<i>In vivo</i> treatment with the NF‐κB inhibitor ursodeoxycholic acid (UDCA) improves tension development in the isolated <i>mdx</i> costal diaphragm

Carlson, C. George; Potter, Ross M.; Yu, V Postnov; Luo, Kevin; Lavin, Jesse; Nielsen, Cory

doi:10.1002/mus.24755

Cited by 3 publications

(3 citation statements)

References 22 publications

(75 reference statements)

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“…More specific targeting of immune and/or stress factors may provide novel therapeutic strategies with fewer side‐effects. Indeed, inhibitors of NFκB have shown promise in improving mdx muscle pathology such as a recent study which revealed improvements in mdx diaphragm force following NFκB inhibition with ursodeoxycholic acid . The pro‐inflammatory cytokine IL‐6, involved in skeletal muscle metabolism and maintenance and remodeling of myocytes, as well as regeneration after exercise and damage, is reported to be elevated in mdx tissue …”

Section: Discussionmentioning

confidence: 99%

Combined XIL‐6R and urocortin‐2 treatment restores MDX diaphragm muscle force

et al. 2017

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Section: Discussionmentioning

confidence: 99%

Combined XIL‐6R and urocortin‐2 treatment restores MDX diaphragm muscle force

et al. 2017

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“…UDCA has been reported to benefit skeletal muscle in chronic inflammatory models such as mdx mice. Specifically, this effect of UDCA is associated with NF-κB-dependent transcriptional repression [ 79 – 81 ]. The present study demonstrated that UDCA induced sarcopenia in adult mice and sarcopenic-like effects in skeletal muscle cells.…”

Section: Discussionmentioning

confidence: 99%

“…C57BL/6J WT male mice (20–24 weeks old) were used in a randomized block experimental design. Each experimental group contained five to six mice and was treated with 200 mg/kg UDCA (Sigma-Aldrich, St. Louis, MO, USA) or vehicle (1.02% NaCl, pH 8.4) intragastrically for 6 weeks [ 81 ]. Male mice were chosen to avoid hormonal changes by reproductive cycles present in the female mice, which could affect muscle mass.…”

Section: Methodsmentioning

confidence: 99%

Ursodeoxycholic acid induces sarcopenia associated with decreased protein synthesis and autophagic flux

et al. 2023

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Background Skeletal muscle generates force and movements and maintains posture. Under pathological conditions, muscle fibers suffer an imbalance in protein synthesis/degradation. This event causes muscle mass loss and decreased strength and muscle function, a syndrome known as sarcopenia. Recently, our laboratory described secondary sarcopenia in a chronic cholestatic liver disease (CCLD) mouse model. Interestingly, the administration of ursodeoxycholic acid (UDCA), a hydrophilic bile acid, is an effective therapy for cholestatic hepatic alterations. However, the effect of UDCA on skeletal muscle mass and functionality has never been evaluated, nor the possible involved mechanisms. Methods We assessed the ability of UDCA to generate sarcopenia in C57BL6 mice and develop a sarcopenic-like phenotype in C2C12 myotubes and isolated muscle fibers. In mice, we measured muscle strength by a grip strength test, muscle mass by bioimpedance and mass for specific muscles, and physical function by a treadmill test. We also detected the fiber’s diameter and content of sarcomeric proteins. In C2C12 myotubes and/or isolated muscle fibers, we determined the diameter and troponin I level to validate the cellular effect. Moreover, to evaluate possible mechanisms, we detected puromycin incorporation, p70S6K, and 4EBP1 to evaluate protein synthesis and ULK1, LC3 I, and II protein levels to determine autophagic flux. The mitophagosome-like structures were detected by transmission electron microscopy. Results UDCA induced sarcopenia in healthy mice, evidenced by decreased strength, muscle mass, and physical function, with a decline in the fiber’s diameter and the troponin I protein levels. In the C2C12 myotubes, we observed that UDCA caused a reduction in the diameter and content of MHC, troponin I, puromycin incorporation, and phosphorylated forms of p70S6K and 4EBP1. Further, we detected increased levels of phosphorylated ULK1, the LC3II/LC3I ratio, and the number of mitophagosome-like structures. These data suggest that UDCA induces a sarcopenic-like phenotype with decreased protein synthesis and autophagic flux. Conclusions Our results indicate that UDCA induces sarcopenia in mice and sarcopenic-like features in C2C12 myotubes and/or isolated muscle fibers concomitantly with decreased protein synthesis and alterations in autophagic flux.

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ER stress disturbs SR/ER-mitochondria Ca2+ transfer: Implications in Duchenne muscular dystrophy

Pauly

Angebault-Prouteau

Dridi

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Besides its role in calcium (Ca) homeostasis, the sarco-endoplamic reticulum (SR/ER) controls protein folding and is tethered to mitochondria. Under pathophysiological conditions the unfolded protein response (UPR) is associated with disturbance in SR/ER-mitochondria crosstalk. Here, we investigated whether ER stress altered SR/ER-mitochondria links, Ca handling and muscle damage in WT (Wild Type) and mdx mice, the murine model of Duchenne Muscular Dystrophy (DMD). In WT mice, the SR/ER-mitochondria links were decreased in isolated FDB muscle fibers after injection of ER stress activator tunicamycin (TM). Ca imaging revealed an increase of cytosolic Ca transient and a decrease of mitochondrial Ca uptake. The force generating capacity of muscle dropped after TM. This impaired contractile function was accompanied by an increase in autophagy markers and calpain-1 activation. Conversely, ER stress inhibitors restored SR/ER-mitochondria links, mitochondrial Ca uptake and improved diaphragm contractility in mdx mice. Our findings demonstrated that ER stress-altered SR/ER-mitochondria links, disturbed Ca handling and muscle function in WT and mdx mice. Thus, ER stress may open up a prospect of new therapeutic targets in DMD.

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In vivo treatment with the NF‐κB inhibitor ursodeoxycholic acid (UDCA) improves tension development in the isolated mdx costal diaphragm

Abstract: Because UDCA is used in treating certain clinical disorders, these results provide a rationale for human clinical trials using this and related drugs for treatment of Duchenne and related muscular dystrophies.

Cited by 3 publications

References 22 publications

Combined XIL‐6R and urocortin‐2 treatment restores MDX diaphragm muscle force

Combined XIL‐6R and urocortin‐2 treatment restores MDX diaphragm muscle force

Ursodeoxycholic acid induces sarcopenia associated with decreased protein synthesis and autophagic flux

ER stress disturbs SR/ER-mitochondria Ca2+ transfer: Implications in Duchenne muscular dystrophy

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