Engineered Skeletal Muscle Tissue for Primary Mitochondrial Myopathies Modeling

• Applicants: Professor Dr. Leonid Ionov; Privatdozentin Sahar Salehi-Müller, Ph.D.
• Subject Area: Biomaterials ; Cell Biology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 409232653

Primary mitochondrial myopathies (PMMs) belong to a larger class of metabolic diseases called mitochondriopathies caused by an underlying defect in mitochondria, the energy-producing organelles of the cell. Mitochondriopathies occur due to numerous mutations in nuclear or mitochondrial-encoded genes. Therefore, mitochondrial disorders are extremely variable in onset, symptom manifestation, and severity and when grouped together, represent the most commonly occurring metabolic diseases. Moreover, patients with PMMs, often manifest skeletal muscle-related symptoms such as muscle fatigue, weakness, and exercise intolerance as muscle is an organ system with high energy demands. There is currently no cure for PMMs and the only available treatments are palliative in which symptoms are managed as they arise. To identify compounds that may causally counteract mitochondrial defects, mostly traditional cell monolayers are used which are not promising candidates as they lack the resemblance to the skeletal muscle structure and its complex metabolism. Therefore, this interdisciplinary project aims to address this challenge by utilizing engineered skeletal muscle tissue (ESMTs) as applicable in vitro models with higher structural and histological similarity to mimic the metabolic landscape of native muscle tissue and envelop more of the metabolic discrepancies that originate from mitochondrial defects. Our approach is based on the fiber-composite constructs developed during the first funded period. We successfully invented a new technology through the integration of touch-spinning for precise fiber deposition in extrusion-based 3D printing of bioinks to fabricate anisotropic constructs such as skeletal muscle, nerve guidance conduits, and microvasculatures. Polymeric fibers reinforced the hydrogels mechanically and supported the cells topographically guiding them to form oriented structures within the 3D-printed hydrogels. As a proof-of-concept, we showed the engineering of contractile skeletal muscle microtissue, and in the new project, we aim to make our ESMTs a disease-specific model for PMMs. The new ESMTs advantages will be i) high histological, ii) metabolic similarity to native skeletal muscle, and iii) high accuracy in reproducing the metabolic and histological abnormalities associated with mitochondrial dysfunction found in patients with PMMs. The project’s main output and impact will be the development of a reliable in vitro model of mitochondrial disorders as a powerful tool for identifying effective compounds in the treatment of mitochondrial disease.

• DFG Programme: Research Grants
• Co-Investigator: Professor Oliver Friedrich