bims-musmir 2026-05-10 papers

J Cachexia Sarcopenia Muscle. 2026 Jun;17(3): e70302

RAGE Re-Expressed at Myofibre Level Drives Muscle Wasting in Cancer Conditions.

Sara Chiappalupi, Giulia Gentili, Laura Salvadori, Martina Paiella, Marcello Manfredi, Vittoria Federica Borrini, Kaamashri Mangar, Ann Marie Schmidt, Maurizio Muscaritoli, Francesca Riuzzi, Guglielmo Sorci.

BACKGROUND: Cancer cachexia (CC) is a highly debilitating syndrome characterized by loss of body and muscle weight affecting most advanced cancer patients. The receptor for advanced glycation end-products (RAGE) is expressed by several cell types and sustains the inflammatory response in acute and chronic diseases. Total ablation of RAGE (Ager-/- mice) translates into restrained CC and increased survival in tumour-bearing mice. RAGE, which is not expressed in adult healthy myofibres, is re-expressed in atrophying myofibres in cancer conditions. However, the specific contribution of muscular RAGE to CC was unknown.
METHODS: Using an HSA/Cre-loxP system, we generated a tamoxifen-inducible conditional AgermKO mouse model in which RAGE is selectively ablated in myofibres. Tamoxifen-treated AgermKO, Agerflox and Ager-/- mice were subcutaneously injected with Lewis lung carcinoma (LLC) cells, and body changes and survival were monitored until 25 dpi, when histological, molecular and proteomic analyses were performed in tumour-bearing and control mice. Muscle samples of pre-cachectic and cachectic pancreatic cancer patients were analysed to validate the results.
RESULTS: Compared with LLC-Agerflox mice, LLC-AgermKO mice showed reduced (7.5% [p = 0.004] vs. 15.1% [p < 0.0001]) body weight loss, no significant reduction of hind-limb muscle mass and strength and myofibre cross-sectional areas, increased survival (69.2% vs. 42.9% mice alive at 25 dpi) and restrained muscle and serum pro-inflammatory factors. Mechanistically, AgermKO muscles resist cancer-induced atrophy by maintaining an active Akt-GSK-3β-PGC-1α pathway, and increasing the synthesis of myosin heavy chain (MyHC)-I and -IIa (71.8% [p = 0.008] and 73.9% [p = 0.002] increase, respectively) along with a 76.3% (p = 0.008) increase in hybrid MyHC-I/IIa myofibres. Distinct proteomic signatures characterize muscles of tumour-bearing mice in dependence on RAGE expression, supporting a protective effect of RAGE ablation in muscles. LLC/AgermKO muscles showed increased amounts of several enzymes involved in glycolysis and glucose catabolism, typical of Warburg metabolism. Noteworthy, muscles of pre-cachectic and cachectic cancer patients showed ~3-fold increase (p < 0.05) in RAGE amounts and reduced Akt-GSK-3β-PGC-1α pathway, compared with healthy control subjects.
CONCLUSIONS: Our data provide evidence that RAGE engagement at myofibre level drives loss of body and muscle weights and inflammation in cancer conditions. RAGE ablation in muscles confers resistance to CC through myofibre remodeling and glycolytic reprogramming. On the clinical side, the overexpression of RAGE is an early event in muscles of cancer patients, suggesting a role for RAGE in the onset of the cachectic syndrome. Thus, the molecular targeting of RAGE might be useful to counteract cachexia and prolong survival in cancer patients.

Keywords: RAGE; animal models; cancer cachexia; muscle wasting; myofibre remodeling

DOI: https://doi.org/10.1002/jcsm.70302

bioRxiv. 2026 Apr 24. pii: 2026.04.21.719997. [Epub ahead of print]

C26 and CT26 colorectal cancer models exhibit divergent cachexia phenotypes, intramuscular inflammation, and protein turnover signaling.

Xinyue Lu, Hanan Tlais, Hamood Rehman, Ashtyn N Martens, Abigail L Hartz, Vandre C Figueiredo, James F Markworth.

Colorectal cancer (CRC) cachexia induces skeletal muscle dysfunction, impeding quality of life and worsening cancer prognosis. Multiple preclinical models, including the widely used mouse model of subcutaneous inoculation with the C26 colorectal carcinoma cell line, have been developed to study the biological mechanisms of CRC cachexia and elucidate potential new treatments. It has been proposed that a distinct cell line of the same origin, namely CT26, is relatively non-cachexic. However, studies evaluating the relative potential of C26 and CT26 cells to induce cancer cachexia in parallel have been limited. The differences in the biological mechanisms by which C26 and CT26 impact skeletal muscle mass and function have also not been fully elucidated. In the current study, we investigated the differential capacity of C26 and CT26 to induce cancer cachexia using both an in vitro cancer-muscle cell co-culture and an in vivo syngeneic mouse model. Our results show that both C26 and CT26 cells induced significant atrophy of murine C2C12 skeletal myotubes. In the mouse model, while C26 and CT26 both reduced skeletal muscle mass and fat mass, only C26 tumors led to loss of body weight and impaired skeletal muscle force output. We further show that C26 tumor-bearing mice exhibit greater muscle inflammation than CT26 tumor-bearing mice. In addition, mice bearing C26 and CT26 tumors showed differential regulation of the innate immune responses and muscle protein turnover. Overall, our data suggests that although both C26 and CT26 cells do exhibit cachexic effects, C26 cells induce greater loss in body weight, fat mass, skeletal muscle mass, and physical function via promoting chronic inflammation and deregulating protein balance of skeletal muscle.

DOI: https://doi.org/10.64898/2026.04.21.719997

iScience. 2026 May 15. 29(5): 115565

Neuromuscular junction innervation and motor function are preserved by restoring muscarinic signaling in perisynaptic glia in ALS.

Elsa Tremblay, Danielle Arbour, Joanne Vallée, Roberta Piovesana, Geneviève Vallières, Emine Mechichi, Richard Robitaille.

Neuromuscular junction (NMJ) denervation is an early pathological event in amyotrophic lateral sclerosis (ALS) causing motor dysfunction and paralysis. Glial cells at the NMJ, perisynaptic Schwann cells (PSCs), ensure a balance between maintenance and repair via muscarinic receptor signaling. However, in ALS mouse models, PSCs show an aberrant muscarinic hyperactivation. We posited that this excessive activation impairs the PSC capacity to support NMJ repair in ALS. Beginning at symptoms onset, SOD1 G37R mice received daily oral administration of darifenacin, a clinically approved type 3 muscarinic receptor antagonist, to reduce PSC hyperactivation. The treatment improved locomotion and preserved NMJ innervation in male mice, with comparable effects observed in females, and extended survival in males. Functional benefits were supported by signs of glial repair and enhanced survival of lumbar motor neurons. These preclinical data indicate that pathological PSC hyperactivity contributes to NMJ denervation in ALS and support therapeutic strategies targeting NMJs in ALS.

Keywords: Cell biology; Molecular biology; Neuroscience; Physiology

DOI: https://doi.org/10.1016/j.isci.2026.115565

Int Immunopharmacol. 2026 May 07. pii: S1567-5769(26)00634-X. [Epub ahead of print]182 116788

FcRn function alone cannot account for elevated IgG clearance in the Lewis lung carcinoma model of cancer cachexia.

PURPOSE: The neonatal Fc receptor (FcRn) protects IgG-based monoclonal antibodies (mAbs) from catabolism by direct binding within endosomes and facilitates their recycling to extracellular spaces. Elevated clearance of immune checkpoint inhibitors (ICIs) and other IgG-based mAbs is often observed in patients with cachexia phenotypes and is associated with worse outcomes. We sought to understand if FcRn's function is altered in cancer cachexia.
EXPERIMENTAL DESIGN: Clearance of IgGs with different FcRn-binding properties were evaluated in cachectic LLC tumor-bearing (TB) and non-cachectic tumor-free mice in both wild-type and FcRn knockout backgrounds. As macrophage depletion with liposomal clodronate affects IgG pharmacokinetics only in the absence of FcRn function, we compared IgG clearance in LLC-TB and TF mice with and without macrophage ablation to assess changes in FcRn's functional status in cachectic tumor-bearing mice.
RESULTS: We noted that the induction of IgG clearance in the presence of a cachectic tumor was dampened by the lack of FcRn engagement in whole body FcRn knockout mice. As expected, clodronate administration did not significantly affect systemic clearance of FcRn-binding IgG, though it significantly reduced clearance of FcRn-null IgG. More importantly, these effects were consistent in both TF and TB cachectic contexts.
CONCLUSIONS: These results suggest that while FcRn accounts for a portion of the observed changes in IgG pharmacokinetics in cancer cachexia, the functional status of FcRn is not significantly different in healthy mice without tumors compared to those with LLC tumors and associated cachexia, which indicates the potential involvement of FcRn-independent mechanisms.

Keywords: Cancer cachexia; FcRn; IgG; Macrophages; Pharmacokinetics

DOI: https://doi.org/10.1016/j.intimp.2026.116788

EMBO J. 2026 May 02.

Peroxisome-derived ether lipids regulate lysosomal exocytosis.

Liang Chen, Danielle Henn, Zhongzheng Dong, Jiaxuan Liang, Aleksander Wielenga, Goncalo Vale, Bala Burugula, Junyi Zou, Yamuna Krishnan, Jeffrey G McDonald, Jacob Kitzman, Ming Li.

Lysosomes and peroxisomes are essential for cellular homeostasis, yet how their activities are coordinated remains poorly understood. Here, we identify peroxisome-derived ether lipids as key regulators of lysosomal function. A genome-wide CRISPR/Cas9 screen in LYSET-deficient mucolipidosis V cells revealed that disruption of ether lipid synthesis genes or peroxins markedly reduces lysosome accumulation and restores degradative capacity. Genetic or pharmacological inhibition of ether lipid synthesis enhanced lysosomal exocytosis and promoted the clearance of undigested material independently of mannose-6-phosphate trafficking. Conversely, supplementation with the ether lipid precursor hexadecylglycerol increased lysosome abundance, while reducing their degradative capacity. These findings uncover a peroxisome-lysosome metabolic axis, in which ether lipids act as bidirectional regulators of lysosomal number and function independently of the lysosomal master regulator TFEB. Our findings reveal how peroxisome-localized lipid metabolism modulates lysosomal homeostasis, and suggest potential new strategies to combat lysosomal and peroxisomal disorders.

DOI: https://doi.org/10.1038/s44318-026-00791-3

Antioxidants (Basel). 2026 Apr 09. pii: 465. [Epub ahead of print]15(4):

The c-Abl-RIPK3 Axis Drives Mitochondrial Dysfunction and Impaired Mitophagy in Gaucher Disease Models.

Cristian M Lamaizon, Renatta Tironi-Hernández, Nohela B Arévalo, Sebastián D Ahumada, Daniela A Gutiérrez, Laura Brito-Fernández, Andrea Del Campo, Silvana Zanlungo, Alejandra R Álvarez.

Gaucher disease (GD) is characterized by the accumulation of glucosylceramide within lysosomes due to mutations in the GBA1 gene, which encodes the enzyme glucocerebrosidase. Current treatments are ineffective for patients suffering from severe neuronopathic forms of the disease. In this context, new therapeutic approaches for neuronopathic GD forms are needed. Lysosomal and mitochondrial dysfunction associated with increased oxidative stress and disturbances in the autophagic process have been described in GD. Here, we address c-Abl-RIPK3 signaling and its contribution to the accumulation of dysfunctional mitochondria in GD. Fibroblasts from patients with GBA1 mutations and neurons treated with the glucocerebrosidase inhibitor CBE exhibited alterations in the ΔΨm and mitochondrial morphology, as well as reduced capacity to form autophagosomes. Pharmacological inhibition of c-Abl or RIPK3 restored mitochondrial function and promoted autophagosome formation, along with an increase in autophagic engulfment of mitochondria in both GD models. In conclusion, the c-Abl-RIPK3 signaling pathway contributes to mitochondrial dysfunction and blockade of autophagy components in the mitochondria, both of which are altered in the neuronopathic forms of GD.

Keywords: Gaucher disease; RIPK3; autophagy; c-Abl; lysosomal storage disorders; mitochondrial dysfunction; mitophagy; oxidative stress

DOI: https://doi.org/10.3390/antiox15040465