Fine-structural distribution of MMP-2 and MMP-9 activities in the rat skeletal muscle upon training: a study by high-resolution in situ zymography

Yeghiazaryan, Marine; Żybura-Broda, Katarzyna; Cabaj, Anna; Włodarczyk, Jakub; Sławińska, Urszula; Rylski, Marcin; Wilczyński, Grzegorz M.

doi:10.1007/s00418-012-0940-5

Cited by 30 publications

(27 citation statements)

References 55 publications

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“…In contrast to our results, increased levels of MMP-2 in muscles have previously been reported after 10 days of endurance exercise in humans, and after two to eight weeks of high-intensity training in rats (Carmeli et al, 2005;Rullman et al, 2009;Carmeli et al, 2010;Deus et al, 2012). Furthermore, a study by Yeghiazaryan et al found gelatinolytic activity in the nucleus of skeletal muscles in rats which increased after 5 days of repeated physical training (Yeghiazaryan et al, 2012). The discrepancy between these studies and ours may be due to species differences, as we have studied mouse muscle, and not rat.…”

Section: Discussioncontrasting

confidence: 99%

Intracellular MMP‐2 Activity in Skeletal Muscle Is Associated With Type II Fibers

Hadler‐Olsen

Solli

Hafstad

et al. 2014

Journal Cellular Physiology

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Matrix metalloproteinase 2 (MMP-2) is a proteolytic enzyme implicated in motility, differentiation and regeneration of skeletal muscle fibers through processing of extracellular substrates. Although MMP-2 has been found to be localized intracellularly in cardiomyocytes where the enzyme is thought to contribute to post-ischemic loss of contractility, little is known about intracellular MMP-2 activity in skeletal muscle fibers. In the present study we demonstrate intracellular MMP-2 in normal skeletal muscle by immunohistochemical staining. Immunogold electron microscopic analyses indicated that the enzyme was concentrated in Z-lines of the sarcomers, in the nuclear membrane and in mitochondria. By use of in situ zymography, we found that gelatinolytic activity in muscle fibers was colocalized with immunofluorecent staining for MMP-2. Staining for MMP-9, the other member of the gelatinase group of the MMPs, was negative. The broad-spectrum metalloprotease inhibitor EDTA and the selective gelatinase inhibitor CTT2, but not the cysteine inhibitor E64, strongly reduced the gelatinolytic activity. The intracellular gelatinolytic activity was much more prominent in fast twitch type II fibers than in slow twitch type I fibers, and there was a decrease in intracellular gelatinolytic activity and MMP-2 expression in muscles from mice exposed to high intensity interval training. Together our results indicate that MMP-2 is part of the intracellular proteolytic network in normal skeletal muscle, especially in fast twitch type II fibers. Further, the results suggest that intracellular MMP-2 in skeletal muscle fibers is active during normal homeostasis, and affected by level of physical activity.3

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Section: Discussioncontrasting

confidence: 99%

Intracellular MMP‐2 Activity in Skeletal Muscle Is Associated With Type II Fibers

Hadler‐Olsen

Solli

Hafstad

et al. 2014

Journal Cellular Physiology

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“…1 The matrix metalloproteinase (MMP) family has been shown to participate in muscle disease inception and progression. [4][5][6] However, genetic and pharmacological interventions aimed at MMP family members resulted in incomplete prevention of muscle remodelling and fibrosis, [7][8][9] suggesting that other proteases may also contribute to such remodelling in injury-related muscle disorders.…”

Section: Introductionmentioning

confidence: 99%

Cathepsin K activity controls cardiotoxin‐induced skeletal muscle repair in mice

Ogasawara

Cheng

Inoue

et al. 2017

J cachexia sarcopenia muscle

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BackgroundCathepsin K (CatK) is a widely expressed cysteine protease that has gained attention because of its enzymatic and non‐enzymatic functions in signalling. Here, we examined whether CatK‐deficiency (CatK−/−) would mitigate injury‐related skeletal muscle remodelling and fibrosis in mice, with a special focus on inflammation and muscle cell apoptosis.MethodsCardiotoxin (CTX, 20 μM/200 μL) was injected into the left gastrocnemius muscle of male wild‐type (CatK+/+) and CatK−/− mice, and the mice were processed for morphological and biochemical studies.ResultsOn post‐injection Day 14, CatK deletion ameliorated muscle interstitial fibrosis and remodelling and performance. At an early time point (Day 3), CatK−/− reduced the lesion macrophage and leucocyte contents and cell apoptosis, the mRNA levels of monocyte chemoattractant protein‐1, toll‐like receptor‐2 and toll‐like receptor‐4, and the gelatinolytic activity related to matrix metalloproteinase‐2/‐9. CatK deletion also restored the protein levels of caspase‐3 and cleaved caspase‐8 and the ratio of the BAX to the Bcl‐2. Moreover, CatK deficiency protected muscle fibre laminin and desmin disorder in response to CTX injury. These beneficial muscle effects were mimicked by CatK‐specific inhibitor treatment. In vitro experiments demonstrated that pharmacological CatK inhibition reduced the apoptosis of C2C12 mouse myoblasts and the levels of BAX and caspase‐3 proteins induced by CTX.ConclusionsThese results demonstrate that CatK plays an essential role in skeletal muscle loss and fibrosis in response to CTX injury, possibly via a reduction of inflammation and cell apoptosis, suggesting a novel therapeutic strategy for the control of skeletal muscle diseases by regulating CatK activity.

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“…Furthermore, the intracellular localization of both the endogenous and epitope tagged Mmp11a proteins and intracellular activation of EMMA-Mmp11a in the presence of a strong furin inhibitor suggests that furin-independent mechanisms may also play roles in the regulation of Mmp11a at least, and perhaps the regulation of other predicted furin targets. We cannot rule out the possibility that the overexpression of EMMA-Mmp11a is simply overwhelming the cellular secretory mechanism, but evasion of the secretory pathway and subsequent cytoplasmic or nuclear localization has been described for a variety of MMPs [47,49,59,61,[74][75][76][77][78], including MMP11 [60,79]. And unless the activated EMMA-Mmp11a we detect in nuclei reached that location through an unknown mechanism, it would not have come into contact with furin and must therefore have been activated by some other mechanism.…”

Section: Figure 7 Schematic Representation Of Hypothesized Activitiementioning

confidence: 83%

Paralogues of Mmp11 and Timp4 Interact during the Development of the Myotendinous Junction in the Zebrafish Embryo

Matchett

Wang

Crawford

2019

JDB

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The extracellular matrix (ECM) of the myotendinous junction (MTJ) undergoes dramatic physical and biochemical remodeling during the first 48 h of development in zebrafish, transforming from a rectangular fibronectin-dominated somite boundary to a chevron-shaped laminin-dominated MTJ. Matrix metalloproteinase 11 (Mmp11, a.k.a. Stromelysin-3) is both necessary and sufficient for the removal of fibronectin at the MTJ, but whether this protease acts directly on fibronectin and how its activity is regulated remain unknown. Using immunofluorescence, we show that both paralogues of Mmp11 accumulate at the MTJ during this time period, but with Mmp11a present early and later replaced by Mmp11b. Moreover, Mmp11a also accumulates intracellularly, associated with the Z-discs of sarcomeres within skeletal muscle cells. Using the epitope-mediated MMP activation (EMMA) assay, we show that despite having a weaker paired basic amino acid motif in its propeptide than Mmp11b, Mmp11a is activated by furin, but may also be activated by other mechanisms intracellularly. One or both paralogues of tissue inhibitors of metalloproteinase-4 (Timp4) are also present at the MTJ throughout this process, and yeast two-hybrid assays reveal distinct and specific interactions between various domains of these proteins. We propose a model in which Mmp11a activity is modulated (but not inhibited) by Timp4 during early MTJ remodeling, followed by a phase in which Mmp11b activity is both inhibited and spatially constrained by Timp4 in order to maintain the structural integrity of the mature MTJ.

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Fine-structural distribution of MMP-2 and MMP-9 activities in the rat skeletal muscle upon training: a study by high-resolution in situ zymography

Cited by 30 publications

References 55 publications

Intracellular MMP‐2 Activity in Skeletal Muscle Is Associated With Type II Fibers

Intracellular MMP‐2 Activity in Skeletal Muscle Is Associated With Type II Fibers

Cathepsin K activity controls cardiotoxin‐induced skeletal muscle repair in mice

Paralogues of Mmp11 and Timp4 Interact during the Development of the Myotendinous Junction in the Zebrafish Embryo

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