Rapamycin Reverses Metabolic Deficits in Lamin A/C-Deficient Mice

Liao, Chen Yu; Anderson, Sydney S; Chicoine, Nicole H.; Mayfield, Jarrott; Academia, Emmeline C.; Wilson, Joy A.; Pongkietisak, Chalermkwan; Thompson, Morgan A.; Lagmay, Earl P.; Miller, Delana M; Hsu, Yueh Mei; McCormick, Mark; O’Leary, Monique N.; Kennedy, Brian K.

doi:10.1016/j.celrep.2016.10.040

Cited by 51 publications

(58 citation statements)

References 47 publications

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“…Rapamycin, a specific inhibitor of mechanistic target of rapamycin (mTOR) signalling with many effects, including anti-inflammatory activity 265 , has an important role in longevity regulation 266 in both animals and humans 267 , and improves survival and healthspan in animal models 268–272 . Aspirin improves lifespan in mice 273 , whereas metformin, which is known to have direct anti-inflammatory effects beyond its canonical glucose-lowering activity 274 , improves lifespan and healthspan in animal models 275 .…”

Section: Inflammageing Is a Pillar Of Gerosciencementioning

confidence: 99%

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

2018

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Most older individuals develop inflammageing, a condition characterized by elevated levels of blood inflammatory markers that carries high susceptibility to chronic morbidity, disability, frailty, and premature death. Potential mechanisms of inflammageing include genetic susceptibility, central obesity, increased gut permeability, changes to microbiota composition, cellular senescence, NLRP3 inflammasome activation, oxidative stress caused by dysfunctional mitochondria, immune cell dysregulation, and chronic infections. Inflammageing is a risk factor for cardiovascular diseases (CVDs), and clinical trials suggest that this association is causal. Inflammageing is also a risk factor for chronic kidney disease, diabetes mellitus, cancer, depression, dementia, and sarcopenia, but whether modulating inflammation beneficially affects the clinical course of non-CVD health problems is controversial. This uncertainty is an important issue to address because older patients with CVD are often affected by multimorbidity and frailty — which affect clinical manifestations, prognosis, and response to treatment — and are associated with inflammation by mechanisms similar to those in CVD. The hypothesis that inflammation affects CVD, multimorbidity, and frailty by inhibiting growth factors, increasing catabolism, and interfering with homeostatic signalling is supported by mechanistic studies but requires confirmation in humans. Whether early modulation of inflammageing prevents or delays the onset of cardiovascular frailty should be tested in clinical trials.

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Section: Inflammageing Is a Pillar Of Gerosciencementioning

confidence: 99%

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

2018

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“…In both WAT and BAT of Lmna −/− mice, rapamycin inhibits mTORC1 but not mTORC2, leading to the suppression of lipolysis and the restoration of thermogenic uncoupling protein 1 (UCP1) levels, respectively. It indicates that altered mTOR signaling in Lmna −/− mice contributes to lipodystrophic phenotype that can be rescued with rapamycin [113].…”

Section: Type 2 Fpld (Fpld2) and Lmnamentioning

confidence: 99%

“…Lmna −/− mice have been employed to study dilated cardiomyopathy and muscular dystrophy [113]. In both WAT and BAT of Lmna −/− mice, rapamycin inhibits mTORC1 but not mTORC2, leading to the suppression of lipolysis and the restoration of thermogenic uncoupling protein 1 (UCP1) levels, respectively.…”

Section: Type 2 Fpld (Fpld2) and Lmnamentioning

confidence: 99%

Lipodystrophy - A Rare Condition with Serious Metabolic Abnormalities

Chung¹,

Qi²

2020

Rare Diseases

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Lipodystrophy is a rare lipid storage disorder that is characterized by a loss of adipose tissue. It can be inherited due to monogenic mutation or acquired by medication and autoimmune illness. Two primary forms of inherited lipodystrophy are congenital generalized lipodystrophy manifested as a near-complete loss of fat tissue since birth and familial partial lipodystrophy with progressive, partial loss of fat tissue during late childhood and puberty. Lipodystrophy results in severe metabolic conditions, including insulin resistance, type 2 diabetes, hepatosteatosis, polycystic ovary syndrome, acanthosis nigricans, and hypertension. This chapter summarizes the symptoms, causes, and treatments of inherited and acquired lipodystrophy.

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“…Skeletal muscle constitutes ∼40% of the body mass and operates as a thermogenic, metabolic, and endocrine organ (Pant et al, 2016;Rowland, Bal, Kozak, & Periasamy, 2015). Metabolic phenotypes are characteristic of HGPS patients (Charar & Gruenbaum, 2017;Liao et al, 2016;Ramos et al, 2012). Thus, we sought to determine whether dysregulated lamin A expression in muscle affects energy expenditure throughout the entire body.…”

Section: Conditional Overexpression Of Human Progerin In Muscle Indmentioning

confidence: 99%

Progerin in muscle leads to thermogenic and metabolic defects via impaired calcium homeostasis

Wang

Lin

et al. 2019

Aging Cell

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Mutations in lamin A (LMNA) are responsible for a variety of human dystrophic and metabolic diseases. Here, we created a mouse model in which progerin, the lamin A mutant protein that causes Hutchinson–Gilford progeria syndrome (HGPS), can be inducibly overexpressed. Muscle‐specific overexpression of progerin was sufficient to induce muscular dystrophy and alter whole‐body energy expenditure, leading to premature death. Intriguingly, sarcolipin (Sln), an endoplasmic reticulum (ER)‐associated protein involved in heat production, is upregulated in progerin‐expressing and Lmna knockout (Lmna−/−) skeletal muscle. The depletion of Sln accelerated the early death of Lmna−/− mice. An examination at the molecular level revealed that progerin recruits Sln and Calnexin to the nuclear periphery. Furthermore, progerin‐expressing myoblasts presented enhanced store‐operated Ca2+ entry, as well as increased co‐localization of STIM1 and ORAI1. These findings suggest that progerin dysregulates calcium homeostasis through an interaction with a subset of ER‐associated proteins, resulting in thermogenic and metabolic abnormalities.

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Rapamycin Reverses Metabolic Deficits in Lamin A/C-Deficient Mice

Cited by 51 publications

References 47 publications

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

Lipodystrophy - A Rare Condition with Serious Metabolic Abnormalities

Progerin in muscle leads to thermogenic and metabolic defects via impaired calcium homeostasis

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