Muscle aging-related disorders: metabolic flexibility and degenerative processes

Contact persons: Prof. Dr. Tim J. Schulz, Dr. Francisco Javier Garcia Carrizo
Team: Dr. Francisco Javier Garcia Carrizo, Darya Oveisi, Susann Richter
Funding: DZD-BMBF, DFG

Analysen zur Fettzellenansammlungen im Muskel.
Fig. 1: Cell biology of fat cell accumulations in skeletal muscle. (A) Hematoxylin / eosin staining for the microscopic assessment of fat cell accumulation in aged skeletal muscle. Colors: pink indicates muscle fibers in cross section; dark purple corresponds to cell nuclei; white circular areas (arrows) show fat cells. (B) Sirius red-staining to show excessive connective tissue deposits (red areas, red arrows) and fat cells (white areas, blue arrows) between the muscle fibers (yellow areas). (C) In vitro evidence for the differentiation of fat cells and fibroblasts from certain stem cells of the muscle tissue: immunofluorescence staining of lipid droplet storage (green; Bodipy dye) and fibroblasts by staining the marker aSMA (red; alpha-smooth muscle actin). (D) Detection of muscle fiber differentiation from certain stem cells of the muscle by immunofluorescence staining for the muscle fiber protein MyHC (green; Myosin heavin chain) and detection of cells not differentiated into muscle fibers (blue; DAPI - cell nucleus staining).

With increasing age, a decrease in skeletal muscle mass is observed which is commonly referred to as sarcopenia. This process is associated with a reduced performance, i.e. muscle strength, and a disturbed metabolic function of the muscles. Due to their high glucose consumption rate during contraction, muscle fibers are an important component of carbohydrate metabolism and a dysfunction may thus contribute to the development of systemic insulin resistance and diabetes.

Adipocytes accumulate within muscle tissue with increasing age. While this process is very desirable in animal rearing for meat production, it is questionable from a health point of view. As it occurs especially in older age it is thought to then contribute to the loss of muscle strength and muscle mass. The appearance of adipocytes in the muscle not only reduces its performance, it also limits the regeneration of new muscle fibers after injury.

Our work explores muscle health and the link to nutrition by examining the cellular origin and the formation of adipocytes in skeletal muscle. In healthy, young muscle, a population of regulatory fibroblast-like cells plays an important role in the activation of the so-called satellite cells, which are responsible for the regeneration of muscle fibers. In contrast, the regulatory fibroblasts tend to differentiate into adipocytes and connective tissue structures (Fig. 1) during aging, although the causative mechanism for this effect is still unknown. Our molecular analysis suggests that the aging process inhibits the function of regulatory fibroblasts by affecting the stem cell niche in muscle. In this way, accumulation of cellular damage could contribute to the loss of function of the aging musculature. In order to investigate the communication routes between the regulatory fibroblasts and the satellite cells in more detail, we are currently investigating the extracellular matrix in cell cultures and animal models, which is the scaffold made of collagens and other proteins that give the muscles structure and shape. The matrix also acts as a reservoir for important signaling molecules. To this end, we ultimately aim to get a deeper insight into the molecular mechanisms that contribute to age-related muscle wasting (sarcopenia) in humans and develop possible approaches to stimulate the new formation of functional muscle fibers in old age.

In further studies, we also examine the metabolic function of the muscle. We were able to identify a protein that mediates the metabolic adaptation of the muscle to dietary composition. This protein helps to adapt biochemical metabolic processes in muscles to food that is high in fat or carbohydrates, but also to energy depletion during fasting.