bims-musmir 2025-04-27 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2025–04–27
seven papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Semaglutide-induced weight loss improves mitochondrial energy efficiency in skeletal muscle.
Myocellular adaptations to short-term weighted wheel-running exercise are largely conserved during C26-tumour induction in male and female mice.
Premature skeletal muscle aging in VPS13A deficiency relates to impaired autophagy.
Skeletal muscle effects of antisense oligonucleotides targeting glycogen synthase 1 in a mouse model of Pompe disease.
Implications of Mutant SOD1 on RNA Processing and Interferon Responses in Amyotrophic Lateral Sclerosis: Omics Data Analysis.
Muscle disease in severe COVID-19 patients: a microangiopathic myopathy.
Risk factors for readmission of COVID-19 ICU survivors: A three-year follow up.

Obesity (Silver Spring). 2025 May;33(5): 974-985

Semaglutide-induced weight loss improves mitochondrial energy efficiency in skeletal muscle.

Ran Hee Choi, Takuya Karasawa, Cesar A Meza, J Alan Maschek, Allison M Manuel, Linda S Nikolova, Kelsey H Fisher-Wellman, James E Cox, Amandine Chaix, Katsuhiko Funai.

OBJECTIVE: Glucagon-like peptide-1 receptor agonists (e.g., semaglutide) potently induce weight loss, thereby reducing obesity-related complications. However, weight regain occurs when treatment is discontinued. An increase in skeletal muscle oxidative phosphorylation (OXPHOS) efficiency upon diet-mediated weight loss has been described, which may contribute to reduced systemic energy expenditure and weight regain. We set out to determine the unknown effect of semaglutide on muscle OXPHOS efficiency.
METHODS: C57BL/6J mice were fed a high-fat diet for 12 weeks before receiving semaglutide or vehicle for 1 or 3 weeks. The rates of ATP production and oxygen (O2) consumption were measured via high-resolution respirometry and fluorometry to determine OXPHOS efficiency in muscle at these two time points.
RESULTS: Semaglutide treatment led to significant reductions in fat and lean mass. Semaglutide improved skeletal muscle OXPHOS efficiency, measured as ATP produced per O2 consumed in permeabilized muscle fibers. Mitochondrial proteomic analysis revealed changes restricted to two proteins linked to complex III assembly (LYRM7 and TTC19; p < 0.05 without multiple corrections) without substantial changes in the abundance of OXPHOS subunits.
CONCLUSIONS: These data indicate that weight loss with semaglutide treatment increases skeletal muscle mitochondrial efficiency. Future studies could test whether it contributes to weight regain.

DOI: https://doi.org/10.1002/oby.24274
Exp Physiol. 2025 Apr 24.

Myocellular adaptations to short-term weighted wheel-running exercise are largely conserved during C26-tumour induction in male and female mice.

Stavroula Tsitkanou, Pieter Koopmans, Calvin Peterson, Ana Regina Cabrera, Ruqaiza Muhyudin, Francielly Morena, Sabin Khadgi, Eleanor R Schrems, Tyrone A Washington, Kevin A Murach, Nicholas P Greene.

  This study investigated whether performing a translatable murine model of concurrent training after tumour induction affects adaptations in juvenile male and female tumour-bearing mice. Male and female Balb/c mice were injected bilaterally with colon-26 adenocarcinoma (C26) cells or PBS at 8 weeks of age. Half the mice then performed 24 days of voluntary wheel running with progressively increased load (PoWeR training), whereas the rest remained sedentary. Deuterium oxide-based protein synthesis, muscle fibre-type composition and size, protein turnover and mitochondrial markers were assessed 25 days after tumour induction. Average gastrocnemius muscle fibre size was smaller with PoWeR regardless of tumour in males and females, concomitant with a pronounced faster-to-slower fibre-type transition. In male tumour-bearing mice, PoWeR training resulted in greater Redd1, Murf1 and Pgc1α mRNA content than all the other groups, along with lower overall running volume, food consumption and protein synthesis relative to control animals. Molecular measures followed a similar pattern in tumour-bearing female mice with PoWeR, but food consumption, running volume and muscle protein synthesis were maintained. PoWeR training lowered gonadal fat during cancer cachexia in both sexes, and greater heart weight was observed regardless of tumour presence. A negative correlation was found between tumour weight and running distance. Collectively, PoWeR has a similar effect on muscle cellular phenotype in both sexes regardless of tumour presence, and a training effect in male mice with cancer cachexia was present despite molecular and protein synthesis dysregulation.

Keywords:  catabolism; colorectal cancer; concurrent training; exercise training; muscle fibre‐type transition

DOI:  https://doi.org/10.1113/EP092504
Acta Neuropathol Commun. 2025 Apr 24. 13(1): 83

Premature skeletal muscle aging in VPS13A deficiency relates to impaired autophagy.

Veronica Riccardi, Carlo Fiore Viscomi, Marco Sandri, Angelo D'Alessandro, Monika Dzieciatkowska, Daniel Stephenson, Enrica Federti, Andreas Hermann, Leonardo Salviati, Angela Siciliano, Immacolata Andolfo, Seth L Alper, Jacopo Ceolan, Achille Iolascon, Gaetano Vattemi, Adrian Danek, Ruth H Walker, Alexander Mensch, Markus Otto, Marcus Deschauer, Moritz Armbrust, Cristiane Beninca', Valentina Salari, Paolo Fabene, Kevin Peikert, Lucia De Franceschi.

  VPS13A disease (chorea-acanthocytosis), is an ultra-rare autosomal recessive neurodegenerative disorder caused by mutations of the VPS13A gene encoding Vps13A. Increased serum levels of the muscle isoform of creatine kinase associated with often asymptomatic muscle pathology are among the poorly understood early clinical manifestations of VPS13A disease. Here, we carried out an integrated analysis of skeletal muscle from Vps13a-/- mice and from VPS13A disease patient muscle biopsies. The absence of Vps13A impaired autophagy, resulting in pathologic metabolic remodeling characterized by cellular energy depletion, increased protein/lipid oxidation and a hyperactivated unfolded protein response. This was associated with defects in myofibril stability and the myofibrillar regulatory proteome, with accumulation of the myocyte senescence marker, NCAM1. In Vps13a-/- mice, the impairment of autophagy was further supported by the lacking effect of starvation alone or in combination with colchicine on autophagy markers. As a proof of concept, we showed that rapamycin treatment rescued the accumulation of terminal phase autophagy markers LAMP1 and p62 as well as NCAM1, supporting a connection between impaired autophagy and accelerated aging in the absence of VPS13A. The premature senescence was also corroborated by local activation of pro-inflammatory NF-kB-related pathways in both Vps13a-/- mice and patients with VPS13A disease. Our data link for the first time impaired autophagy and inflammaging with muscle dysfunction in the absence of VPS13A. The biological relevance of our mouse findings, supported by human muscle biopsy data, shed new light on the role of VPS13A in muscle homeostasis.

Keywords:  Autophagy; Energy; Inflammaging; Metabolome; NF-kB

DOI:  https://doi.org/10.1186/s40478-025-01997-y
Clin Transl Med. 2025 Apr;15(4): e70314

Skeletal muscle effects of antisense oligonucleotides targeting glycogen synthase 1 in a mouse model of Pompe disease.

Lan Weiss, Michele Carrer, Alyaa Shmara, Angela Martin, Hong Yin, Pallabi Pal, Cheng Cheng, Lac Ta, Victoria Boock, Yasamin Fazeli, Mindy Chang, Marvin Paguio, Jonathan Lee, Howard Yu, John Weiss, Tamar R Grossman, Nina Raben, Paymaan Jafar-Nejad, Virginia Kimonis.

  Pompe disease (PD) is a progressive myopathy caused by the aberrant accumulation of glycogen in skeletal and cardiac muscle resulting from the deficiency of the enzyme acid alpha-glucosidase (GAA). Administration of recombinant human GAA as enzyme replacement therapy (ERT) works well in alleviating the cardiac manifestations of PD but loses sustained benefit in ameliorating the skeletal muscle pathology. The limited efficacy of ERT in skeletal muscle is partially attributable to its inability to curb the accumulation of new glycogen produced by the muscle enzyme glycogen synthase 1 (GYS1). Substrate reduction therapies aimed at knocking down GYS1 expression represent a promising avenue to improve Pompe myopathy. However, finding specific inhibitors for GYS1 is challenging given the presence of the highly homologous GYS2 in the liver. Antisense oligonucleotides (ASOs) are chemically modified oligomers that hybridise to their complementary target RNA to induce their degradation with exquisite specificity. In the present study, we show that ASO-mediated Gys1 knockdown in the Gaa-/- mouse model of PD led to a robust reduction in glycogen accumulation in skeletal muscle. In addition, combining Gys1 ASO with ERT slightly further reduced glycogen content in muscle, eliminated autophagic buildup and lysosomal dysfunction, and improved motor function in Gaa-/- mice. Our results provide a strong foundation for validation of the use of Gys1 ASO, alone or in combination with ERT, as a therapy for PD. We propose that early administration of Gys1 ASO in combination with ERT may be the key to preventative treatment options in PD. KEY POINTS: Antisense oligonucleotide (ASO) treatment in a mouse model of Pompe disease achieves robust knockdown of glycogen synthase (GYS1). ASO treatment reduces glycogen content in skeletal muscle. Combination of ASO and enzyme replacement therapy (ERT) further improves motor performance compared to ASO alone in a mouse model of Pompe disease.

Keywords:  Enzyme replacement therapy (ERT); Gaa‐/‐ mouse model; Pompe disease; antisense oligonucleotides (ASOs); glycogen synthase 1 (GYS1); skeletal muscle

DOI:  https://doi.org/10.1002/ctm2.70314
Cureus. 2025 Mar;17(3): e81045

Implications of Mutant SOD1 on RNA Processing and Interferon Responses in Amyotrophic Lateral Sclerosis: Omics Data Analysis.

Naoto Honda, Yasuhiro Watanabe, Hiroki Honda, Mika Uemoto, Hayate Fukuhara, Ritsuko Hanajima.

   INTRODUCTION: Cytoplasmic inclusions are observed in motor neurons in amyotrophic lateral sclerosis (ALS) associated with the Cu/Zn superoxide dismutase mutation (mtSOD1). Although these inclusions are a hallmark of the disorder, degeneration is not necessarily initiated in the cytoplasm, nor are these structures the culprit of ALS. The nucleus stores genetic material and acts as the cell's control center, and a small fraction of mtSOD1 is reported to be distributed in the nucleus. We hypothesized that mtSOD1 in the nucleus contributes to motor neuron degeneration.
METHODS: We explored the roles of mtSOD1 in relation to nuclear proteins, chromosomal DNA, and mRNA expression. An immortalized cell line derived from a transgenic ALS mouse model expressing mtSOD1-L126delTT with a FLAG was used for stable immunoprecipitation of mtSOD1-binding molecules using shotgun proteomics and chromatin immunoprecipitation-sequencing (ChIP-seq). We also examined mRNA expression by silencing whole SOD1 (innate mouse Sod1 and mtSOD1) or mtSOD1 alone and compared these patterns against those in non-silenced counterparts.
RESULTS: We identified 392 mtSOD1-interacting proteins in the nucleus. Gene ontology (GO) revealed these proteins to be enriched for "mRNA processing." Notably, more than 11% of mtSOD1-interacting proteins were expressed concurrently with previously reported wild-type TAR DNA-binding protein 43 (TDP-43)-interacting proteins. ChIP-seq revealed that mtSOD1-interacting DNA portions showed a preference for zinc finger protein-binding motifs. GO analysis of the ChIP-seq data revealed that "mRNA processing" was again enriched among the genes harboring mtSOD1-binding domains. RNA expression analyses revealed that the presence of mouse Sod1 and mtSOD1 induced the overexpression of molecules related to "type 1 IFN responses."
CONCLUSIONS: We revealed that mtSOD1 interacted with nuclear proteins and specific DNA segments and that RNA expression was notably altered when mouse Sod1 and mtSOD1 were silenced. These interactions could play a pivotal role in motor neuron degeneration.

Keywords:  amyotrophic lateral sclerosis; cu/zn superoxide dismutase; mrna processing; tar dna-binding protein of 43; type 1 interferon response

DOI:  https://doi.org/10.7759/cureus.81045
Ultrastruct Pathol. 2025 Apr 21. 1-10

Muscle disease in severe COVID-19 patients: a microangiopathic myopathy.

Josep Lloreta-Trull, Judith Marin-Corral, Nuria Juanpere, Sergi Pascual-Guardia, Javier Gimeno, Dolores Naranjo, Laura Segalés, Silvia Hernández, Mercedes Simón, Laia Serrano, Beatriz Casado, Belén Lloveras, Joaquim Gea.

  Patients surviving coronavirus disease of 2019 (COVID-19) often complain of skeletal muscle weakness that may be very limiting and long-lasting. There are almost no studies on the skeletal muscle of these patients, and electron microscopic data are scarce. We assessed the ultrastructural changes in the quadriceps of eight patients with COVID-19 and found a combination of features different from those reported in corticosteroid myopathy and acute relaxant-steroid myopathy. The most remarkable and constant changes involved the endothelial cells and consisted of massive amounts of pinocytotic vesicles, degenerative changes, platelet aggregates and, most characteristic of all, an increase in the external lamina thickness that seems to stem from reduplication due to successive bouts of endothelial cell damage and subsequent regeneration. Viral particles were not found in any of the cases. This distinct and quite common set of alterations defines the myopathy associated with infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This association seems to be the result of an inflammatory process that would arise in infected cells but could damage non-infected endomysial blood vessels, thus resulting in persistent changes of the microvasculature that would be related to long-standing myopathic clinical features.

Keywords:  COVID-19; blood capillary; early COVID-19; endomysium; external lamina thickening; external làmina reduplication; myopathy; persistent COVID-19; skeletal muscle

DOI:  https://doi.org/10.1080/01913123.2025.2488809
Indian J Med Res. 2025 Feb;pii: 10.25259/IJMR_726_2024. [Epub ahead of print]161(2): 190-198

Risk factors for readmission of COVID-19 ICU survivors: A three-year follow up.

Estrela Caamaño, Laura Velasco Rodrigo, Sergio Garcia-Ramos, Alberto Calvo Garcia, Silvia Ramos Cerro, Mercedes Power, Jose Manuel Asencio, Patricia Piñeiro, Javier Hortal, Ignacio Garutti.

  Background & objectives Evidence suggests that individuals who have been hospitalised due to COVID-19 are more susceptible to future mortality and readmission, thereby imposing a substantial strain on their quality of life. The available data on intensive care unit (ICU) survivors, particularly in terms of long-term outcomes, is notably insufficient. This study focused on the long-term outcomes for ICU survivors of COVID-19, specifically readmission and mortality, as well as possible risk factors that could lead to their need for readmission. Methods We conducted a prospective observational study of 505 individuals admitted to the ICU of a tertiary care hospital between March 2020 and March 2021. Follow up concluded in January 2024. We evaluated the need for hospital and ICU readmissions, examining potential risk factors, including patient comorbidities, clinical situation at the time of the previous hospital and ICU admission, and evolution and treatment in the ICU. As a secondary objective, we determined the prevalence of long-term mortality. Results Among 341 ICU survivors, 75 (22%) required hospital readmission, with a median time to readmission of 415 days (IQR: 166-797). The most frequent cause of readmission was respiratory conditions (29.3%). The median hospital stay during readmission was six days. Independent risk factors for hospital readmission included age, elevated creatinine levels at ICU admission, and length of stay in the ICU. Of the 75 readmitted to the hospital, 19 required ICU readmission. Ten individuals died following hospital discharge. Interpretation & conclusions Patients requiring ICU admission due to COVID-19 have a significant risk of hospital readmission, particularly those with advanced age, elevated creatinine levels at ICU admission, and longer ICU stays.

Keywords:  COVID-19; long-COVID; post-COVID; post-ICU; readmission; severe COVID

DOI:  https://doi.org/10.25259/IJMR_726_2024