bims-musmir 2026-06-07 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–06–07
sixteen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Exercise training prior to and during cancer in mice preserves muscle mass, reduces tumour weight and suppresses molecular mediators of cachexia.
miR-146a is a pleiotropic regulator of motor neuron degeneration.
PEBP4 alleviates muscle wasting in lung cancer cachexia via KEAP1-NRF2-mediated redox homeostasis.
Oxidative Stress and Diminished Mitochondrial Proteostatic Reserve Are Linked to Enhanced mtUPR Initiation in Aged Mouse Muscle.
Single-fiber morphometry and spatial transcriptomics reveal selective oxidative muscle fiber atrophy in non-metastatic breast cancer.
Bilateral versus unilateral injection of Lewis lung carcinoma cells in female mice fed a Western diet: effects on cachexia severity, tumor burden, and tumor ulcerations.
Argonaute-2 slicing of Rtl1 promotes skeletal muscle development and postnatal survival.
Mitochondrial Dysfunction in Myoblasts: A TSPO-Dependent Mechanism of Sarcopenia.
High-content screening identifies mTORC1-independent TFEB activators that promote protective autophagy.
TDP-43 oxidation and PP1 crosstalk at RNA granule-mitochondria contact sites.
Early-onset neuroinflammation drives neurodegeneration caused by lysosomal PI(3,5)P2 insufficiency.
A microRNA atlas of the human prefrontal cortex across the adult lifespan.
Novel Long-Acting Ghrelin Analogue PEP-064 Restores Energy Balance in C26 and Lewis Lung Carcinoma-Induced cachexia in Mice.
The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway.
Sex-specific effects of fatiguing exercise on skeletal muscle passive mechanics are preserved in aging.
Neuroprotective Effects of RNS60 in TDP-43 Pathology-Associated Amyotrophic Lateral Sclerosis.

J Physiol. 2026 Jun 04.

Exercise training prior to and during cancer in mice preserves muscle mass, reduces tumour weight and suppresses molecular mediators of cachexia.

Stavroula Tsitkanou, Pieter J Koopmans, Ana Regina Cabrera, Nathan Serrano, Calvin S Peterson, Ruqaiza Muhyudin, Zain B Malik, Micah Goeke, Eleanor R Schrems, Francielly Morena, Yuan Wen, Tyrone A Washington, Kevin A Murach, Nicholas P Greene.

  We investigated the prophylactic effects of exercise before and during cancer cachexia (CC) using a model designed to mimic endurance and resistance (i.e., concurrent) adaptations. Male and female Balb/c mice were randomly assigned to exercise or control groups whereby exercise groups were subjected to an 8-week voluntary progressive weighted wheel running (PoWeR) programme of habitual loading-mediated physical activity beginning at 8 weeks of age. At 16 weeks of age, mice were injected bilaterally with colon-26 adenocarcinoma (C26) cells or phosphate-buffered saline, and exercise training was maintained throughout disease progression. Twenty-five days post-tumour induction, we assessed whole-body and muscle phenotype, muscle protein synthesis, a priori targeted gene expression, and transcriptomic adaptations via RNA sequencing. PoWeR training preserved skeletal muscle mass across nearly all muscle groups and maintained tumour-free body and cardiac mass. Muscle mass adaptations related to running volume, and running distance relative to controls were not appreciably reduced by tumour status. Tumour burden was reduced after ∼11.5 weeks of PoWeR compared to sedentary, but this was not explanatory for muscle adaptations. PoWeR induced a faster-to-slower muscle fibre type transition in the gastrocnemius and suppressed key protein turnover markers (Redd1, Murf1, Atrogin, Ubc, Gadd45a) as well as the mitophagy-related marker Bnip3 in tumour-bearing muscle; 24 h muscle protein synthesis remained stable. PoWeR counteracted tumour-induced impairments in the muscle mitochondrial- and metabolic-related transcriptome. Collectively, physical activity prior to and during cancer preserves muscle mass, reduces tumour growth and mitigates molecular drivers of CC, underscoring its preventive and therapeutic potential as a lifestyle intervention. KEY POINTS: Cancer cachexia (CC) is a severe, multifactorial syndrome with limited effective therapies. Exercise training has emerged as a promising non-pharmacological approach to mitigate CC. Concurrent endurance and resistance training, initiated prior to and maintained during cancer, preserves skeletal muscle mass and reduces tumour burden in C26 colorectal tumour-bearing mice. Concurrent exercise training suppresses key mitochondrial- and metabolic-related molecular mediators of CC. Concurrent exercise training may serve as a preventive and therapeutic non-pharmacological strategy against CC.

Keywords:  PoWeR; colon cancer; concurrent exercise training; mitochondrial adaptations; mitophagy; muscle fibre type; progressive weighted wheel‐running; protein degradation

DOI:  https://doi.org/10.1113/JP290740
Proc Natl Acad Sci U S A. 2026 Jun 09. 123(23): e2526314123

miR-146a is a pleiotropic regulator of motor neuron degeneration.

Dylan A Galloway, Hunter L Patterson, Mariah L Hoye, Tao Shen, Mark Shabsovich, Kathleen M Schoch, Cindy V Ly, Timothy M Miller.

  Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. Here, we have profiled motor neuron microRNAs (miRNAs) during motor neuron degeneration in vivo to gain a better understanding of ALS pathophysiology. We demonstrate that one miRNA, miR-146a, is downregulated in diseased motor neurons despite upregulation in bulk tissue. Genetic deletion of miR-146a significantly extended survival in SOD1G93A mice with heterozygous animals demonstrating the largest benefit. A corresponding reduction in spinal cord gliosis but not motor neuron loss was observed. Finally, we observed that a proportion of miR-146a knockout animals develop spontaneous paralysis, motor neuron loss and chronic neuroinflammation with advanced age. Together these findings demonstrate that a single miRNA influences multiple aspects of motor neuron disease and highlights the complex role for neuroinflammation in ALS pathogenesis.

Keywords:  amyotrophic lateral sclerosis; microRNA; neuroinflammation

DOI:  https://doi.org/10.1073/pnas.2526314123
Cell Death Dis. 2026 Jun 03.

PEBP4 alleviates muscle wasting in lung cancer cachexia via KEAP1-NRF2-mediated redox homeostasis.

Yaru Xia, Yuqi Han, Weiquan Li, Tiexi Yu, Diaoyi Tan, Daojia Miao, Wen Li, Jiaming Wu, Qianqian Luo, Jiemin Li, Pian Liu, Hongli Liu, Guixiao Huang, Xiaoping Zhang, Hongmei Yang.

Cancer-associated cachexia (CAC) is a multifactorial metabolic syndrome characterized by progressive skeletal muscle wasting. However, the molecular link between tumor metabolic stress and muscle degradation remains elusive. Here, we identify phosphatidylethanolamine-binding protein 4 (PEBP4) as a key regulator of muscle homeostasis under cachectic conditions. PEBP4 expression is markedly suppressed in lung cachectic models and is inversely correlated with tumor-derived lactate levels. Mechanistically, PEBP4 stabilizes NRF2 by competitively binding to KEAP1, enhancing antioxidant defense, inhibiting NF-κB signaling, and downregulating muscle atrophy-related genes MuRF1 and Fbxo32 (also known as Atrogin-1). In vitro and in vivo overexpression of PEBP4 mitigates oxidative stress, preserves muscle mass, and improves strength and endurance in Lewis lung carcinoma tumor-bearing mice. These protective effects are significantly attenuated by NRF2 inhibition, highlighting its critical role in PEBP4-mediated signaling. Collectively, our findings uncover a tumor lactate-PEBP4-NRF2 axis linking cancer metabolism to redox imbalance and muscle wasting, and suggest the therapeutic potential of targeting the PEBP4-NRF2 pathway in lung cancer-associated cachexia.

DOI: https://doi.org/10.1038/s41419-026-08925-5
Aging Cell. 2026 Jun;25(6): e70573

Oxidative Stress and Diminished Mitochondrial Proteostatic Reserve Are Linked to Enhanced mtUPR Initiation in Aged Mouse Muscle.

Grant R Laskin, Baylah R Mazonson, LaDora V Thompson.

Mitochondrial dysfunction, impaired proteostasis, and reduced stress resistance and resilience are aging hallmarks. At the core of these hallmarks, the mitochondrial unfolded protein response (mtUPR) is a transcriptional pathway that restores mitochondrial proteostasis in response to proteotoxicity. Although the mtUPR is well studied in invertebrates and cell culture models, how the mtUPR is engaged in aged mammalian tissue is poorly defined. Here, we defined the extent to which repeated physical stress initiates mtUPR transcription in aged mouse skeletal muscle and assessed candidate regulatory mechanisms in vivo. Aged muscle exhibited reduced mitoprotective chaperone and protease availability and greater carbonylation of intermyofibrillar mitochondria relative to young muscle, suggesting diminished proteostatic reserve and increased oxidative burden. Short-term physical stress induced a greater initiation of mtUPR genes in aged muscle than young muscle, coinciding with reduced physiological reserve. Physical stress shifted ATF5 localization from the mitochondria to the nucleus in the muscle of both ages, whereas CHOP mRNA and nuclear localization were selectively elevated in aged muscle. Mechanistically, we show mitochondrial reactive oxygen species (mtROS) contribute to mtUPR initiation in aged skeletal muscle. Using in vivo ChIP-qPCR and in vitro knockdown/inhibition experiments, we provide support for CHOP as a redox-sensitive factor contributing in part to the enhanced mtUPR initiation in aged mouse muscle, potentially linked to JNK signaling. Collectively, these data suggest reduced mitochondrial proteostatic reserve and mtROS signaling in aged muscle contribute to an amplified mtUPR transcriptional response following repetitive physical stress, providing the foundation to explore the mtUPR in mammalian aging.

DOI: https://doi.org/10.1111/acel.70573
medRxiv. 2026 May 20. pii: 2026.05.11.26351978. [Epub ahead of print]

Single-fiber morphometry and spatial transcriptomics reveal selective oxidative muscle fiber atrophy in non-metastatic breast cancer.

Alan D Mizener, Stuart A Clayton, Alexa L Bostic, Isabelle A Oberhauser, Hannah E Wilson, Marcella A Whetsell, Hannah Hazard-Jenkins, Jessica F Partin, Emidio E Pistilli.

Cancer-related fatigue is the most common and persistent symptom in breast cancer, with fatigue reported up to 10 years post-diagnosis. Unlike many cancers, fatigue in breast cancer often arises during early-stage disease in the absence of cachexia. While many factors contribute to fatigue, the direct contribution of cancer-associated skeletal muscle pathology remains poorly understood. Here we analyzed pectoralis major muscle biopsies from individuals with non-metastatic breast cancer and non-cancer controls using single-fiber morphometry and spatial transcriptomics. We identified fiber-type-specific structural alterations and spatially localized transcriptional reprogramming within the muscle microenvironment. Single-fiber morphometry revealed selective atrophy of oxidative type I and type IIa muscle fibers, while glycolytic type IIx fibers were relatively preserved. Concordant spatial transcriptomic profiling revealed suppression of oxidative metabolic programs, evidence of mitochondrial dysfunction, and spatially localized catabolic signaling originating from intramuscular adipocytes. This study introduces an integrated framework for profiling skeletal muscle architecture and spatially localized gene expression in surgically obtained muscle biopsies and represents the first application of spatial transcriptomics to human skeletal muscle from individuals with cancer. These findings demonstrate structural and metabolic remodeling of skeletal muscle in non-metastatic breast cancer and suggest targeting muscle metabolism represents a promising therapeutic strategy for cancer-related fatigue.

DOI: https://doi.org/10.64898/2026.05.11.26351978
BMC Res Notes. 2026 Jun 02.

Bilateral versus unilateral injection of Lewis lung carcinoma cells in female mice fed a Western diet: effects on cachexia severity, tumor burden, and tumor ulcerations.

Rebecca F Rodriguez, Lauren F Boone, Michelle L Law.

   OBJECTIVE: Cachexia leads to weight loss and muscle wasting, reducing quality and length of life for advanced cancer patients. There is increasing interest in studying cachexia in the context of obesity due to its increasing worldwide prevalence. C57Bl6 mice are susceptible to diet-induced obesity and Lewis lung carcinoma (LLC)-induced cachexia; however, challenges with this model include large tumor sizes with ulcerations and a mild cachexia phenotype in females. Therefore, this study tested the effect of injecting fewer LLC cells compared to previous studies at either one or two sites in female mice on a Western diet. We hypothesized this would decrease tumor growth rate and ulcerations, enabling longer study duration and overt cachexia development.
RESULTS: Contrary to our hypothesis, over half of tumors developed ulcerations, requiring study termination at 19 days. However, mice with one and two tumors still developed mild and severe cachexia, respectively. Total tumor mass was less predictive of cachexia severity than tumor number. These data show bilateral injections of 250,000 LLC cells induced significant cachexia in female mice on a Western diet, despite a shortened study timeline. These findings are important for improving pre-clinical modeling of cachexia in the context of Western-style obesogenic diets and obesity.

Keywords:  Atrophy; Cancer; High-fat diet; Mouse model; Muscle; Obesity; Weight loss

DOI:  https://doi.org/10.1186/s13104-026-07902-7
bioRxiv. 2026 May 24. pii: 2026.05.22.727060. [Epub ahead of print]

Argonaute-2 slicing of Rtl1 promotes skeletal muscle development and postnatal survival.

Nickolas Almodovar, Caroline Dunn, Benjamin Kleaveland.

Argonaute (AGO) proteins associate with small guide RNAs to bind and repress mRNA targets. AGO2 is the primary AGO slicer in mammals, cleaving RNAs that base-pair extensively to its guide RNA. Disrupting the slicing activity of AGO2 in mice causes neonatal lethality, however, the specific cell types and substrates that contribute to this lethality are not known. Through a combination of genetic, histologic, and molecular approaches, we identify retrotransposon-like-1 ( Rtl1 ) as a key AGO2 slicing substrate in placental endothelium and skeletal muscle, and show that AGO2 slicing in skeletal muscle, but not endothelium, is required for postnatal viability. Loss of AGO2 slicing causes cell-autonomous, pathologic changes in skeletal muscle, characterized by larger fibers, increased central nuclei, prominent central clearings, and induction of transcripts associated with an unfolded protein response. Forced expression of RTL1 in myoblasts induces a similar unfolded protein response, highlighting the importance of preventing excess Rtl1 during muscle development. Taken together, our findings demonstrate a critical role for AGO2 slicing in skeletal muscle development that is, at least in part, due to its repression of Rtl1 .

DOI: https://doi.org/10.64898/2026.05.22.727060
J Gerontol A Biol Sci Med Sci. 2026 Jun 02. pii: glag145. [Epub ahead of print]

Mitochondrial Dysfunction in Myoblasts: A TSPO-Dependent Mechanism of Sarcopenia.

Peng Zhang, Hongyu Zheng, Zhao Lin, Hanhao Dai, Minjuan Zhang, Linhai Yang, Zhibo Deng, Chao Song, Yibin Su, Rongsheng Zhang, Guoyu Yu, Jun Luo, Jie Xu, Fenqi Luo.

  Sarcopenia, the age-related loss of muscle mass and function, poses a significant health burden in aging societies. Although mitochondrial dysfunction is a recognized driver, the upstream molecular regulators remain poorly defined. Here, we identify the mitochondrial translocator protein (TSPO) as a novel negative regulator of myogenesis that is consistently upregulated in aged and sarcopenic muscle. Using gain- and loss-of-function approaches in C2C12 myoblasts, we show that TSPO overexpression disrupts mitochondrial homeostasis, impairs proliferation and differentiation, while TSPO knockdown produces opposite effects-establishing TSPO as a critical modulator of myogenic capacity. Mechanistically, TSPO suppresses the Wnt/β-catenin pathway, and this effect is partially mediated by ROS accumulation. Importantly, in vivo AAV9-mediated TSPO knockdown in aged mice not only restores mitochondrial integrity but also significantly improves muscle mass, strength, and exercise performance. Collectively, our findings uncover a TSPO-Wnt/β-catenin axis that links mitochondrial dysfunction to impaired muscle regeneration in aging. Targeting TSPO may offer a dual-action therapeutic strategy to combat sarcopenia by simultaneously enhancing mitochondrial bioenergetics and reactivating pro-myogenic signaling.

Keywords:  TSPO; Wnt/β-catenin signaling pathway; differentiation; proliferation; sarcopenia

DOI:  https://doi.org/10.1093/gerona/glag145
Biochem Biophys Res Commun. 2026 Jun 01. pii: S0006-291X(26)00841-7. [Epub ahead of print]827 154077

High-content screening identifies mTORC1-independent TFEB activators that promote protective autophagy.

Takashi Miyano, Kanzo Suzuki, Toshihiro Sera.

  Transcription factor EB (TFEB) is a master regulator of the autophagy-lysosome pathway. It becomes active upon nuclear translocation and induces the expression of genes involved in autophagy and lysosomal function. Mechanistic target of rapamycin complex 1 (mTORC1) inhibition typically triggers this process; however, chronic mTORC1 suppression often induces adverse metabolic and proliferative effects, necessitating the identification of mTORC1-independent mechanisms driving TFEB nuclear translocation. Therefore, this study aimed to identify pharmacological activators of TFEB nuclear translocation that function independently of mTORC1 inhibition. In this study, we developed a high-content screening assay to quantify TFEB nuclear translocation in HeLa cells and screened a library of 560 approved compounds. We identified two compounds, NSC-319726 and ML-SA1, that promoted TFEB nuclear translocation without reducing p70S6K phosphorylation, supporting an mTORC1-independent mechanism. Both compounds significantly increased LC3-II accumulation and the signal intensity of an autolysosomal marker, indicating enhanced autophagic flux. Functionally, these compounds protected the cells against staurosporine-induced apoptosis and hydrogen peroxide-induced oxidative stress. Notably, pre-treatment conferred significantly greater protection than co-treatment, suggesting that TFEB-mediated transcriptional remodeling is necessary for maximal cytoprotection. Overall, these findings highlight the potential of high-content phenotypic screening to identify mTORC1-independent TFEB activators and suggest NSC-319726 and ML-SA1 as pharmacological inducers of protective autophagy in vitro.

Keywords:  Autophagy; Cellular stress; Screening; TFEB; mTORC1

DOI:  https://doi.org/10.1016/j.bbrc.2026.154077
Nat Commun. 2026 Jun 05.

TDP-43 oxidation and PP1 crosstalk at RNA granule-mitochondria contact sites.

Hannah E Ball, Abby C Woods, Yvette C Wong.

Inter-organelle contact sites are key hubs for organelle bidirectional crosstalk. However, how mitochondria and RNA granules interact at contact sites and its regulation by mitochondrial oxidative phosphorylation (OXPHOS) remain unclear. Here, using Super-Resolution live microscopy, we identify RNA granule-mitochondria contact site formation in OXPHOS conditions. Reactive oxygen species (ROS) generated by mitochondrial OXPHOS promotes TDP-43 localization to cytoplasmic RNA granules via TDP-43 cysteine oxidation at Cys173/Cys175. Mechanistically, RNA granule-mitochondria contact tethering is mediated by TDP-43 on RNA granules binding to GADD34 on mitochondria, while contact untethering is regulated by TDP-43 oxidation. Functionally, this allows for GADD34 and its binding partner PP1 to regulate TDP-43 RNA granule dynamics, and conversely, for TDP-43 oxidation to regulate the ability of the phosphatase PP1 to form granules. Finally, disease-associated mutant TDP-43 misregulates this pathway, ultimately leading to PP1 granules lacking TDP-43. This dynamic crosstalk between TDP-43 oxidation and PP1 has significant consequences for TDP-43-associated diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).

DOI: https://doi.org/10.1038/s41467-026-74009-9
Neurobiol Dis. 2026 Jun 03. pii: S0969-9961(26)00212-3. [Epub ahead of print] 107467

Early-onset neuroinflammation drives neurodegeneration caused by lysosomal PI(3,5)P2 insufficiency.

Bridget Wong, Morgan Payne, Alexander Silva, Emma Kurniawan, Alison S Eidman, Donald Pizzo, Rachana Rajupalem, Guy M Lenk, Joao A Paulo, Taimur Khan, Eeva-Liisa Eskelinen, Steve P Gygi, Nicholas G Brown, Miriam H Meisler, Andrew S Mendiola, Brandon M Gassaway, Cole J Ferguson.

  Phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] is a lysosomal signaling lipid whose deficiency, caused by mutations in the PIKfyve complex subunits Fig. 4 or VAC14, underlies a spectrum of fatal neurologic diseases including Charcot-Marie-Tooth type 4 J (CMT4J) and amyotrophic lateral sclerosis (ALS). To map the molecular consequences of PI(3,5)P2 insufficiency in the brain, we performed quantitative proteomic and transcriptomic analyses of three mouse lines bearing distinct loss-of-function mutations in Fig. 4 or Vac14, examining the brain at the presymptomatic and end stages. Strikingly, profound neuroinflammation was already present at postnatal day 5 (before significant neurodegeneration), characterized by complement activation, interferon signaling, and parenchymal infiltration of peripheral myeloid cells and T-cells. Isolated mutant microglia exhibited a markedly pro-oxidative transcriptional state with elevated reactive oxygen species, a partly non-cell-autonomous phenotype, being present in microglia from mice with conditional Fig. 4 inactivation in just neurons and astrocytes. Comparison of early (P5) and late (P25) proteomics data revealed that PI(3,5)P2 insufficiency impairs developmental remodeling of the brain proteome: proteins typically upregulated during postnatal maturation failed to accumulate, implicating lysosomal function in neurodevelopment. We identify coordinated elevation of p53, Fas receptor, inflammatory caspases, Gasdermin D, RIPK1, and ZBP1, consistent with multifactorial inflammatory cell death with features of apoptosis, pyroptosis, and necroptosis. Many of the dysregulated proteins are encoded by genes mutated in lysosomal storage disorders, ALS, CMT, Alzheimer's and Parkinson diseases, extending the pathogenic relevance of PI(3,5)P2 insufficiency. Together, these findings establish that early neuroinflammation is a defining - and likely initiating - feature of neurodegeneration caused by disruption of lysosomal PI(3,5)P2.

Keywords:  Astrocyte; Fas; Fig4; Lysosome; Microglia; Neuroinflammation; PI(3,5)P2; PIKfyve; Phosphoinositide; Reactive oxygen species; Vac14; cGAS-STING; p53

DOI:  https://doi.org/10.1016/j.nbd.2026.107467
bioRxiv. 2026 May 28. pii: 2026.05.27.728239. [Epub ahead of print]

A microRNA atlas of the human prefrontal cortex across the adult lifespan.

Irais Erendira Valenzuela-Arzeta, Pourya Naderi Yeganeh, Anupama Rai, Jane Banahan, Artemis Iatrou, Leinal Sejour, Madison Uyemura, Isaac H Solomon, Nikolaos P Daskalakis, Ioannis Vlachos, Winston Hide, Frank J Slack, Maria Mavrikaki.

Aging of the human brain is characterized by widespread changes in gene expression regulated in part by microRNAs (miRNAs). We present a lifespan miRNA atlas of the human dorsolateral prefrontal cortex generated from small RNA sequencing of 113 postmortem samples spanning 18 to 100 years of age. Differential expression analysis revealed progressive age-associated remodeling of miRNA expression, with the strongest differences observed between old and young individuals. Among the significantly altered miRNAs, miR-34a-5p emerged as one of the most robustly upregulated miRNAs in the aged cortex, alongside additional aging-associated miRNAs including miR-155-5p, miR-132-3p, miR-212-3p, miR-449a, and members of the miR-302 family. This atlas provides a resource for investigating miRNA dysregulation and small RNA regulatory networks during human cortical aging.

DOI: https://doi.org/10.64898/2026.05.27.728239
J Cachexia Sarcopenia Muscle. 2026 Jun;17(3): e70318

Novel Long-Acting Ghrelin Analogue PEP-064 Restores Energy Balance in C26 and Lewis Lung Carcinoma-Induced cachexia in Mice.

J E Hunt, C Lund, B Chen, A R Diaz, O Dmytriyeva, J Marcotorchino, K Löbner, K Mörl, N R Andersen, Z K J Ogueboule, E Frank, J Stöhr, D Meseguer, V Panajotova, J Roux, C Clemmensen, L Sylow, M Schneeberger, A G Beck-Sickinger, S L Pedersen, K Fosgerau.

   BACKGROUND: Cancer cachexia is a debilitating syndrome marked by involuntary weight loss resulting from reduced food intake and intricate metabolic reprogramming. Despite its high prevalence, cancer cachexia remains undertreated, with a lack of effective and approved pharmacotherapies. Ghrelin has emerged as a therapeutic target for cancer cachexia due to its beneficial effects on energy balance. However, the clinical application of ghrelin is hampered by its short half-life. In this study, we introduce PEP-064, a novel stabilized, long-acting and efficacious ghrelin analogue and assess its effects on C26-induced and Lewis lung carcinoma (LLC)-induced cachexia in mice.
METHODS: The in vivo efficacy of PEP-064 was evaluated in healthy CD-1 mice after repeated dosing for 7 days and in the C26 and LLC cancer cachexia mouse models. Additionally, the pharmacokinetic profile and whole brain neuronal activity mapping were conducted in healthy mice following a single subcutaneous injection of PEP-064. Growth hormone secretion was measured in healthy rats following a single administration of PEP-064.
RESULTS: In healthy mice, PEP-064 exhibited a dose-dependent (100, 300 and 1000 nmol/kg) increase in both delta body weight (BW) and total food intake (FI) compared to the vehicle (BW: 2.7 g vs. 3.5, 4.8 and 5.3 g; FI: 50 g vs. 57 g, 60 and 70 g). In the C26 model, PEP-064 protected against loss of tumour-free (TF) BW (-1.2 g vs. 1.7 g, p < 0.0001), increased food intake (33 g vs. 41 g, p < 0.01), prevented losses in fat (-1.1 g vs. 0.9 g, p < 0.0001) and lean mass (-0.07 g vs. 0.4 g, p < 0.05) without affecting tumour growth. In the LLC model, PEP-064 induced hyperphagia (52.2 g vs. 61.6 g, p < 0.0001) and protected against TF-BW loss (-1.4 g vs. - 0.01 g, p < 0.05) and fat mass loss (-0.9 g vs. 0.8 g, p < 0.0001). In mice, PEP-064 had a T1/2 of 6.6 h and a Tmax at 4 h. PEP-064 increased neuronal activity (c-Fos) in the hypothalamic and amygdala regions, with the tuberal nucleus of the hypothalamus showing the highest increase compared to the vehicle (p < 0.05). Lastly, circulating growth hormone was increased 20 min after subcutaneous PEP-064 dosing, peaking at 30 min at 93 ng/mL and returning to approximately baseline by 120 min.
CONCLUSIONS: The novel, long-acting and efficacious ghrelin analogue, PEP-064, restored energy balance in cancer cachexia by increasing food intake and body weight, preserving lean mass and increasing adiposity, without affecting tumour growth. Considering the unmet medical need for safe and effective treatments for cachexia, our study demonstrates the feasibility of a long-acting ghrelin approach for treating cancer cachexia.

Keywords:  C26 colon carcinoma; Lewis lung carcinoma; cancer cachexia; ghrelin; peptide

DOI:  https://doi.org/10.1002/jcsm.70318
Sci Adv. 2026 Jun 05. 12(23): eaed2478

The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway.

Jaydeep Sharma, Somnath Mondal, Aparna Rai, Mahima Kumari, Anushree Bharadwaj, Sam J Mathew.

The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7, encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration. Our findings link skeletal muscle contractility to metabolic homeostasis, identifying the NRF2 pathway as a key therapeutic target.

DOI: https://doi.org/10.1126/sciadv.aed2478
bioRxiv. 2026 May 27. pii: 2026.05.22.727297. [Epub ahead of print]

Sex-specific effects of fatiguing exercise on skeletal muscle passive mechanics are preserved in aging.

Grace E Privett, Julissa Ortiz-Delatorre, Austin W Ricci, Karen Wiedenfeld Needham, Damien M Callahan.

Skeletal muscle function is central to the preservation of functional mobility. Given global shifts to an increasingly aged population, it is paramount that researchers and clinicians better understand the effectors of age-related functional decline. Muscle fatiguability acutely modifies skeletal muscle mechanics in ways that may affect joint stability. We have previously reported sex-specific reductions in cellular passive stress and modulus with fatigue in young males, but not females. Here, we assess whether older adults, who are more susceptible to fatigue during dynamic contractions, exhibit changes to cellular passive mechanics following fatiguing exercise. Muscle tissue biopsies were collected from 11 young and 11 older adults to measure passive stress and Young's Modulus at the single fiber and bundle level. Biopsy samples were acquired from rested muscle and immediately following intermittent maximal contractions to task failure. Fatigue was associated with persistent reduction in elastic modulus that was specific to male participants, regardless of age. In muscle fiber bundles, containing both myofibrillar proteins and the extracellular matrix, fatigue-induced changes in modulus were largely negated, with the only significant change observed in young females, who demonstrated enhanced modulus with fatigue. Taken together our findings suggest a preservation of sex-based differences in the acute response to fatigue across the adult lifespan when measured at the myofilament level. However, further research is needed to understand how and whether these findings translate to the whole tissue level.
New and noteworthy: Acute modifications to muscle tissue mechanics are poorly understood but may have important impacts on functional outcomes in at-risk populations. Our findings suggest myocellular mechanics respond to acute fatigue stress in a sex specific manner that persists across the lifespan.

DOI: https://doi.org/10.64898/2026.05.22.727297
Muscle Nerve. 2026 Jun 04.

Neuroprotective Effects of RNS60 in TDP-43 Pathology-Associated Amyotrophic Lateral Sclerosis.

Danny R Vesevick, Supurna Ghosh, Andreas Kalmes, P Hande Ozdinler, Mukesh Gautam.

INTRODUCTION: TDP-43 pathology is broadly observed in the cerebral cortex of patients with amyotrophic lateral sclerosis (ALS). RNS60, an experimental treatment for acute ischemic stroke and ALS, enhanced mitochondrial biogenesis and function in other preclinical models. We investigated whether RNS60 improved mitochondrial stability and upper motor neuron (UMN) health in a TDP-43 mouse model of ALS.
METHODS: prpTDP-43A315T-UeGFP mice, in which UMNs express green fluorescent protein (eGFP), and WT-UeGFP mice were treated with RNS60 or placebo intraperitoneally every other day from post-natal day (P) 30 until P90. Astrogliosis and microgliosis in brain and spinal cord were quantified by immunocytochemistry. Mitochondrial ultrastructure was studied via electron microscopy, and mitochondrial function was assessed using flow cytometry. Neuromuscular junction (NMJ) integrity was assessed in gastrocnemius, tibialis, and diaphragm muscles.
RESULTS: RNS60 treatment reduced defective mitochondria in UMNs (prpTDP-43A315T + vehicle: 53.2% ± 0.71%; prpTDP-43A315T + RNS60: 19.6% ± 1.4%, p = 0.0001) and spinal motor neurons (prpTDP-43A315T + vehicle: 70.1% ± 0.4.48%; prpTDP-43A315T + RNS60: 33.5% ± 4.43%, p = 0.001). It increased mitochondrial membrane polarization (prpTDP-43A315T-UeGFP + vehicle: 7184 ± 1689 mean intensity; prpTDP-43A315T-UeGFP+RNS60: 22120 ± 4818 mean intensity, p = 0.032), reduced the extent of astrogliosis and microgliosis in motor cortex and spinal cord, protected UMNs compared to placebo, and enhanced the proportion of intact NMJs in leg and diaphragm muscles (prpTDP-43A315T-UeGFP + vehicle: 29.6% ± 3.6%; prpTDP-43A315T-UeGFP + RNS60: 64.3% ± 4.4%, p = 0.0002).
DISCUSSION: These results suggest that RNS60 treatment promotes motor neuron health in ALS by protecting mitochondrial structure and function, preserving NMJ integrity, and reducing gliosis.

DOI: https://doi.org/10.1002/mus.70289