Muscle Damage in Dystrophic mdx Mice Is Influenced by the Activity of Ca2+-Activated KCa3.1 Channels

Morotti, Marta; Garofalo, Stefano; Cocozza, Germana; Antonangeli, Fabrizio; Bianconi, Valeria; Mozzetta, Chiara; Stefano, Maria Egle De; Capitani, Riccardo; Wulff, Heike; Limatola, Cristina; Grassi, Francesca

doi:10.3390/life12040538

Cited by 3 publications

(1 citation statement)

References 54 publications

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“…Such cycles of muscle damage and regeneration repeat during this intense growth period and from ⁓12 weeks of age onwards, the pathology stabilizes with continuous degeneration (akin to DMD patients) seen solely in diaphragm, which recapitulates the most the human condition. Persistent pathological progression is observed after the age of 12 months, however, adult muscles typically present only mild necrosis while modestly increased fibrosis [ 1 – 3 ].…”

Section: Introductionmentioning

confidence: 99%

Targeted expression of heme oxygenase-1 in satellite cells improves skeletal muscle pathology in dystrophic mice

Florczyk-Soluch,

Polak,

Jelinkova

et al. 2024

Skeletal Muscle

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Background Adult muscle-resident myogenic stem cells, satellite cells (SCs), that play non-redundant role in muscle regeneration, are intrinsically impaired in Duchenne muscular dystrophy (DMD). Previously we revealed that dystrophic SCs express low level of anti-inflammatory and anti-oxidative heme oxygenase-1 (HO-1, HMOX1). Here we assess whether targeted induction of HMOX1 affect SC function and alleviates hallmark symptoms of DMD. Methods We generated double-transgenic mouse model (mdx;HMOX1Pax7Ind) that allows tamoxifen (TX)-inducible HMOX1 expression in Pax7 positive cells of dystrophic muscles. Mdx;HMOX1Pax7Ind and control mdx mice were subjected to 5-day TX injections (75 mg/kg b.w.) followed by acute exercise protocol with high-speed treadmill (12 m/min, 45 min) and downhill running to worsen skeletal muscle phenotype and reveal immediate effects of HO-1 on muscle pathology and SC function. Results HMOX1 induction caused a drop in SC pool in mdx;HMOX1Pax7Ind mice (vs. mdx counterparts), while not exaggerating the effect of physical exercise. Upon physical exercise, the proliferation of SCs and activated CD34− SC subpopulation, was impaired in mdx mice, an effect that was reversed in mdx;HMOX1Pax7Ind mice, however, both in vehicle- and TX-treated animals. This corresponded to the pattern of HO-1 expression in skeletal muscles. At the tissue level, necrotic events of selective skeletal muscles of mdx mice and associated increase in circulating levels of muscle damage markers were blunted in HO-1 transgenic animals which showed also anti-inflammatory cytokine profile (vs. mdx). Conclusions Targeted expression of HMOX1 plays protective role in DMD and alleviates dystrophic muscle pathology.

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Section: Introductionmentioning

confidence: 99%

Targeted expression of heme oxygenase-1 in satellite cells improves skeletal muscle pathology in dystrophic mice

Florczyk-Soluch,

Polak,

Jelinkova

et al. 2024

Skeletal Muscle

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

Dubuisson

Versele

Planchon

et al. 2022

IJMS

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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.

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The Role of Mitochondria in Mediation of Skeletal Muscle Repair

Paez

Pitzer

2023

Muscles

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Musculoskeletal health is directly linked to independence and longevity, but disease and aging impairs muscle mass and health. Complete repair after a pathological or physiological muscle injury is critical for maintaining muscle function, yet muscle repair is compromised after disuse, or in conditions such as metabolic diseases, cancer, and aging. Regeneration of damaged tissue is critically dependent upon achieving the optimal function of satellite cells (muscle stem cells, MSCs). MSC remodeling in muscle repair is highly dependent upon its microenvironment, and metabolic health of MSCs, which is dependent on the functional capacity of their mitochondria. Muscle repair is energy demanding and mitochondria provide the primary source for energy production during regeneration. However, disease and aging induce mitochondrial dysfunction, which limits energy production during muscle regeneration. Nevertheless, the role of mitochondria in muscle repair likely extends beyond the production of ATP and mitochondria could provide potentially important regulatory signaling to MSCs during repair from injury. The scope of current research in muscle regeneration extends from molecules to exosomes, largely with the goal of understanding ways to improve MSC function. This review focuses on the role of mitochondria in skeletal muscle myogenesis/regeneration and repair. A therapeutic strategy for improving muscle mitochondrial number and health will be discussed as a means for enhancing muscle regeneration. Highlights: (a). Mitochondrial dysfunction limits muscle regeneration; (b). Muscle stem cell (MSC) function can be modulated by mitochondria; (c). Enhancing mitochondria in MSCs may provide a strategy for improving muscle regeneration after an injury.

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Muscle Damage in Dystrophic mdx Mice Is Influenced by the Activity of Ca2+-Activated KCa3.1 Channels

Cited by 3 publications

References 54 publications

Targeted expression of heme oxygenase-1 in satellite cells improves skeletal muscle pathology in dystrophic mice

Targeted expression of heme oxygenase-1 in satellite cells improves skeletal muscle pathology in dystrophic mice

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

The Role of Mitochondria in Mediation of Skeletal Muscle Repair

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