The combination of obesity with low muscle mass, termed sarcopenic obesity, is a huge risk factor for disease and early death. Yet, we do not know much yet about the effects of diet, sex and age on sarcopenic obesity.
Project AmyloAge has three objectives (O):
O1: To identify and quantify the variations in genes and proteins related to protein aggregation in the muscle
I am preparing a publication in which I demonstrate that aggregation-prone proteins other than amyloid-β also accumulate with calory-rich diets. Moreover, increased amounts of aggregation-prone proteins are correlated with perturbed mitochondria. Chaperones in the α-crystallin/Hsp20 family correlate negatively with these aggregation-prone proteins. Moreover, humans with higher expression of α-crystallins seem to have increased muscle mass and increased basal metabolism.
O2: To uncover the impact of mitochondrial activity on muscle proteostasis
I made use of the worm RIAILS reference genetic population. Here, the project identified new genetic determinants of mitochondrial stress triggered by the mitochondrial ribosome inhibitor doxycycline. From every worm line, we assessed molecular and phenotypic traits. Short-lived strains benefit more from doxycycline, and the longer the worms took to develop and lay eggs, the longer they lived. I collaborated with other lab members to genetically map and validate new compounds that trigger beneficial mitochondrial stresses.
I next investigated whether the mitochondrial response to diet is different between male and female mice. I found that the ratios of certain important mitochondrial complexes are perturbed when mice are fed a high-fat diet. Moreover, some of these perturbations are different between male and female mice. The project furthermore revealed that exercising results in the production of an important inflammation-stimulating protein in the brain which causes the muscles to burn more fat.
O3: To uncover the genetic and metabolic pathways that drive muscle aging
Through a collaboration with a geology research group in France, I was able to assess the metal contents (“metallome”) in mice at different ages. The metallome shows consistent changes with aging. The project reveals for example that iron concentration and copper isotope composition are related to age-related muscle metabolism.
The project further suggests that muscle protein aggregation diseases are worst displays of a natural variation in protein aggregation during aging. AmyloAge identifies an important class of fatty acids, the sphingolipids, as key regulators of disease severity in Duchenne muscular dystrophy. Sphingolipids accumulate in the muscles of mouse models for Duchenne muscular dystrophy. Myriocin, a potent inhibitor of sphingolipid synthesis, strongly reduces sphingolipids, and improves the molecular signature, as well as the functional performance in our mouse model.
