Assessing Collagen Deposition During Aging in Mammalian Tissue and in Caenorhabditis elegans

Teuscher, Alina C.; Statzer, Cyril; Pantasis, Sophia; Bordoli, Mattia R; Ewald, Collin Y.

doi:10.1007/978-1-4939-9095-5_13

Cited by 46 publications

(43 citation statements)

References 34 publications

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“…Since three collagens ( col-35 , col-36, and col-37 ) were also found among the five most strongly repressed genes upon loss of nsun-1 ( Figure 7A ), we decided to assess whether collagen deposition is indeed altered in the animals. In order to test this possibility, we performed a specific histological staining aimed at distinguishing young collagen, detected in blue, from mature collagen, highlighted in pink/brownish-red ( Herovici, 1963 ; Teuscher et al, 2019 ). While young adult worms exposed to RNAi control showed presence of both young and mature collagen, animals subjected to nsun-1 RNAi displayed a strikingly overall reduction of collagen deposition compared to the cytoplasmatic counter-stain (yellow) ( Figure 7D ).…”

Section: Resultsmentioning

confidence: 99%

The ribosomal RNA m5C methyltransferase NSUN-1 modulates healthspan and oogenesis in Caenorhabditis elegans

Heissenberger

Rollins

Krammer

et al. 2020

eLife

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Our knowledge about the repertoire of ribosomal RNA modifications and the enzymes responsible for installing them is constantly expanding. Previously, we reported that NSUN-5 is responsible for depositing m5C at position C2381 on the 26S rRNA in Caenorhabditis elegans. Here, we show that NSUN-1 is writing the second known 26S rRNA m5C at position C2982. Depletion of nsun-1 or nsun-5 improved thermotolerance and slightly increased locomotion at midlife, however, only soma-specific knockdown of nsun-1 extended lifespan. Moreover, soma-specific knockdown of nsun-1 reduced body size and impaired fecundity, suggesting non-cell-autonomous effects. While ribosome biogenesis and global protein synthesis were unaffected by nsun-1 depletion, translation of specific mRNAs was remodeled leading to reduced production of collagens, loss of structural integrity of the cuticle, and impaired barrier function. We conclude that loss of a single enzyme required for rRNA methylation has profound and highly specific effects on organismal development and physiology.

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Section: Resultsmentioning

confidence: 99%

The ribosomal RNA m5C methyltransferase NSUN-1 modulates healthspan and oogenesis in Caenorhabditis elegans

Heissenberger

Rollins

Krammer

et al. 2020

eLife

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“…6A), we decided to assess whether collagen deposition is indeed altered. For this aim, we performed a specific histological staining protocol in which young collagen is strained blue and mature collagen is stained pink to brownish-red (Herovici, 1963; Teuscher et al, 2019). While young adult worms exposed to RNAi control showed presence of both young and mature collagen, animals subjected to nsun-1 RNAi displayed a strikingly reduced collagen deposition compared to the cytoplasmatic counter-stain (yellow) (Fig.…”

Section: Resultsmentioning

confidence: 99%

The ribosomal RNA m⁵C methyltransferase NSUN-1 modulates healthspan and oogenesis inCaenorhabditis elegans

Heissenberger

Krammer

Rollins

et al. 2020

Preprint

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21Our knowledge about the repertoire of ribosomal RNA modifications and the enzymes 22 responsible for installing them is constantly expanding. Previously, we reported that NSUN-5 23 is responsible for depositing m 5 C at position C2381 on the 26S rRNA in Caenorhabditis 24 elegans. 25 Here, we show that NSUN-1 is writing the second known 26S rRNA m 5 C at position C2982. 26 Depletion of nsun-1 or nsun-5 improved locomotion at midlife and resistance against heat 27 stress, however, only soma-specific knockdown of nsun-1 extended lifespan. Moreover, 28 soma-specific knockdown of nsun-1 reduced body size and impaired fecundity, suggesting 29 non-cell-autonomous effects. While ribosome biogenesis and global protein synthesis were 30 unaffected by nsun-1 depletion, translation of specific mRNAs was remodelled leading to 31 reduced production of collagens, loss of structural integrity of the cuticle and impaired barrier 32 function. 33 We conclude that loss of a single enzyme required for rRNA methylation has profound and 34 highly specific effects on organismal physiology. 102Therefore, we investigated the RNA substrate of NSUN-1 (also formerly known as NOL-1, 103 NOL-2 or W07E6.1) and its potential roles in worm physiology. NSUN-1 is also a member 104 of the NOP2/Sun RNA methyltransferase family. Since there are only two known m 5 C 105 residues on worm 26S rRNA (Sharma and Lafontaine, 2015; Trixl and Lusser, 2019), one of 106 them at C2381, being installed by NSUN-5, we speculated that NSUN-1 might be required 107 6 for introducing the second m 5 C residue at position C2982. Notably, both 26S m 5 C sites are 108 localized close to important functional regions of the ribosome, and they are highly conserved 109 during evolution ( Fig. 1A,B). 110In order to test if NSUN-1 is involved in large ribosomal subunit m 5 C methylation, 26S 111 rRNA was purified from worms treated with siRNAs specific to NSUN-1-encoding mRNAs 112 on sucrose gradients, digested to single nucleosides and analysed by quantitative HPLC. In 113 our HPLC assay, the m 5 C nucleoside eluted at 12 min, as established with a m 5 C calibration 114 control (data not shown). 115The depletion of NSUN-1 was conducted in two genetic backgrounds: N2 (wildtype), and 116 NL2099 (an RNAi-hypersensitive strain due to mutation in rrf-3) (Figure 1-figure 117 supplement 1). Treating N2 worms with an empty control vector, not expressing any RNAi, 118did not significantly reduce the levels of 26S rRNA m 5 C methylation (Fig. 1C, 97% instead 119 of 100%). Interestingly, treating N2 worms with an RNAi construct targeting nsun-1 led to a 120 reduction of 26S rRNA m 5 C methylation by 35% (Fig. 1C). In the NL2099 strain, nsun-1 121 RNAi treatment also led to a reduction of 26S rRNA m 5 C methylation by 26% ( Fig. 1D). 122As there are only two known modified m 5 C residues on worm 26S rRNA, and since one of 123 them is introduced by NSUN-5 (Adamla et al., 2019; Schosserer et al., 2015), a complete loss 124 of NSUN-1 activity was expected to result in a 50% decrease...

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“…Moreover, inflammation proceeds fibrosis [35] and during aging there is a steady increase of inflammation. This inflammation-induced matreotype, which is characteristic for fibrosis and amorphous collagen deposition during aging, can be assessed through tissue staining and biochemical techniques [36]. A third aspect for consideration is that there is also heterogeneity within cell types and tissues due to randomness in cellular gene expression including the expression and biosynthesis of ECM proteins.…”

Section: Technical Challenges For Quantifying Matreotypesmentioning

confidence: 99%

The Matrisome during Aging and Longevity: A Systems-Level Approach toward Defining Matreotypes Promoting Healthy Aging

Ewald¹

2019

Gerontology

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Accumulation of damage is generally considered the cause of aging. Interventions that delay aging mobilize mechanisms that protect and repair cellular components. Consequently, research has been focused on studying the protective and homeostatic mechanisms within cells. However, in humans and other multicellular organisms, cells are surrounded by extracellular matrices (ECMs), which are important for tissue structure, function, and intercellular communication. During aging, components of the ECM become damaged through fragmentation, glycation, crosslinking, and accumulation of protein aggregation, all of which contribute to age-related pathologies. Interestingly, placing senescent cells into a young ECM rejuvenates them. Furthermore, we found that many longevity-assurances pathways reactivate de novo synthesis of ECM proteins during aging. This raises the question of what constitutes a young ECM to reverse aging or maintain health? In order to make inroads to answering this question, I suggest a systems-level approach of quantifying the matrisome or ECM compositions reflecting health, pathology, or phenotype and propose a novel term, the "matreotype," to describe this. The matreotype is defined as the composition and modification of ECM or matrisome proteins associated with or caused by a phenotype, such as longevity, or a distinct and acute physiological state, as observed during aging or disease. Every cell type produces its unique ECM. Intriguingly, cancer-cell types can even be identified based on their unique ECM composition. Thus, the matreotype reflects cellular identity and physiological status. Defined matreotypes could be used as biomarkers or prognostic factors for disease or health status during aging with potential relevance for personalized medicine. Treatment with biologics that alter ECM-to-cell mechanotransduction might be a strategy to reverse age-associated pathologies. An understanding of how to reverse from an old to a young matreotype might point toward novel strategies to rejuvenate cells and help maintain tissue homeostasis to promote health during aging.

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Assessing Collagen Deposition During Aging in Mammalian Tissue and in Caenorhabditis elegans

Cited by 46 publications

References 34 publications

The ribosomal RNA m5C methyltransferase NSUN-1 modulates healthspan and oogenesis in Caenorhabditis elegans

The ribosomal RNA m5C methyltransferase NSUN-1 modulates healthspan and oogenesis in Caenorhabditis elegans

The ribosomal RNA m⁵C methyltransferase NSUN-1 modulates healthspan and oogenesis inCaenorhabditis elegans

The Matrisome during Aging and Longevity: A Systems-Level Approach toward Defining Matreotypes Promoting Healthy Aging

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Assessing Collagen Deposition During Aging in Mammalian Tissue and in Caenorhabditis elegans

Cited by 46 publications

References 34 publications

The ribosomal RNA m5C methyltransferase NSUN-1 modulates healthspan and oogenesis in Caenorhabditis elegans

The ribosomal RNA m5C methyltransferase NSUN-1 modulates healthspan and oogenesis in Caenorhabditis elegans

The ribosomal RNA m5C methyltransferase NSUN-1 modulates healthspan and oogenesis inCaenorhabditis elegans

The Matrisome during Aging and Longevity: A Systems-Level Approach toward Defining Matreotypes Promoting Healthy Aging

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The ribosomal RNA m⁵C methyltransferase NSUN-1 modulates healthspan and oogenesis inCaenorhabditis elegans