levels, preserved mitochondrial cristae integrity, limited mtDNA release, and suppressed cGAS-STING and NLRP3 inflammasome signaling, thereby attenuating microglial innate immune activation and galectin-3 expression. MA-5 also prolonged survival and reversed accelerated transcriptomic aging across multiple brain cell types, with particularly prominent effects in microglia. In the liver, GD was similarly associated with inflammatory, stress-related, and aging-associated transcriptional changes, whereas MA-5 improved liver function, restored mitochondrial morphology, suppressed inflammatory and stress responses, restored metabolic programs, and reduced transcriptomic age. Overall, MA-5 suppresses neuroinflammation and reverses accelerated transcriptomic aging, supporting its potential as a therapeutic strategy for GD and other lysosomal storage disorders, as well as for diseases characterized by mitochondrial dysfunction, chronic inflammation, and pathological accumulation.

Keywords:  Aging clock (tAge); Gaucher disease; NLRP3 inflammasome; cGAS-STING pathway; galectin-3; inflammation; microglia; mitochondria

DOI:  https://doi.org/10.21203/rs.3.rs-10994808/v1
J Cell Physiol. 2026 Sep;241(9): e70231

Chronic Contractile Activity Remediates Lysosomal Dysfunction in a Muscle Cell Lysosomal Disease Model.

Debasmita Bhattacharya, Neushaw Moradi, David A Hood.

  Lysosomes are important organelles for the degradation of unwanted biomolecules via autophagy. Lysosomal dysfunction is apparent in ageing tissues, and can cause various neurodegenerative diseases. It is imperative to understand the mechanisms and implications of lysosomal malfunction and to find strategies to ameliorate diseases. To investigate this, we induced lysosomal dysfunction with Bafilomycin A1 (BAF), a drug that hinders lysosomal acidification by blocking vATPase-mediated proton pumping, in myoblasts and myotubes. Myotubes were subjected to chronic contractile activity (CCA) to mimic "exercise" to evaluate any therapeutic potential and reversal of pathophysiology. Induced lysosomal dysfunction was evident from impaired processing of the protease cathepsin B, enhanced lysosomal accumulation and increased autophagic markers Lamp1, p62, and the LC3II/I ratio. BAF attenuated lysosomal protease degradation measured using the substrate DQ-BSA in both myoblasts and myotubes. Many of the adverse effects generated by BAF in myotubes were reversed by CCA, manifested by a decrease in immature cathepsin B, a down-regulation of Lamp1, p62, LC3II/I and partial restoration of lysosomal protein degradation enzymatic capacity. To investigate further improvements in lysosomal function in a healthy cellular model, we treated myotubes with C1, a curcumin analogue. C1 decreased Lamp1, p62 and the LC3II/I ratio, all of which indicate improved lysosomal function and autophagosome clearance with a greater lysosomal ability to degrade substrates. Additionally, C1 was able to mimic the improved mitochondrial content induced by CCA. Thus, contractile activity and curcumin analogues may provide useful therapeutic potential to resuscitate lysosomal function, improve muscle health and ameliorate lysosome-mediated diseases. NEW AND NOTEWORTHY: This study explores the potential of chronic contractile activity (CCA) in reversing the compromised lysosomes caused by the disruption of lysosomal acidification in myotubes. Remarkably, CCA mitigated the effects of Bafilomycin A1-induced lysosomal dysfunction, enhancing protease activity and increased mitochondrial content. Treatment of myotubes with the curcumin analogue C1 reduced lysosomal accumulation and enhanced mitochondrial content suggesting that contractile activity-based interventions and small-molecule modulators of lysosomal pathways may represent promising complementary strategies for treating lysosome-related diseases and enhancing muscle health.

Keywords:  autophagy; bafilomycin A; exercise; lysosomes; mitochondria

DOI:  https://doi.org/10.1002/jcp.70231
J Comput Neurosci. 2026 Sep 25.

Context-Dependent modulation of astrocytic Ca2+ signals by mitochondria: a computational study.

Thiago Ohno Bezerra, Antonio C Roque.

  Mitochondria regulate intracellular Ca2+ by uptake through the mitochondrial Ca2+ uniporter (MCU) and release via the mitochondrial permeability transition pore (mPTP). In astrocytes, neurotransmitter stimulation evokes Ca2+ signaling, yet the role of mitochondria in shaping these responses remains unclear. We extended a compartmental astrocyte model developed by our group to include MCU- and mPTP-mediated dynamics, and simulated glutamatergic and dopaminergic inputs modeled as Poisson processes driving IP3 synthesis through the phospholipase-C (PLC) pathway. Both unipolar and bifurcated-terminal morphologies were considered, with mitochondria positioned in alternating compartments starting from the soma; distal compartments contained mitochondria only when sufficiently large. Simulations show that mitochondria modulate Ca2+ signaling in a context-dependent manner: under weak glutamatergic input, they reduce oscillation frequency and limit signal propagation, whereas under strong glutamatergic input or dopaminergic modulation, they enhance Ca2+ responses by reducing Ca2+-dependent IP3 degradation. These results suggest that mitochondria can play an important role in shaping the spatial organization of Ca2+ signaling in astrocytes.

Keywords:  Astrocytes; Calcium signaling; Glia; Mitochondria

DOI:  https://doi.org/10.1007/s10827-026-00956-3
Pharmaceuticals (Basel). 2026 Sep 11. pii: 1442. [Epub ahead of print]19(9):

Design, Synthesis, and Biological Evaluation of Novel ML-167 Analogues as Therapeutic Candidates Against Sarcopenia-Induced Muscle Wasting.

Issam Ameziane El Hassani, Shabnam Alizadeh, Sajda Ashraf, N Ceren Suer, Aybuke Ozturk, Woonghee Kim, Muhammed Melik Saracoglu, Edanur Yildiz, Seymanur Baycelebi, Gonca Candan, Gizem Bati Ayaz, Mustafa Kara, Murat Ozdemir, Busra Turan, Neaz Ahmed, Onur Ceylan, Sevilay Ozmen, Fatih Isik, Eda Sahin, Fatih Alper, Hasan Turkez, Adil Mardinoglu.

  Background: Sarcopenia is an aging-related syndrome characterized by loss of skeletal muscle mass, strength, and function, with no approved pharmacological treatment. This study aimed to design, synthesize, and evaluate novel ML-167 derivatives for sarcopenia-associated muscle wasting. Methods: ML-167 derivatives were synthesized and characterized by 1H NMR, 13C NMR, and mass spectrometry. Biological activity was evaluated in C2C12 myoblasts using MTT and Western blot assays. Selected compounds were evaluated in a dexamethasone-induced muscle wasting model. Muscle strength, mass, biochemical parameters, and histopathology were assessed. Structure-activity relationships were analysed using cell viability, molecular docking, and ligand efficiency data, alongside physicochemical properties. Results: Compounds 6b (116%), 3a (115%), 8d (114%), 4c (112%), 3m (112%), and 3c (111%) showed the highest C2C12 viability at 1 μM. Compounds 3a, 3c, and 6b increased MyH3 expression by approximately 1.6-1.7-fold, while MyoG remained near basal levels. In vivo, these compounds improved muscle strength, mass, and biochemical parameters without overt hepatic or renal abnormalities based on assessed serum and histopathological findings. Among the evaluated derivatives, compound 6b emerged as the most promising overall lead candidate, showing the greatest improvement in skeletal muscle mass and metabolic parameters, whereas compound 3c demonstrated the strongest histopathological protection and favourable effects on muscle strength with favourable physicochemical properties. Molecular docking supported the SAR trends, although did not consistently correlate with cellular activity. Conclusions: The findings identify 3a, 3c, and 6b as promising lead compounds and support further investigation of ML-167 derivatives as potential pharmacological approaches for sarcopenia-associated muscle wasting.

Keywords:  in vivo rat model; muscle atrophy; myogenic differentiation; myogenin (MyoG); myosin heavy chain 3 (MyH3); preclinical efficacy; sarcopenia

DOI:  https://doi.org/10.3390/ph19091442
J Cachexia Sarcopenia Muscle. 2026 Oct;17(5): e70388

Sarcopenia Is Associated With Severe Treatment Toxicity and Mortality in Older Adults With Advanced Cancer: A Secondary Analysis.

Lindsey J Mattick, Mostafa Mohammed, Chin-Shang Li, Rachael G Tylock, Kah Poh Loh, Marie A Flannery, Luke J Peppone, Po-Ju Lin, Marcus D Goncalves, Bette J Caan, Elizabeth M Cespedes Feliciano, Karteek Popuri, Mirza Faisal Beg, James D Bearden, Jeffrey Berenberg, Khalil Katato, Karen M Mustian, Supriya G Mohile, Richard F Dunne.

   BACKGROUND: Sarcopenia, a loss of muscle strength, quantity and performance that occurs primarily from ageing or secondary to disease, is hypothesized to worsen treatment outcomes in patients with cancer. Most published studies, however, focus solely on muscle quantity in patients under 70. Here, we evaluate the association between sarcopenia, defined as both a loss of strength and muscle quantity, and treatment tolerability in older adults receiving cancer treatment.
METHODS: This secondary analysis examines data from a randomized clinical trial evaluating a geriatric assessment intervention (NCT02054741). Older adults (≥ 70 years) with advanced cancer starting a new treatment regimen were recruited from community oncology practices across the United States. We analysed data from 161 participants in the usual care arm with baseline standard of care computed tomography (CT) scans. Sarcopenia was defined by reduced strength (chair stand > 16.7 s for five rises) and either a reduction in muscle quantity (skeletal muscle index [SMI] < 41 cm2/m2 women, < 43 cm2/m2 men with BMI < 24.9 kg/m2 or < 53 cm2/m2 men with BMI ≥ 25 kg/m2) or muscle quality. Sarcopenia was considered severe when the above criteria were met along with impaired physical performance (TUG > 13.5 s). Treatment toxicity was assessed via Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
RESULTS: Among 161 participants (mean age: 76.6 ± 4.7; 61% male, 94% non-Hispanic white), 57% (91/161) met criteria for sarcopenia, of which 59% (54/91) were considered severe. Sarcopenia was associated with deficits in multiple geriatric assessment domains (nutrition, activities of daily living, instrumental activities and cognition; p < 0.05). In multivariable logistic regression and Cox proportional hazards regression analyses, patients with sarcopenia were more likely to experience severe non-hematologic toxicities (Grades 3-5; OR = 2.24, 95% confidence interval [CI]: 1.12-4.47). In participants receiving first-line therapy, sarcopenia was associated with worse 1-year survival (46% survival [95% CI: 35%-55%]; HR = 2.12 [95% CI: 1.14-3.93]; 49 events) compared to those without sarcopenia (60% survival [95% CI: 48%-70%]; 28 events). SMI alone was not significantly associated with severe nonhematologic toxicity or survival.
CONCLUSION: Sarcopenia is highly prevalent in older patients with cancer and is associated with severe toxicity and mortality. Our findings highlight the importance of assessing muscle strength, quantity, quality and performance when evaluating older adults with cancer.
TRIAL REGISTRATION: CLINICALTRIALS.GOV NCT02054741.

Keywords:  cancer; geriatric oncology; sarcopenia; treatment tolerability

DOI:  https://doi.org/10.1002/jcsm.70388
Mov Disord. 2026 Sep 21.

Lysosomal Expression Profile in Plasma Associates with Disease Severity in Parkinson's Disease.

Janna van Wetering, Manon M van Ingen, Evelien Timmermans, Sjors G J G In't Veld, Henk W Berendse, Charlotte E Teunissen, Wilma D J van de Berg.

   BACKGROUND: Parkinson's disease (PD) is a clinically and biologically heterogeneous neurodegenerative disorder, driven by multiple mechanisms among which are lysosomal and mitochondrial dysfunction. Here, we explored blood-based lysosomal and mitochondrial profiles in relation to PD diagnosis and severity.
METHODS: Plasma samples (n = 504) were analyzed using SomaScan, targeting 394 lysosomal and 502 mitochondrial proteins in a discovery (ProPARK: 145 PD, 73 controls) and a validation cohort (Alzheimer's Disease Research Center [ADRC]: 104 PD, 182 controls). Linear and LASSO regression were included to compare groups and select PD-predictive proteins. Associations with Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr, Montreal Cognitive Assessment (MoCA), levodopa equivalent daily dose (LEDD) and disease duration were assessed and age-, sex-, and false discovery rate (FDR)-adjusted.
RESULTS: In ProPARK, 29 dysregulated lysosomal and 46 mitochondrial proteins were identified in PD; upregulated lysosomal sulfatase-modifying factor 1 (SUMF1) (FC = 1.41) and arrestin domain containing 3 (ARRDC3) (1.36) survived correction. LASSO identified eight lysosomal proteins (area under the curve [AUC] train: 0.83, test: 0.75) and two mitochondrial proteins (AUC train: 0.66, test: 0.65). Lysosomal score associated with disease duration, LEDD, and UPDRS-IV, whereas mitochondrial score did not. SUMF1 associated with disease duration, LEDD, and UPDRS-IV; ARRDC3 only with disease duration. In ADRC, upregulation of SUMF1 and ARRDC3 in PD (FC = 1.72 and 1.36), their association with LEDD, discriminatory AUCs of lysosomal and mitochondrial scores (0.80 and 0.58), and the association between lysosomal score and LEDD replicated.
CONCLUSIONS: Lysosomal expression scores discriminated PD from controls and associated with disease severity. SUMF1 and ARRDC3 emerged as blood-based biomarkers for PD. These findings support the use of pathway-specific biomarkers for improving PD diagnostics and monitoring disease progression. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords:  blood biomarker; diagnostic accuracy; lysosomal pathway; molecular profiling; motor dysfunction; proteomics

DOI:  https://doi.org/10.1002/mds.70542