Browsing by Subject "MUSCULAR-DYSTROPHY"

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  • Hentila, Jaakko; Nissinen, Tuuli A.; Korkmaz, Ayhan; Lensu, Sanna; Silvennoinen, Mika; Pasternack, Arja; Ritvos, Olli; Atalay, Mustafa; Hulmi, Juha J. (2019)
    Muscle wasting in cancer cachexia can be alleviated by blocking activin receptor type 2 (ACVR2) ligands through changes in protein synthesis/degradation. These changes in cellular and protein metabolism may alter protein homeostasis. First, we elucidated the acute (1-2 days) and 2-week effects of blocking ACVR2 ligands by soluble activin receptor 2B (sACVR2B-Fc) on unfolded protein response (UPR), heat shock proteins (HSPs) and redox balance in a healthy mouse skeletal muscle. Second, we examined UPR, autophagy and redox balance with or without sACVR2B-Fc administration in muscle and liver of C26 tumor-bearing mice. The indicators of UPR and HSPs were not altered 1-2 days after a single sACVR2B-Fc administration in healthy muscles, but protein carbonyls increased (p <0.05). Two weeks of sACVR2B-Fc administration increased muscle size, which was accompanied by increased UPR markers: GRP78 <0.05), phosphorylated elF2 alpha <0.01) and HSP47 (p <0.01). Additionally, protein carbonyls and reduced form of glutathione increased (GSH) (p <0.05). On the other hand, C26 cancer cachexia manifested decreased UPR markers (p-elF2 alpha, HSP47, p-JNK; p <0.05) and antioxidant GSH (p <0.001) in muscle, whereas the ratio of oxidized to reduced glutathione increased (GSSG/GSH; p <0.001). Administration of sACVR2B-Fc prevented the decline in GSH and increased some of the UPR indicators in tumor-bearing mice. Additionally, autophagy markers LC3II/I (p <0.05), Beclin-1 (p <0.01), and P62 (p <0.05) increased in the skeletal muscle of tumor-bearing mice. Finally, indicators of UPR, PERK, p-elF2 alpha and GRP78, increased (p <0.05), whereas ATF4 was strongly decreased (p <0.01) in the liver of tumor-bearing mice while sACVR2B-Fc had no effect. Muscle GSH and many of the altered UPR indicators correlated with tumor mass, fat mass and body mass loss. In conclusion, experimental cancer cachexia is accompanied by distinct and tissue-specific changes in proteostasis. Muscle hypertrophy induced by blocking ACVR2B ligands may be accompanied by the induction of UPR and increased protein carbonyls but blocking ACVR2B ligands may upregulate antioxidant protection.
  • Hulmi, Juha J.; Penna, Fabio; Pöllänen, Noora; Nissinen, Tuuli A.; Hentila, Jaakko; Euro, Liliya; Lautaoja, Juulia H.; Ballarò, Riccardo; Soliymani, Rabah; Baumann, Marc; Ritvos, Olli; Pirinen, Eija; Lalowski, Maciej (2020)
    Objective Cancer cachexia and muscle loss are associated with increased morbidity and mortality. In preclinical animal models, blocking activin receptor (ACVR) ligands has improved survival and prevented muscle wasting in cancer cachexia without an effect on tumour growth. However, the underlying mechanisms are poorly understood. The present study aimed to identify cancer cachexia and soluble ACVR (sACVR) administration-evoked changes in muscle proteome. Methods Healthy and C26 tumour-bearing (TB) mice were treated with recombinant sACVR. The sACVR or PBS control were administered either prior to the tumour formation or by continued administration before and after tumour formation. Muscles were analysed by quantitative proteomics with further examination of mitochondria and nicotinamide adenine dinucleotide (NAD+) metabolism. To complement the first prophylactic experiment, sACVR (or PBS) was injected as a treatment following tumour cell inoculation. Results Muscle proteomics in TB cachectic mice revealed downregulated signatures for mitochondrial oxidative phosphorylation (OXPHOS) and increased acute phase response (APR). These were accompanied by muscle NAD+ deficiency, alterations in NAD+ biosynthesis including downregulation of nicotinamide riboside kinase 2 (Nrk2), and decreased muscle protein synthesis. The disturbances in NAD+ metabolism and protein synthesis were rescued upontreatment with sACVR. Across the whole proteome and APR in particular, Serpina3n represented the most upregulated protein and the strongest predictor of cachexia. However, the increase in Serpina3n expression associated with increased inflammation rather than decreased muscle mass and/or protein synthesis. Conclusions We present here an evidence implicating disturbed muscle mitochondrial OXPHOS proteome and NAD+ homeostasis in experimental cancer cachexia. Treatment of tumour-bearing mice with a blocker of activin receptor ligands restores depleted muscle NAD+ and Nrk2 as well as decreased muscle protein synthesis. These results point out putative new treatment therapies for cachexia. Our results also reveal that although acute phase protein Serpina3n may serve as a predictor of cachexia, it more likely reflects a condition of elevated inflammation.
  • Vihola, Anna; Palmio, Johanna; Danielsson, Olof; Penttilä, Sini; Louiselle, Daniel; Pittman, Sara; Weihl, Conrad; Udd, Bjarne (2019)
    Objective We report a second family with autosomal dominant transportinopathy presenting with congenital or early-onset myopathy and slow progression, causing proximal and less pronounced distal muscle weakness. Methods Patients had clinical examinations, muscle MRI, EMG, and muscle biopsy studies. The MYOcap gene panel was used to identify the gene defect in the family. Muscle biopsies were used for histopathologic and protein expression studies, and TNPO3 constructs were used to study the effect of the mutations in transfected cells. Results We identified a novel heterozygous mutation, c.2757delC, in the last part of the transportin-3 (TNPO3) gene in the affected family members. The mutation causes an almost identical frameshift affecting the stop codon and elongating the C-term protein product of the TNPO3 transcript, as was previously reported in the first large Spanish-Italian LGMD1F kindred. TNPO3 protein was increased in the patient muscle and accumulated in the subsarcolemmal and perinuclear areas. At least one of the cargo proteins, the splicing factor SRRM2 was normally located in the nucleus. Transiently transfected mutant TNPO3 constructs failed to localize to cytoplasmic annulate lamellae pore complexes in cells. Conclusions We report the clinical, molecular genetic, and histopathologic features of the second transportinopathy family. The variability of the clinical phenotype together with histopathologic findings suggests that several molecular pathways may be involved in the disease pathomechanism, such as nucleocytoplasmic shuttling, protein aggregation, and defective protein turnover.
  • Rudnik-Schoeneborn, Sabine; Wallgren-Pettersson, Carina (2019)
    Reports on pregnancy and delivery issues in women with congenital myopathies are scarce. In this review, we summarize the medical literature along with updates of our own data. Included are patients with nemaline myopathy (n = 11), central core disease (n = 6), multi-minicore disease (n = 2), cytoplasmic body myopathy (n = 1), and congenital fiber-type disproportion (n = 1). Apart from 1 patient with nemaline myopathy, who had used a wheelchair from the age of 18 years, all other women were able to walk when becoming pregnant. In comparison with the general population, there were no increased pregnancy or delivery complications, apart from the fact that 38% elective Cesarean sections took place. Neonatal outcome was favorable. In cases where a possible influence of gestation on muscle function was assessed, a deterioration during or after pregnancy was not observed. Patients who wish to have children should be advised by a multidisciplinary team according to the specific diagnosis, severity, and distribution of muscle weakness. (C) 2019 Elsevier Inc. All rights reserved.
  • Freyermuth, Fernande; Rau, Frederique; Kokunai, Yosuke; Linke, Thomas; Sellier, Chantal; Nakamori, Masayuki; Kino, Yoshihiro; Arandel, Ludovic; Jollet, Arnaud; Thibault, Christelle; Philipps, Muriel; Vicaire, Serge; Jost, Bernard; Udd, Bjarne; Day, John W.; Duboc, Denis; Wahbi, Karim; Matsumura, Tsuyoshi; Fujimura, Harutoshi; Mochizuki, Hideki; Deryckere, Francois; Kimura, Takashi; Nukina, Nobuyuki; Ishiura, Shoichi; Lacroix, Vincent; Campan-Fournier, Amandine; Navratil, Vincent; Chautard, Emilie; Auboeuf, Didier; Horie, Minoru; Imoto, Keiji; Lee, Kuang-Yung; Swanson, Maurice S.; Lopez de Munain, Adolfo; Inada, Shin; Itoh, Hideki; Nakazawa, Kazuo; Ashihara, Takashi; Wang, Eric; Zimmer, Thomas; Furling, Denis; Takahashi, Masanori P.; Charlet-Berguerand, Nicolas (2016)
    Myotonic dystrophy (DM) is caused by the expression of mutant RNAs containing expanded CUG repeats that sequester muscleblind-like (MBNL) proteins, leading to alternative splicing changes. Cardiac alterations, characterized by conduction delays and arrhythmia, are the second most common cause of death in DM. Using RNA sequencing, here we identify novel splicing alterations in DM heart samples, including a switch from adult exon 6B towards fetal exon 6A in the cardiac sodium channel, SCN5A. We find that MBNL1 regulates alternative splicing of SCN5A mRNA and that the splicing variant of SCN5A produced in DM presents a reduced excitability compared with the control adult isoform. Importantly, reproducing splicing alteration of Scn5a in mice is sufficient to promote heart arrhythmia and cardiac-conduction delay, two predominant features of myotonic dystrophy. In conclusion, misregulation of the alternative splicing of SCN5A may contribute to a subset of the cardiac dysfunctions observed in myotonic dystrophy.