Dataset Information

Concurrent BMP Signaling Maintenance and TGF-β Signaling Inhibition Is a Hallmark of Natural Resistance to Muscle Atrophy in the Hibernating Bear.

ABSTRACT: Muscle atrophy arises from a multiplicity of physio-pathological situations and has very detrimental consequences for the whole body. Although knowledge of muscle atrophy mechanisms keeps growing, there is still no proven treatment to date. This study aimed at identifying new drivers for muscle atrophy resistance. We selected an innovative approach that compares muscle transcriptome between an original model of natural resistance to muscle atrophy, the hibernating brown bear, and a classical model of induced atrophy, the unloaded mouse. Using RNA sequencing, we identified 4415 differentially expressed genes, including 1746 up- and 2369 down-regulated genes, in bear muscles between the active versus hibernating period. We focused on the Transforming Growth Factor (TGF)-β and the Bone Morphogenetic Protein (BMP) pathways, respectively, involved in muscle mass loss and maintenance. TGF-β- and BMP-related genes were overall down- and up-regulated in the non-atrophied muscles of the hibernating bear, respectively, and the opposite occurred for the atrophied muscles of the unloaded mouse. This was further substantiated at the protein level. Our data suggest TGF-β/BMP balance is crucial for muscle mass maintenance during long-term physical inactivity in the hibernating bear. Thus, concurrent activation of the BMP pathway may potentiate TGF-β inhibiting therapies already targeted to prevent muscle atrophy.

SUBMITTER: Cussonneau L

PROVIDER: S-EPMC8393865 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Concurrent BMP Signaling Maintenance and TGF-β Signaling Inhibition Is a Hallmark of Natural Resistance to Muscle Atrophy in the Hibernating Bear.

Cussonneau Laura L Boyer Christian C Brun Charlotte C Deval Christiane C Loizon Emmanuelle E Meugnier Emmanuelle E Gueret Elise E Dubois Emeric E Taillandier Daniel D Polge Cécile C Béchet Daniel D Gauquelin-Koch Guillemette G Evans Alina L AL Arnemo Jon M JM Swenson Jon E JE Blanc Stéphane S Simon Chantal C Lefai Etienne E Bertile Fabrice F Combaret Lydie L

Cells 20210723 8

Muscle atrophy arises from a multiplicity of physio-pathological situations and has very detrimental consequences for the whole body. Although knowledge of muscle atrophy mechanisms keeps growing, there is still no proven treatment to date. This study aimed at identifying new drivers for muscle atrophy resistance. We selected an innovative approach that compares muscle transcriptome between an original model of natural resistance to muscle atrophy, the hibernating brown bear, and a classical mod ...[more]

PMID: 34440643

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Project description:BackgroundIn mammals, the hibernating state is characterized by biochemical adjustments, which include metabolic rate depression and a shift in the primary fuel oxidized from carbohydrates to lipids. A number of studies of hibernating species report an upregulation of the levels and/or activity of lipid oxidizing enzymes in muscles during torpor, with a concomitant downregulation for glycolytic enzymes. However, other studies provide contrasting data about the regulation of fuel utilization in skeletal muscles during hibernation. Bears hibernate with only moderate hypothermia but with a drop in metabolic rate down to ~ 25% of basal metabolism. To gain insights into how fuel metabolism is regulated in hibernating bear skeletal muscles, we examined the vastus lateralis proteome and other changes elicited in brown bears during hibernation.ResultsWe show that bear muscle metabolic reorganization is in line with a suppression of ATP turnover. Regulation of muscle enzyme expression and activity, as well as of circulating metabolite profiles, highlighted a preference for lipid substrates during hibernation, although the data suggested that muscular lipid oxidation levels decreased due to metabolic rate depression. Our data also supported maintenance of muscle glycolysis that could be fuelled from liver gluconeogenesis and mobilization of muscle glycogen stores. During hibernation, our data also suggest that carbohydrate metabolism in bear muscle, as well as protein sparing, could be controlled, in part, by actions of n-3 polyunsaturated fatty acids like docosahexaenoic acid.ConclusionsOur work shows that molecular mechanisms in hibernating bear skeletal muscle, which appear consistent with a hypometabolic state, likely contribute to energy and protein savings. Maintenance of glycolysis could help to sustain muscle functionality for situations such as an unexpected exit from hibernation that would require a rapid increase in ATP production for muscle contraction. The molecular data we report here for skeletal muscles of bears hibernating at near normal body temperature represent a signature of muscle preservation despite atrophying conditions.

Project description:Articular cartilage plays an essential role in health and mobility, but is frequently damaged or lost in millions of people that develop arthritis. The molecular mechanisms that create and maintain this thin layer of cartilage that covers the surface of bones in joint regions are poorly understood, in part because tools to manipulate gene expression specifically in this tissue have not been available. Here we use regulatory information from the mouse Gdf5 gene (a bone morphogenetic protein [BMP] family member) to develop new mouse lines that can be used to either activate or inactivate genes specifically in developing joints. Expression of Cre recombinase from Gdf5 bacterial artificial chromosome clones leads to specific activation or inactivation of floxed target genes in developing joints, including early joint interzones, adult articular cartilage, and the joint capsule. We have used this system to test the role of BMP receptor signaling in joint development. Mice with null mutations in Bmpr1a are known to die early in embryogenesis with multiple defects. However, combining a floxed Bmpr1a allele with the Gdf5-Cre driver bypasses this embryonic lethality, and leads to birth and postnatal development of mice missing the Bmpr1a gene in articular regions. Most joints in the body form normally in the absence of Bmpr1a receptor function. However, articular cartilage within the joints gradually wears away in receptor-deficient mice after birth in a process resembling human osteoarthritis. Gdf5-Cre mice provide a general system that can be used to test the role of genes in articular regions. BMP receptor signaling is required not only for early development and creation of multiple tissues, but also for ongoing maintenance of articular cartilage after birth. Genetic variation in the strength of BMP receptor signaling may be an important risk factor in human osteoarthritis, and treatments that mimic or augment BMP receptor signaling should be investigated as a possible therapeutic strategy for maintaining the health of joint linings.

Dataset Information

Concurrent BMP Signaling Maintenance and TGF-β Signaling Inhibition Is a Hallmark of Natural Resistance to Muscle Atrophy in the Hibernating Bear.

Publications

Concurrent BMP Signaling Maintenance and TGF-β Signaling Inhibition Is a Hallmark of Natural Resistance to Muscle Atrophy in the Hibernating Bear.

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