RESUMO
BACKGROUND: As a result of aging, skeletal muscle undergoes atrophy and a decrease in function. This age-related skeletal muscle weakness is known as "sarcopenia". Sarcopenia is part of the frailty observed in humans. In order to discover treatments for sarcopenia, it is necessary to determine appropriate preclinical models and the genes and signaling pathways that change with age in these models. METHODS AND RESULTS: To understand the changes in gene expression that occur as a result of aging in skeletal muscles, we generated a multi-time-point gene expression signature throughout the lifespan of mice and rats, as these are the most commonly used species in preclinical research and intervention testing. Gastrocnemius, tibialis anterior, soleus, and diaphragm muscles from male and female C57Bl/6J mice and male Sprague Dawley rats were analyzed at ages 6, 12, 18, 21, 24, and 27 months, plus an additional 9-month group was used for rats. More age-related genes were identified in rat skeletal muscles compared with mice; this was consistent with the finding that rat muscles undergo more robust age-related decline in mass. In both species, pathways associated with innate immunity and inflammation linearly increased with age. Pathways linked with extracellular matrix remodeling were also universally downregulated. Interestingly, late downregulated pathways were exclusively found in the rat limb muscles and these were linked to metabolism and mitochondrial respiration; this was not seen in the mouse. CONCLUSIONS: This extensive, side-by-side transcriptomic profiling shows that the skeletal muscle in rats is impacted more by aging compared with mice, and the pattern of decline in the rat may be more representative of the human. The observed changes point to potential therapeutic interventions to avoid age-related decline in skeletal muscle function.
Assuntos
Diafragma , Sarcopenia , Humanos , Camundongos , Feminino , Masculino , Ratos , Animais , Transcriptoma , Ratos Sprague-Dawley , Músculo Esquelético , Sarcopenia/genética , Camundongos Endogâmicos C57BLRESUMO
Low-protein (LP) diets are associated with a decreased risk of diabetes in humans, and promote leanness and glycaemic control in both rodents and humans. While the effects of an LP diet on glycaemic control are mediated by reduced levels of the branched-chain amino acids, we have observed that reducing dietary levels of the other six essential amino acids leads to changes in body composition. Here, we find that dietary histidine plays a key role in the response to an LP diet in male C57BL/6J mice. Specifically reducing dietary levels of histidine by 67% reduces the weight gain of young, lean male mice, reducing both adipose and lean mass without altering glucose metabolism, and rapidly reverses diet-induced obesity and hepatic steatosis in diet-induced obese male mice, increasing insulin sensitivity. This normalization of metabolic health was associated not with caloric restriction or increased activity, but with increased energy expenditure. Surprisingly, the effects of histidine restriction do not require the energy balance hormone Fgf21. Histidine restriction that was started in midlife promoted leanness and glucose tolerance in aged males but not females, but did not affect frailty or lifespan in either sex. Finally, we demonstrate that variation in dietary histidine levels helps to explain body mass index differences in humans. Overall, our findings demonstrate that dietary histidine is a key regulator of weight and body composition in male mice and in humans, and suggest that reducing dietary histidine may be a translatable option for the treatment of obesity. KEY POINTS: Protein restriction (PR) promotes metabolic health in rodents and humans and extends rodent lifespan. Restriction of specific individual essential amino acids can recapitulate the benefits of PR. Reduced histidine promotes leanness and increased energy expenditure in male mice. Reduced histidine does not extend the lifespan of mice when begun in midlife. Dietary levels of histidine are positively associated with body mass index in humans.
Assuntos
Histidina , Magreza , Masculino , Humanos , Animais , Camundongos , Idoso , Histidina/metabolismo , Camundongos Endogâmicos C57BL , Dieta , Obesidade/metabolismo , Proteínas , Metabolismo EnergéticoRESUMO
A subset of hospitalized COVID-19 patients, particularly the aged and those with comorbidities, develop the most severe form of the disease, characterized by acute respiratory disease syndrome (ARDS), coincident with experiencing a "cytokine storm." Here, we demonstrate that cytokines which activate the NF-κB pathway can induce activin A. Patients with elevated activin A, activin B, and FLRG at hospital admission were associated with the most severe outcomes of COVID-19, including the requirement for mechanical ventilation, and all-cause mortality. A prior study showed that activin A could decrease viral load, which indicated there might be a risk to giving COVID-19 patients an inhibitor of activin. To evaluate this, the role for activin A was examined in a hamster model of SARS-CoV-2 infection, via blockade of activin A signaling. The hamster model demonstrated that use of an anti-activin A antibody did not worsen the disease and there was no evidence for increase in lung viral load and pathology. The study indicates blockade of activin signaling may be beneficial in treating COVID-19 patients experiencing ARDS.
Assuntos
Ativinas/sangue , Anticorpos Monoclonais Humanizados/uso terapêutico , Tratamento Farmacológico da COVID-19 , Proteínas Relacionadas à Folistatina/sangue , SARS-CoV-2/efeitos dos fármacos , Adulto , Idoso , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , COVID-19/mortalidade , COVID-19/virologia , Linhagem Celular , Células Cultivadas , Cricetinae , Método Duplo-Cego , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Taxa de SobrevidaRESUMO
Low-protein diets promote metabolic health in rodents and humans, and the benefits of low-protein diets are recapitulated by specifically reducing dietary levels of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, we demonstrate that each BCAA has distinct metabolic effects. A low isoleucine diet reprograms liver and adipose metabolism, increasing hepatic insulin sensitivity and ketogenesis and increasing energy expenditure, activating the FGF21-UCP1 axis. Reducing valine induces similar but more modest metabolic effects, whereas these effects are absent with low leucine. Reducing isoleucine or valine rapidly restores metabolic health to diet-induced obese mice. Finally, we demonstrate that variation in dietary isoleucine levels helps explain body mass index differences in humans. Our results reveal isoleucine as a key regulator of metabolic health and the adverse metabolic response to dietary BCAAs and suggest reducing dietary isoleucine as a new approach to treating and preventing obesity and diabetes.
Assuntos
Aminoácidos de Cadeia Ramificada/metabolismo , Dieta , Isoleucina/metabolismo , Valina/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Índice de Massa Corporal , Dieta/veterinária , Metabolismo Energético , Fatores de Crescimento de Fibroblastos/deficiência , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Fígado/metabolismo , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/metabolismo , Obesidade/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMO
Calorie restriction (CR) extends the healthspan and lifespan of diverse species. In mammals, a broadly conserved metabolic effect of CR is improved insulin sensitivity, which may mediate the beneficial effects of a CR diet. This model has been challenged by the identification of interventions that extend lifespan and healthspan yet promote insulin resistance. These include rapamycin, which extends mouse lifespan yet induces insulin resistance by disrupting mTORC2 (mechanistic target of rapamycin complex 2). Here, we induce insulin resistance by genetically disrupting adipose mTORC2 via tissue-specific deletion of the mTORC2 component Rictor (AQ-RKO). Loss of adipose mTORC2 blunts the metabolic adaptation to CR and prevents whole-body sensitization to insulin. Despite this, AQ-RKO mice subject to CR experience the same increase in fitness and lifespan on a CR diet as wild-type mice. We conclude that the CR-induced improvement in insulin sensitivity is dispensable for the effects of CR on fitness and longevity.
Assuntos
Adiposidade/fisiologia , Resistência à Insulina/fisiologia , Insulina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Adiposidade/efeitos dos fármacos , Animais , Restrição Calórica/métodos , Ingestão de Energia/efeitos dos fármacos , Ingestão de Energia/fisiologia , Humanos , Longevidade/efeitos dos fármacos , Longevidade/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Sirolimo/farmacologiaRESUMO
The mechanistic target of rapamycin (mTOR) is an evolutionarily conserved protein kinase that regulates growth and metabolism. mTOR is found in two protein complexes, mTORC1 and mTORC2, that have distinct components and substrates and are both inhibited by rapamycin, a macrolide drug that robustly extends lifespan in multiple species including worms and mice. Although the beneficial effect of rapamycin on longevity is generally attributed to reduced mTORC1 signaling, disruption of mTORC2 signaling can also influence the longevity of worms, either positively or negatively depending on the temperature and food source. Here, we show that loss of hypothalamic mTORC2 signaling in mice decreases activity level, increases the set point for adiposity, and renders the animals susceptible to diet-induced obesity. Hypothalamic mTORC2 signaling normally increases with age, and mice lacking this pathway display higher fat mass and impaired glucose homeostasis throughout life, become more frail with age, and have decreased overall survival. We conclude that hypothalamic mTORC2 is essential for the normal metabolic health, fitness, and lifespan of mice. Our results have implications for the use of mTORC2-inhibiting pharmaceuticals in the treatment of brain cancer and diseases of aging.