AdipoRon enhances healthspan in middle‐aged obese mice: striking alleviation of myosteatosis and muscle degenerative markers
BackgroundObesity among older adults has increased tremendously. Obesity accelerates ageing and predisposes toage-related conditions and diseases, such as loss of endurance capacity, insulin resistance and features of the metabolicsyndrome. Namely, ectopic lipids play a key role in the development o...
| Autores: | , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universidad de Sevilla (US) |
| Repositorio: | idUS. Depósito de Investigación de la Universidad de Sevilla |
| OAI Identifier: | oai:idus.us.es:11441/152541 |
| Acceso en línea: | https://hdl.handle.net/11441/152541 https://doi.org/10.1002/jcsm.13148 |
| Access Level: | acceso abierto |
| Palabra clave: | adiponectin myosteatosis intramyocellular lipids ageing nonalcoholic fatty liver disease endurance |
| Sumario: | BackgroundObesity among older adults has increased tremendously. Obesity accelerates ageing and predisposes toage-related conditions and diseases, such as loss of endurance capacity, insulin resistance and features of the metabolicsyndrome. Namely, ectopic lipids play a key role in the development of nonalcoholic fatty liver disease (NAFLD) andmyosteatosis, two severe burdens of ageing and metabolic diseases. Adiponectin (ApN) is a hormone, mainly secretedby adipocytes, which exerts insulin-sensitizing and fat-burning properties in several tissues including the liver and themuscle. Its overexpression also increases lifespan in mice. In this study, we investigated whether an ApN receptor ag-onist, AdipoRon (AR), could slow muscle dysfunction, myosteatosis and degenerative muscle markers in middle-agedobese mice. The effects on myosteatosis were compared with those on NAFLD.MethodsThree groups of mice were studied up to 62 weeks of age: One group received normal diet (ND), another,high-fat diet (HFD); and the last, HFD combined with AR given orally for almost 1 year. An additional group of youngmice under an ND was used. Treadmill tests and micro-computed tomography (CT) were carried out in vivo. Histolog-ical, biochemical and molecular analyses were performed on tissues ex vivo. Bodipy staining was used to assessintramyocellular lipid (IMCL) and lipid droplet morphology.ResultsAR did not markedly alter diet-induced obesity. Yet, this treatment rescued exercise endurance in obese mice(up to 2.4-fold,P<0.05), an event that preceded the improvement of insulin sensitivity. Dorsal muscles and liver den-sities, measured by CT, were reduced in obese mice ( 42% and 109%, respectively,P<0.0001), suggesting fatty in-filtration. This reduction tended to be attenuated by AR. Accordingly, AR significantly mitigated steatosis and cellularballooning at liver histology, thereby decreasing the NALFD activity score ( 30%,P<0.05). AR also strikingly reversedIMCL accumulation either due to ageing in oxidativefibres (types 1/2a, soleus) or to HFD in glycolytic ones (types2x/2b, extensor digitorum longus) ( 50% to 85%,P<0.05 or less). Size of subsarcolemmal lipid droplets, knownto be associated with adverse metabolic outcomes, was reduced as well. Alleviation of myosteatosis resulted from im-proved mitochondrial function and lipid oxidation. Meanwhile, AR halved aged-related accumulation of dysfunctionalproteins identified as tubular aggregates and cylindrical spirals by electron microscopy (P<0.05).ConclusionsLong-term AdipoRon treatment promotes‘healthy ageing’in obese middle-aged mice by enhancing en-durance and protecting skeletal muscle and liver against the adverse metabolic and degenerative effects of ageingand caloric excess. |
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