Adiponectin receptor agonist AdipoRon improves skeletal muscle function in aged mice

Balasubramanian, Priya; Schaar, Anne; Gustafson, Grace E.; Smith, Alex; Howell, Porsha R.; Greenman, Angela; Baum, Scott; Colman, Ricki J.; Lamming, Dudley W.; Diffee, Gary M.; Anderson, Rozalyn M.

doi:10.1101/2021.09.16.460597

Cited by 6 publications

(3 citation statements)

References 70 publications

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“…14 However, its potential beneficial properties on ageing muscle have been scarcely addressed. 15 It is also un-known whether this molecule does effectively prolong life span in normal (wild-type) mice. An effect on longevity has been observed in a mouse model with a severe form of genetic diabetes; hence, the marked alleviation of diabetes provoked by AdipoRon was, in this case, a major confounding factor.…”

Section: Introductionmentioning

confidence: 99%

AdipoRon enhances healthspan in middle‐aged obese mice: striking alleviation of myosteatosis and muscle degenerative markers

Selvais¹,

Carrizosa

Nachit³

et al. 2022

J cachexia sarcopenia muscle

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Background Obesity among older adults has increased tremendously. Obesity accelerates ageing and predisposes to age‐related conditions and diseases, such as loss of endurance capacity, insulin resistance and features of the metabolic syndrome. Namely, ectopic lipids play a key role in the development of nonalcoholic fatty liver disease (NAFLD) and myosteatosis, two severe burdens of ageing and metabolic diseases. Adiponectin (ApN) is a hormone, mainly secreted by adipocytes, which exerts insulin‐sensitizing and fat‐burning properties in several tissues including the liver and the muscle. Its overexpression also increases lifespan in mice. In this study, we investigated whether an ApN receptor agonist, AdipoRon (AR), could slow muscle dysfunction, myosteatosis and degenerative muscle markers in middle‐aged obese mice. The effects on myosteatosis were compared with those on NAFLD. Methods Three 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 young mice under an ND was used. Treadmill tests and micro‐computed tomography (CT) were carried out in vivo. Histological, biochemical and molecular analyses were performed on tissues ex vivo. Bodipy staining was used to assess intramyocellular lipid (IMCL) and lipid droplet morphology. Results AR 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 densities, measured by CT, were reduced in obese mice (−42% and −109%, respectively, P < 0.0001), suggesting fatty infiltration. This reduction tended to be attenuated by AR. Accordingly, AR significantly mitigated steatosis and cellular ballooning at liver histology, thereby decreasing the NALFD activity score (−30%, P < 0.05). AR also strikingly reversed IMCL accumulation either due to ageing in oxidative fibres (types 1/2a, soleus) or to HFD in glycolytic ones (types 2x/2b, extensor digitorum longus) (−50% to −85%, P < 0.05 or less). Size of subsarcolemmal lipid droplets, known to be associated with adverse metabolic outcomes, was reduced as well. Alleviation of myosteatosis resulted from improved mitochondrial function and lipid oxidation. Meanwhile, AR halved aged‐related accumulation of dysfunctional proteins identified as tubular aggregates and cylindrical spirals by electron microscopy (P < 0.05). Conclusions Long‐term AdipoRon treatment promotes ‘healthy ageing’ in obese middle‐aged mice by enhancing endurance and protecting skeletal muscle and liver against the adverse metabolic and degenerative effects of ageing and caloric excess.

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Section: Introductionmentioning

confidence: 99%

AdipoRon enhances healthspan in middle‐aged obese mice: striking alleviation of myosteatosis and muscle degenerative markers

Selvais¹,

Carrizosa

Nachit³

et al. 2022

J cachexia sarcopenia muscle

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“…Singh et al 19 found that activated APNrs could mitigate dexamethasone-induced muscle atrophy in vivo through the AMPK pathway, thereby simulating PPAR-γ coactivator 1α. Balasubramanian et al 52 observed that APNr activation promoted skeletal muscle repair in aged mice, which was linked to changes in fibre types, especially oxidative fibres. Given that APNr activation could promote osteogenesis and attenuate adipogenesis in AMUSCs, we verified that whether age-induced skeletal muscle dysfunction could be improved via…”

Section: Discussionmentioning

confidence: 99%

Adiponectin receptors activation performs dual effects on regulating myogenesis and adipogenesis of young and aged muscle satellite cells

Liu

et al. 2022

Cell Proliferation

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Objectives Skeletal muscle mass and function deteriorate with ageing. Adiponectin receptors (APNrs), mainly activated by adiponectin, participate in various physiological activities and have varying signalling pathways at different ages. This study aimed to explore whether discrepant performance exists in APNr activation regulating young and aged muscle satellite cells (MUSCs) and whether age‐related muscle dysfunction could be alleviated upon APNr activation. Methods The gastrocnemius muscle phenotype was observed in male mice aged 2 and 18 months. An APNr agonist (AdipoRon) was used in vitro and in vivo to investigate the changes in cell biological behaviours and whether muscle dysfunction could be retarded after APNr activation. Results Aged mice exhibited decreased muscle mass and increased fat infiltration. APNr activation inhibited C2C12 cells and young MUSCs (YMUSCs) proliferation but showed no obvious effect on aged MUSCs (AMUSCs). Moreover, APNr activation inhibited the migration of both YMUSCs and AMUSCs. Interestingly, APNr activation hampered the myogenic differentiation but advanced the adipogenic differentiation of YMUSCs, yet exact opposite results were presented in AMUSCs. It was demonstrated that Wnt and PI3K signalling pathways may mediate the phenotypic differences. Furthermore, in vivo experiments verified that APNr activation ameliorated age‐related muscle atrophy and excessive fat infiltration. Conclusions APNr activation exerted dual effects on the regulation of myogenesis and adipogenesis of YMUSCs and AMUSCs and rescued age‐related skeletal muscle dysfunction.

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“…As CR works to slow aging in all tissues, it has been suggested that CR may work in part through endocrine factors. The role of hormones, including growth hormone, insulin, insulin-like growth factor 1 (IGF-1) and adiponectin, have been explored by numerous groups, but evidence that one of these hormones is responsible for the beneficial effects of CR remains elusive (Balasubramanian et al, 2021; Bonkowski, Rocha, Masternak, Al Regaiey, & Bartke, 2006; Yu et al, 2019). One endocrine factor that could play a role in CR that has not yet been fully explored is fibroblast growth factor 21 (FGF21).…”

Section: Introductionmentioning

confidence: 99%

FGF21 has a sex-specific role in calorie-restriction-induced beiging of white adipose tissue in mice

Calubag

Ademi

Yeh

et al. 2022

Preprint

Self Cite

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Calorie restriction (CR) promotes healthspan and extends the lifespan of diverse organisms, including mice, and there is intense interest in understanding the molecular mechanisms by which CR functions. Some studies have demonstrated that CR induces fibroblast growth factor 21 (FGF21), a hormone that regulates energy balance and that when overexpressed, promotes metabolic health and longevity in mice, but the role of FGF21 in the response to CR has not been investigated. We directly examined the role of FGF21 in the physiological and metabolic response to a CR diet by feeding Fgf21-/- and wild-type control mice either ad libitum (AL) diet or a 30% CR diet. Here, we find that FGF21 is largely dispensable for CR-induced improvements in body composition and energy balance, but that lack of Fgf21 blunts CR-induced changes in glucose tolerance and insulin sensitivity in females. Surprisingly, despite not affecting CR-induced changes in energy expenditure, loss of Fgf21 significantly blunts CR-induced beiging of white adipose tissue in male but not female mice. Our results shed new light on the molecular mechanisms involved in the beneficial effects of a CR diet, clarify that FGF21 is largely dispensable for the metabolic effects of a CR diet, and highlight a sex-dependent role for FGF21 in the molecular adaptation of white adipose tissue to CR.

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Adiponectin receptor agonist AdipoRon improves skeletal muscle function in aged mice

Cited by 6 publications

References 70 publications

AdipoRon enhances healthspan in middle‐aged obese mice: striking alleviation of myosteatosis and muscle degenerative markers

AdipoRon enhances healthspan in middle‐aged obese mice: striking alleviation of myosteatosis and muscle degenerative markers

Adiponectin receptors activation performs dual effects on regulating myogenesis and adipogenesis of young and aged muscle satellite cells

FGF21 has a sex-specific role in calorie-restriction-induced beiging of white adipose tissue in mice

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