Givinostat as metabolic enhancer reverting mitochondrial biogenesis deficit in Duchenne Muscular Dystrophy

Giovarelli, Matteo; Zecchini, Silvia; Catarinella, Giorgia; Moscheni, Claudia; Sartori, Patrizia; Barbieri, Christian; Roux-Biejat, Paulina; Napoli, Alessandra; Vantaggiato, Chiara; Cervia, Davide; Perrotta, Cristiana; Clementi, Emilio; Latella, Lucia; Palma, Clara De

doi:10.1016/j.phrs.2021.105751

Cited by 27 publications

(22 citation statements)

References 77 publications

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“…Figure 9 shows that mdx mice and wild-type animals show similar levels of Drp1 and Mfn2 expression, but dystrophin-deficient mice exhibit a significant reduction in the expression of the transcription factor Ppargc1a, indicating suppression of mitochondrial biogenesis. In addition, we noted a decrease in the level of mitochondrial DNA in the skeletal muscles of mdx mice, which is also consistent with the known data [25] and indicates a significant decrease in the number of organelles in DMD. In this case, alisporivir treatment is accompanied by a decrease in the expression of both Drp1 and Mfn2 indicating the suppression of mitochondrial dynamics.…”

Section: Alisporivir Suppresses Mitochondrial Dynamics and Biogenesis In Skeletal Musclesupporting

confidence: 91%

“…One could speculate that in the long term, suppression of cyclophilin D may adversely affect the growth and differentiation of muscle fibers and other tissues, as seen in the case of alisporivir-treated wild-type animals. In this regard, it is possible that the combination of alisporivir and the histone deacetylase inhibitor givinostat reversing the suppression of mitochondrial biogenesis in DMD [25] may contribute to addressing this issue. Nevertheless, we can summarize that the MPT pore targeting approach may be used as an effective adjunctive strategy in the treatment of DMD.…”

Section: Discussionmentioning

confidence: 99%

“…It is known that DMD is accompanied by inhibition of mitochondrial biogenesis and changes in the dynamics of organelles (processes of fission and fusion) [23][24][25]. Taking this into account, as well as the important role of cyclophilin D in the regulation of mitochondrial dynamics [26], we evaluated the effect of alisporivir on the expression of proteins responsible for these processes.…”

Section: Alisporivir Suppresses Mitochondrial Dynamics and Biogenesis In Skeletal Musclementioning

confidence: 99%

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Alisporivir Improves Mitochondrial Function in Skeletal Muscle of mdx Mice but Suppresses Mitochondrial Dynamics and Biogenesis

Dubinin

Starinets

Talanov

et al. 2021

IJMS

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Mitigation of calcium-dependent destruction of skeletal muscle mitochondria is considered as a promising adjunctive therapy in Duchenne muscular dystrophy (DMD). In this work, we study the effect of intraperitoneal administration of a non-immunosuppressive inhibitor of calcium-dependent mitochondrial permeability transition (MPT) pore alisporivir on the state of skeletal muscles and the functioning of mitochondria in dystrophin-deficient mdx mice. We show that treatment with alisporivir reduces inflammation and improves muscle function in mdx mice. These effects of alisporivir were associated with an improvement in the ultrastructure of mitochondria, normalization of respiration and oxidative phosphorylation, and a decrease in lipid peroxidation, due to suppression of MPT pore opening and an improvement in calcium homeostasis. The action of alisporivir was associated with suppression of the activity of cyclophilin D and a decrease in its expression in skeletal muscles. This was observed in both mdx mice and wild-type animals. At the same time, alisporivir suppressed mitochondrial biogenesis, assessed by the expression of Ppargc1a, and altered the dynamics of organelles, inhibiting both DRP1-mediated fission and MFN2-associated fusion of mitochondria. The article discusses the effects of alisporivir administration and cyclophilin D inhibition on mitochondrial reprogramming and networking in DMD and the consequences of this therapy on skeletal muscle health.

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Section: Alisporivir Suppresses Mitochondrial Dynamics and Biogenesis In Skeletal Musclesupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Alisporivir Suppresses Mitochondrial Dynamics and Biogenesis In Skeletal Musclementioning

confidence: 99%

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Alisporivir Improves Mitochondrial Function in Skeletal Muscle of mdx Mice but Suppresses Mitochondrial Dynamics and Biogenesis

Dubinin

Starinets

Talanov

et al. 2021

IJMS

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“…These findings show that in both healthy and dystrophic conditions fibrosis increases with aging. They also confirm that DF is the most involved among muscles and that fibrotic muscles in mdx represent a direct marker for evaluating phenotype degeneration, performance/force impairment, as well as a direct readout of therapeutic strategies [ 37 ].…”

Section: Resultsmentioning

confidence: 66%

Characterisation of Progressive Skeletal Muscle Fibrosis in the Mdx Mouse Model of Duchenne Muscular Dystrophy: An In Vivo and In Vitro Study

Giovarelli

Arnaboldi

Zecchini

et al. 2022

IJMS

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Duchenne muscular dystrophy (DMD) is a rare genetic disease leading to progressive muscle wasting, respiratory failure, and cardiomyopathy. Although muscle fibrosis represents a DMD hallmark, the organisation of the extracellular matrix and the molecular changes in its turnover are still not fully understood. To define the architectural changes over time in muscle fibrosis, we used an mdx mouse model of DMD and analysed collagen and glycosaminoglycans/proteoglycans content in skeletal muscle sections at different time points during disease progression and in comparison with age-matched controls. Collagen significantly increased particularly in the diaphragm, quadriceps, and gastrocnemius in adult mdx, with fibrosis significantly correlating with muscle degeneration. We also analysed collagen turnover pathways underlying fibrosis development in cultured primary quadriceps-derived fibroblasts. Collagen secretion and matrix metalloproteinases (MMPs) remained unaffected in both young and adult mdx compared to wt fibroblasts, whereas collagen cross-linking and tissue inhibitors of MMP (TIMP) expression significantly increased. We conclude that, in the DMD model we used, fibrosis mostly affects diaphragm and quadriceps with a higher collagen cross-linking and inhibition of MMPs that contribute differently to progressive collagen accumulation during fibrotic remodelling. This study offers a comprehensive histological and molecular characterisation of DMD-associated muscle fibrosis; it may thus provide new targets for tailored therapeutic interventions.

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“…The whole body tension (WBT) assay was used to determine the ability of mice to exert tension in a forward pulling maneuver that is elicited by stroking the tail of the mice [ 1 , 52 ]. The tails were connected to an MP150 System transducer (BIOPAC Systems, Goleta, CA, USA) with a 4.0 silk thread (one end of the thread being tied to the tail and the other end to the transducer).…”

Section: Methodsmentioning

confidence: 99%

Acid Sphingomyelinase Controls Early Phases of Skeletal Muscle Regeneration by Shaping the Macrophage Phenotype

Roux-Biejat

Coazzoli

Marrazzo

et al. 2021

Cells

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Skeletal muscle regeneration is a complex process involving crosstalk between immune cells and myogenic precursor cells, i.e., satellite cells. In this scenario, macrophage recruitment in damaged muscles is a mandatory step for tissue repair since pro-inflammatory M1 macrophages promote the activation of satellite cells, stimulating their proliferation and then, after switching into anti-inflammatory M2 macrophages, they prompt satellite cells’ differentiation into myotubes and resolve inflammation. Here, we show that acid sphingomyelinase (ASMase), a key enzyme in sphingolipid metabolism, is activated after skeletal muscle injury induced in vivo by the injection of cardiotoxin. ASMase ablation shortens the early phases of skeletal muscle regeneration without affecting satellite cell behavior. Of interest, ASMase regulates the balance between M1 and M2 macrophages in the injured muscles so that the absence of the enzyme reduces inflammation. The analysis of macrophage populations indicates that these events depend on the altered polarization of M1 macrophages towards an M2 phenotype. Our results unravel a novel role of ASMase in regulating immune response during muscle regeneration/repair and suggest ASMase as a supplemental therapeutic target in conditions of redundant inflammation that impairs muscle recovery.

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Givinostat as metabolic enhancer reverting mitochondrial biogenesis deficit in Duchenne Muscular Dystrophy

Cited by 27 publications

References 77 publications

Alisporivir Improves Mitochondrial Function in Skeletal Muscle of mdx Mice but Suppresses Mitochondrial Dynamics and Biogenesis

Alisporivir Improves Mitochondrial Function in Skeletal Muscle of mdx Mice but Suppresses Mitochondrial Dynamics and Biogenesis

Characterisation of Progressive Skeletal Muscle Fibrosis in the Mdx Mouse Model of Duchenne Muscular Dystrophy: An In Vivo and In Vitro Study

Acid Sphingomyelinase Controls Early Phases of Skeletal Muscle Regeneration by Shaping the Macrophage Phenotype

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