The role of gut microbiota derived branched chain amino acids for sarcopenia, osteoporosis and fracture risk

Loss of bone and muscle mass with aging leads to an increased prevalence of osteoporosis and sarcopenia, resulting in falls and fractures in the elderly.

Proteins constitute a large proportion of muscle and bone mass, and several have signaling properties regulating bone and muscle metabolism.

The branched-chain amino acids (BCAAs; valine, leucine, and isoleucine), influence skeletal muscle, and BCAAa metabolism has been implicated in sarcopenia and osteoporosis. The gut microbiota (GM) produces BCAA and regulates bone mass in mice and in humans. With aging, BCAA synthesis is reduced and GM dysbiosis develops.

We hypothesize that the aging-induced dysbiosis impairs the GM-mediated regulation of BCAAs contributing to the development of sarcopenia and osteoporosis, resulting in the increased incidence of falls and fractures, in older adults.

In the proposed project we will use large, well-characterized cohorts to determine if circulating BCAA levels and GM components related to BCAA synthesis are associated with muscle and bone parameters and fracture risk. We will also use Mendelian randomization to investigate if these associations are causal.

The causality of BCAA-producing GM will also be investigated using fecal transplantation studies in mice.

If the project is successful, fracture risk prediction can be improved, and novel treatments targeting GM BCAA production can be developed to treat osteoporosis and sarcopenia, which will result in fewer falls and fractures.