RESUMO
Obesity is a worldwide health crisis, and the identification of genetic modifiers of weight gain is crucial in understanding this complex disorder. A common null polymorphism in the fast fiber-specific gene ACTN3 (R577X) is known to influence skeletal muscle function and metabolism. α-Actinin-3 deficiency occurs in an estimated 1.5 billion people worldwide, and results in reduced muscle strength and a shift towards a more efficient oxidative metabolism. The X-allele has undergone strong positive selection during recent human evolution, and in this study, we sought to determine whether ACTN3 genotype influences weight gain and obesity in mice and humans. An Actn3 KO mouse has been generated on two genetic backgrounds (129X1/SvJ and C57BL/6J) and fed a high-fat diet (HFD, 45% calories from fat). Anthropomorphic features (including body weight) were examined and show that Actn3 KO 129X1/SvJ mice gained less weight compared to WT. In addition, six independent human cohorts were genotyped for ACTN3 R577X (Rs1815739) and body mass index (BMI), waist-to-hip ratio-adjusted BMI (WHRadjBMI) and obesity-related traits were assessed. In humans, ACTN3 genotype alone does not contribute to alterations in BMI or obesity.
Assuntos
Actinina/deficiência , Actinina/genética , Obesidade/genética , Aumento de Peso/genética , Actinina/metabolismo , Animais , Dieta Hiperlipídica , Feminino , Expressão Gênica , Genótipo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Obesidade/fisiopatologia , RNA Mensageiro/genética , Aumento de Peso/fisiologiaRESUMO
Homozygosity for a common null polymorphism (R577X) in the ACTN3 gene results in the absence of the fast fibre-specific protein, α-actinin-3 in â¼16% of humans worldwide. α-Actinin-3 deficiency is detrimental to optimal sprint performance and benefits endurance performance in elite athletes. In the general population, α-actinin-3 deficiency is associated with reduced muscle mass, strength and fast muscle fibre area, and poorer muscle function with age. The Actn3 knock-out (KO) mouse model mimics the human phenotype, with fast fibres showing a shift towards slow/oxidative metabolism without a change in myosin heavy chain (MyHC) isoform. We have recently shown that these changes are attributable to increased activity of the calcineurin-dependent signalling pathway in α-actinin-3 deficient muscle, resulting in enhanced response to exercise training. This led us to hypothesize that the Actn3 genotype influences muscle adaptation to disuse, irrespective of neural innervation. Separate cohorts of KO and wild-type mice underwent 2 weeks immobilization and 2 and 8 weeks of denervation. Absence of α-actinin-3 resulted in reduced atrophic response and altered adaptation to disuse, as measured by a change in MyHC isoform. KO mice had a lower threshold to switch from the predominantly fast to a slower muscle phenotype (in response to immobilization) and a higher threshold to switch to a faster muscle phenotype (in response to denervation). We propose that this change is mediated through baseline alterations in the calcineurin signalling pathway of Actn3 KO muscle. Our findings have important implications for understanding individual responses to muscle disuse/disease and training in the general population.
Assuntos
Actinina/deficiência , Calcineurina/metabolismo , Fibras Musculares de Contração Rápida/fisiologia , Força Muscular/genética , Músculo Esquelético/metabolismo , Atrofia Muscular/genética , Actinina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Desempenho Atlético , Denervação , Metabolismo Energético/genética , Feminino , Elevação dos Membros Posteriores , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Músculo Esquelético/inervação , Músculo Esquelético/fisiologia , Doenças Musculares/genética , Cadeias Pesadas de Miosina/genética , Condicionamento Físico Animal , Polimorfismo de Nucleotídeo Único , Isoformas de Proteínas , Transdução de Sinais/genética , Adulto JovemRESUMO
Neurofibromatosis Type 1 (NF1) is a genetic neurocutaneous disorder with multisystem manifestations, including a predisposition to tumor formation and bone dysplasias. Studies over the last decade have shown that NF1 can also be associated with significant motor deficits, such as poor coordination, low muscle tone, and easy fatigability. These have traditionally been ascribed to developmental central nervous system and cognitive deficits. However, recent preclinical studies have also illustrated a primary role for the NF1 gene product in muscle growth and metabolism; these findings are consistent with clinical studies demonstrating reduced muscle size and muscle weakness in individuals with NF1. Currently there is no evidence-based intervention for NF1 muscle and motor deficiencies; this review identifies key research areas where improved mechanistic understanding could unlock new therapeutic options.