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Molecular and phenotypic analysis of rodent models reveals conserved and species-specific modulators of human sarcopenia.

ABSTRACT: Sarcopenia, the age-related loss of skeletal muscle mass and function, affects 5-13% of individuals aged over 60 years. While rodents are widely-used model organisms, which aspects of sarcopenia are recapitulated in different animal models is unknown. Here we generated a time series of phenotypic measurements and RNA sequencing data in mouse gastrocnemius muscle and analyzed them alongside analogous data from rats and humans. We found that rodents recapitulate mitochondrial changes observed in human sarcopenia, while inflammatory responses are conserved at pathway but not gene level. Perturbations in the extracellular matrix are shared by rats, while mice recapitulate changes in RNA processing and autophagy. We inferred transcription regulators of early and late transcriptome changes, which could be targeted therapeutically. Our study demonstrates that phenotypic measurements, such as muscle mass, are better indicators of muscle health than chronological age and should be considered when analyzing aging-related molecular data.

SUBMITTER: Borsch A

PROVIDER: S-EPMC7881157 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Molecular and phenotypic analysis of rodent models reveals conserved and species-specific modulators of human sarcopenia.

Börsch Anastasiya A Ham Daniel J DJ Mittal Nitish N Tintignac Lionel A LA Migliavacca Eugenia E Feige Jérôme N JN Rüegg Markus A MA Zavolan Mihaela M

Communications biology 20210212 1

Sarcopenia, the age-related loss of skeletal muscle mass and function, affects 5-13% of individuals aged over 60 years. While rodents are widely-used model organisms, which aspects of sarcopenia are recapitulated in different animal models is unknown. Here we generated a time series of phenotypic measurements and RNA sequencing data in mouse gastrocnemius muscle and analyzed them alongside analogous data from rats and humans. We found that rodents recapitulate mitochondrial changes observed in h ...[more]

PMID: 33580198

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Project description:Aims: Sarcopenia is the degenerative loss of skeletal muscle mass and function at high age, which affects 5-13% of people aged 60-70 years. Although a number of factors have been linked to sarcopenia, it remains unclear what determines its emergence in some but not all individuals and there are no medical treatments available. Mice and rats are widely used as model organisms to identify factors predisposing to sarcopenia, but the extent to which age-related molecular changes in wild-type mice and rats recapitulate those occurring in humans is not known. The aim of this project was to define a conserved set of regulators of aging-related reduction in muscle function that could be targeted by future therapies. Methods: We comparatively analyzed phenotypic parameters as well as the transcriptomes of the Gastrocnemius muscle from mice, rats and humans of a wide range of ages. We further inferred computationally the transcription regulators that likely underlie the molecular changes associated with aging-related loss in muscle functionality. Results: The analysis showed that the biological age of rodents that muscle mass is a better indicator of muscle functionality than the chronological age. Investigating the molecular changes associated with the aging-related loss of muscle mass, we discovered changes in gene expression that are shared between the studied species at the level of molecular pathways rather than at the level of individual genes. Beyond the known involvement of inflammation and mitochondrial function in aging, we found that the transcription regulators SPIB, ESRRB and YY1/YY2 consistently underlie aging-related molecular changes across the studied species. Conclusions: Rodents recapitulate well the molecular changes observed in human sarcopenia, but the conservation is stronger at the molecular pathway level than at the level of individual genes. Phenotypic parameters such as the muscle mass should be taken into account in stratifying samples for analyzing aging-related processes, as the chronological age is a poorer indicator of organ functionality. The shared regulators of aging-related muscle loss that we identified here can be studied further in rodent models of sarcopenia toward defining new targets for therapy in humans.

Project description:We have addressed the question of how different rodent species cope with the life-threatening homeostatic challenge of dehydration at the level of transcriptome modulation in the supraoptic nucleus (SON), a specialised hypothalamic neurosecretory apparatus responsible for the production of the antidiuretic peptide hormone arginine vasopressin (AVP). AVP maintains water balance by promoting water conservation at the level of the kidney. Dehydration evokes a massive increase in the regulated release of AVP from SON axon terminals located in the posterior pituitary, and this is accompanied by a plethora of changes in the morphology, electrophysiological properties, biosynthetic and secretory activity of this structure. Microarray analysis was used to generate a definitive catalogue of the genes expressed in the mouse SON, and to describe how the gene expression profile changes in response to dehydration. Comparison of the genes differentially expressed in the mouse SON as a consequence of dehydration with those of the rat has revealed many similarities, pointing to common processes underlying the function-related plasticity in this nucleus. In addition we have identified many genes that are differentially expressed in a species-specific manner. However, in many cases, we have found that the hyperosmotic cue can induce species-specific alterations in the expression of different genes in the same pathway. The same functional end can be served by different means, via differential modulation, in different species, of different molecules in the same pathway. We suggest that pathways, rather than specific genes, should be the focus of integrative physiological studies based on transcriptome data. Animals. Adult male C57BL/6 mice (Harlan Sera-Lab, Loughborough, UK) were group housed (4 per cage) under controlled temperature (21+ 2ºC) and diurnal light conditions (14-h light, 10-h dark, lights on at 05.00). Food and water were available ad libitum until the experiment commenced. Complete fluid deprivation was imposed for 48 hours starting at 11.00 a.m. Control animals maintained free access to drinking water, and both groups had access to standard laboratory rodent chow. Experiments on adult male rats described previously (27). All procedures were conducted in strict accordance with the Animal Scientific Procedures Act (1986), UK, and were approved by the local University of Bristol Ethical Review Process. Tissue collection. Mice were killed using cervical dislocation and the brain was carefully removed from the cranium and snap frozen using powdered dry ice and stored at -80oC for no more than 14 days. Sections of brain (14μm) were cut using an RNase free cryostat and mounted onto RNase free membrane coated glass slides (P.A.L.M. Membrane slides; P.A.L.M. Microlaser Technologies). Immediately after sectioning, frozen sections were thawed and fixed (30s; in 95% [v/v] EtOH), rehydrated (30s in each of 75% [v/v] and 50% [v/v] EtOH) before being stained (60s 1% [v/v] cresyl violet). Sections were then dehydrated in a graded EtOH series (30s in each of 50% [v/v], 75% [v/v] and 95% [v/v]. then 2x 30s in 100% [v/v]). Laser microdissection was performed using a P.A.L.M. MicrolaserSystem (P.A.L.M. Microlaser Technologies). The SON was identified with reference to Franklin and Paxinos (28) and the tissue from each animal was independently pooled into collection vials containing RNAlater® (Ambion, Huntingdon, UK). A single operative carried out all dissections. Total RNA was isolated without delay (within 24h) according to standard procedures that accompany the Ambion RNAqueous MicroKit (Ambion). Microarray analysis. Separate microarrays (n=4) were probed using independently generated target. For each completely independent replicate, tissue from 1 mouse was used for RNA extraction.

Dataset Information

Molecular and phenotypic analysis of rodent models reveals conserved and species-specific modulators of human sarcopenia.

Publications

Molecular and phenotypic analysis of rodent models reveals conserved and species-specific modulators of human sarcopenia.

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