<i>Mss51</i>
            deletion increases endurance and ameliorates histopathology in the
            <i>mdx</i>
            mouse model of Duchenne muscular dystrophy

Gonzalez, Yazmin I. Rovira; Moyer, Adam L.; LeTexier, Nicolas J; Bratti, August D; Feng, Siyuan; Peña, Vanessa N.; Sun, Congshan; Pulcastro, Hannah C.; Liu, Ting; Iyer, Shama R.; Lovering, Richard M.; O’Rourke, Brian; Wagner, Kathryn R.

doi:10.1096/fj.202002106rr

Cited by 9 publications

(7 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, TGFẞ is a positive regulator of Mss51 and increased Mss51 expression compromises mitochondrial function via complex IV (84). In mdx mice, the genetic deletion of Mss51 increased the mitochondrial respiratory capacity of isolated extensor digitorum brevis myofibers and reduced diaphragm histopathology – including markers of fibrosis (85). Further highlighting the potential significance of versican to skeletal muscle metabolic health, single- nucleotide polymorphisms in versican ( VCAN ; rs2287926) have been found to be to be associated with lean mass and lean appendicular mass, as well as metabolic protection (86, 87).…”

Section: Discussionmentioning

confidence: 99%

In dystrophicmdxhindlimb muscles where fibrosis is limited versican haploinsufficiency transiently improves contractile function without decreasing inflammation

Debruin,

McRae,

Addinsall

et al. 2024

Preprint

View full text Add to dashboard Cite

The provisional matrix protein versican is upregulated in Duchenne muscular dystrophy. Versican heightens inflammation in fibrotic diseases and is involved in myogenesis. In fibrotic diaphragm muscles from dystrophic mdx mice, versican reduction attenuated macrophage infiltration and improved contractile function. We investigated the association between versican and mdx hindlimb muscle pathology, where inflammation and regeneration are increased but fibrosis is minimal. Immunohistochemistry and qRT-PCR were used to assess how fiber type and glucocorticoids (α-methylprednisolone) modulate versican expression. Female mdx and male versican haploinsufficient (hdf) mice were bred resulting in male mdx-hdf and mdx (control) pups. Versican expression, contractile function, and pathology were evaluated in fast extensor digitorum longus (EDL) and slow soleus muscles, excised under medetomidine-midazolam-fentanyl anesthesia. Versican immunoreactivity was highest in soleus muscles. Versican mRNA transcripts were reduced by α-methylprednisolone in soleus, but not EDL, muscles. Versican expression was decreased in soleus muscles from 6-week-old mdx-hdf mice leading to increased force output and a modest reduction in fatiguability. These functional benefits were not accompanied by decreased inflammation; muscle architecture, regeneration markers, and fiber type also did not differ between genotypes. Improvements in soleus function were lost in adult (20-week-old) mdx-hdf mice with no significant effect of versican haploinsufficiency on macrophage infiltration and regeneration markers. Soleus muscles from juvenile mdx mice were most responsive to pharmacological or genetic approaches targeting versican; however, the benefits of versican reduction were limited due to low fibrosis. Pre-clinical matrix research in dystrophy should account for muscle phenotype and the interdependence between the fibrosis and inflammation.

show abstract

Section: Discussionmentioning

confidence: 99%

In dystrophicmdxhindlimb muscles where fibrosis is limited versican haploinsufficiency transiently improves contractile function without decreasing inflammation

Debruin,

McRae,

Addinsall

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Disrupted mitochondrial function and metabolism are associated with Duchenne muscular dystrophy (DMD) (1, 2, 30). In mouse models of DMD (mdx mice), disrupted mitochondrial metabolism was observed early on in disease progression, suggesting disrupted mitochondrial metabolism may contribute to DMD pathophysiology (2).…”

Section: Discussionmentioning

confidence: 99%

“…In mouse models of DMD (mdx mice), disrupted mitochondrial metabolism was observed early on in disease progression, suggesting disrupted mitochondrial metabolism may contribute to DMD pathophysiology (2). Deletion of MSS51 in mdx mice improves basal and maximal respiration relative to control mdx mice (30). Given our evidence that S1P promotes MSS51 expression, a role for S1P in DMD disease progression is possible.…”

Section: Discussionmentioning

confidence: 99%

Site-1 Protease inhibits mitochondrial metabolism by controlling the TGF-β target gene MSS51

Mousa

Vuppaladhadiam

Kelly

et al. 2022

Preprint

View full text Add to dashboard Cite

The mitochondrial response to changes in cellular energy demand is necessary for cellular adaptation and organ function. Many genes are essential in orchestrating this response, including the transforming growth factor (TGFβ) target gene MSS51, which is an inhibitor of skeletal muscle mitochondrial metabolism. Despite the potential importance of MSS51 in the pathophysiology of obesity and musculoskeletal disease, how MSS51 is regulated is not entirely understood. Site-1 Protease (S1P) is a Golgi-resident protease that is a key activator of several transcription factors required for cellular adaptation. However, the role of S1P in muscle and mitochondrial function are unknown. Here, we identify S1P as a negative regulator of muscle mass and mitochondrial metabolism. Disruption of S1P in mouse skeletal muscle and cultured myofibers leads to a reduction in MSS51 expression, increased muscle mass, and increased mitochondrial oxygen consumption. The effects of S1P deficiency on mitochondrial activity are counteracted by overexpressing MSS51, suggesting that S1P inhibits mitochondrial metabolism by regulating the expression of MSS51. Furthermore, S1P suppression enhances TGFβ signaling via the AKT pathway, potentially explaining muscle hypertrophy in S1P deficient mice. The discovery of S1P as a regulator of mitochondrial metabolism and muscle mass expands our understanding of TGF-β signaling and suggests this protease could be a target for therapeutic intervention in muscle.

show abstract

“…Hence, Ca 2+ overload and malfunction of muscle mitochondria [131,132] also contribute to chronic inflammation and progressive cell death in DMD physiopathology (Figure S1). Notably, therapeutic interventions directly or indirectly improving mitochondrial function led to reduced inflammation and improved respiration, among other positive physiological effects, but most importantly, they ameliorated in vivo muscle function [133][134][135][136].…”

Section: Mitochondrial Functionmentioning

confidence: 99%

Histological Methods to Assess Skeletal Muscle Degeneration and Regeneration in Duchenne Muscular Dystrophy

Dubuisson

Versele

Planchon

et al. 2022

IJMS

View full text Add to dashboard Cite

Duchenne muscular dystrophy (DMD) is a progressive disease caused by the loss of function of the protein dystrophin. This protein contributes to the stabilisation of striated cells during contraction, as it anchors the cytoskeleton with components of the extracellular matrix through the dystrophin-associated protein complex (DAPC). Moreover, absence of the functional protein affects the expression and function of proteins within the DAPC, leading to molecular events responsible for myofibre damage, muscle weakening, disability and, eventually, premature death. Presently, there is no cure for DMD, but different treatments help manage some of the symptoms. Advances in genetic and exon-skipping therapies are the most promising intervention, the safety and efficiency of which are tested in animal models. In addition to in vivo functional tests, ex vivo molecular evaluation aids assess to what extent the therapy has contributed to the regenerative process. In this regard, the later advances in microscopy and image acquisition systems and the current expansion of antibodies for immunohistological evaluation together with the development of different spectrum fluorescent dyes have made histology a crucial tool. Nevertheless, the complexity of the molecular events that take place in dystrophic muscles, together with the rise of a multitude of markers for each of the phases of the process, makes the histological assessment a challenging task. Therefore, here, we summarise and explain the rationale behind different histological techniques used in the literature to assess degeneration and regeneration in the field of dystrophinopathies, focusing especially on those related to DMD.

show abstract

Mss51 deletion increases endurance and ameliorates histopathology in the mdx mouse model of Duchenne muscular dystrophy

Cited by 9 publications

References 55 publications

In dystrophicmdxhindlimb muscles where fibrosis is limited versican haploinsufficiency transiently improves contractile function without decreasing inflammation

In dystrophicmdxhindlimb muscles where fibrosis is limited versican haploinsufficiency transiently improves contractile function without decreasing inflammation

Site-1 Protease inhibits mitochondrial metabolism by controlling the TGF-β target gene MSS51

Histological Methods to Assess Skeletal Muscle Degeneration and Regeneration in Duchenne Muscular Dystrophy

Contact Info

Product

Resources

About