Recent advances in healthcare technologies are associated with a substantial increase of lifespan. A crucial challenge ahead is to promote healthy aging, which requires a better understanding of age-associated pathology mechanisms. A key determinant of frailty is the loss of muscle mass and functional capacity with age, known as sarcopenia, a predictor of poor health outcomes in elderly populations. Among the different biological mechanisms promoting muscle wasting during aging, energy metabolism and mitochondria dysfunctions take a crucial part. sarcopenia is defined as the progressive loss of muscle mass and function. This pathology affects 6 to 22% of persons aged more than 65. Sarcopenia is mainly du to an imbalance between protein synthesis and degradation, an increased inflammation, a mitochondria-dependent alteration of cell metabolism and an accumulation of fibrosis. In this project, we hypothesized that adipose tissue could play a trole in muscle weakness by its age-related proinflammatory endocrine functions. We previously performed a proteomic study and isolated haptoglobin as an up-regulated adipocyte production during aging. Haptoglobin is proinflammatory glycoprotein mainly synthesized by hepatocytes and adipocytes and involved in hemoglobin transport. Interestingly, Maffei and collaborators showed that haptoglobin deficient mice exhibited muscle alterations. Moreover, preliminary results obtained in our labo indicated that 3 months old mice treated with haptoglobin exhibited muscle weakness.
In this context, our project aims to better understand the regulation of adipocyte haptoglobin and its role on age-associated skeletal muscle weakness. To do so, we will use complementary in vitro and in vivo models to precisely identify the role of the cytokine on the different steps of myogenesis.Thus, young and older mice (3, 12 and 24 months old) will be supplemented with haptoglobin and human muscle cells will be treatde by the cytokine. In both model, muscle function and structure will be analyzed.In parallel, we will use Zebrafish as a model to invalidate or overexpress haptoglin specifically in adipocyte and will assess the muscle consequences during aging. With a strong collaboration with Pr. Bruno Vellas at the Toulouse Gerontopole, we are setting up a biobank with plasma and adipose tissue biopsies from sarcopenic patient aged more than 65.
Finally, the third part of the project aims to decipher the underlying mechanisms of adipocyte haptoglobin production during aging. In a translation point of view, we will establish different strategies (caloric restriction or physical exercise) known to modify the adipose tissue physiology during aging and will analyse the possibilities to modify the haptoglobin production .
Altogether, the obtained data will pave the road of a better characterisation of haptoglobin's role in age-related muscle weakness and more widely will consider the role of adipose tissue and its encrine productions in age-associated pathologies.
Monsieur Cedric DRAY (INSTITUT DES MALADIES METABOLIQUES ET CARDIOVASCULAIRES)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Inserm INSTITUT DES MALADIES METABOLIQUES ET CARDIOVASCULAIRES
Help of the ANR 322,758 euros
Beginning and duration of the scientific project: September 2019 - 36 Months