VEGA 2/0091/19

Mechanisms of skeletal muscle adaptation to regular exercise in patients with chronic metabolic and inflammatory disease

Principal Investigator: Marta Novotová

Duration: January 2019 – December 2022
Coordinating Organization: Institute of Experimental Endocrinology BRC SAS

Annotation:

Low physical fitness is associated with impaired muscle functional parameters and high risk of chronic metabolic disease. In patients with idiopathic inflammatory myopathy, skeletal muscle function deteriorates also because of systemic inflammatory process, but it often persists even after suppression of inflammation. Regular exercise positively affects energy metabolism and muscle functional state in healthy individuals as well as in patients with metabolic disease or myopathy. Aim of this project is to identify structural, functional and molecular determinants of beneficial effects of exercise on mitochondrial respiration, metabolic substrate preference, myocyte ultrastructure and contractile function. Skeletal muscle biopsy & differentiated muscle cells obtained from metabolically well-characterized patients before/after the exercise intervention will be used. This knowledge is a key to our efforts to tackle the basic pathophysiological determinants of idiopathic inflammatory myopathy.

Keywords:

exercise, diabetes, idiopatic inflammation myopathy, human skeletal muscle, metabolism, structure and function of myotubes

Objectives:

The aim of the study is to define adaptive changes of skeletal muscle to regular exercise in patients with chronic metabolic and/or inflammatory disease. Specifically, we will study:

exercise-induced adaptive changes of skeletal muscle gene expression and protein content, using available biopsy material from well phenotyped patients and healthy volunteers.
mitochondrial respiration and level of coenzyme Q10, essential bioenergy regulating factor in muscle mitochondria will be determined in muscle fibers and differentiated muscle cells from primary cell cultures derived from patients before/after exercise training.
ultrastructure and intracellular localization of proteins defining functional state of myotubes differentiated from muscle satellite cells cultured before/after training.
exercise-induced adaptive changes in myotubes excitability, contractility, and calcium signaling.
circulating and muscle levels those bioactive molecules, which will be experimentally regulated in muscle cells from sedentary and exercise-trained individuals with or without chronic metabolic and inflammatory disease by a) in vitro induction of contractile activity, or b) by modulation of gene expresion.

Collectively, we aim to identify structural, functional and molecular determinants of beneficial effects of exercise on skeletal muscle by generating the complex map of disease and exercise-related alterations. These will include muscle mitochondrial respiration, metabolic substrate preference, excitation-contraction coupling and organization of the key sub-cellular components in skeletal muscle & differentiated muscle cells, from clinically well-characterized patients as well as from healthy volunteers taken before and after the exercise intervention. We will generate the knowledge essential for our efforts to tackle the key pathophysiological determinants of metabolic disease and idiopathic inflammatory myopathies.

Publications:

Koci J, Novotova M, Slavikova M, Klempa B, Zahradnik I (2022). SARS-CoV-2 Exploits Non-Canonical Autophagic Processes to Replicate, Mature, and Egress the Infected Vero E6 Cells. Pathogens 11: 1535. doi: 10.3390/pathogens11121535.

Grimbert L, Sanz MN, Gressette M, Rucker-Martin C, Novotova M, Solgadi A, Karoui A, Gomez S, Bedouet K, Jacquet E, Lemaire C, Veksler V, Mericskay M, Ventura-Clapier R, Piquereau JM, Garnier A (2021): Spatiotemporal AMPK alpha 2 deletion in mice induces cardiac dysfunction, fibrosis and cardiolipin remodeling associated with mitochondrial dysfunction in males only. Biol Sex Differ, vol 12: 52. doi: 10.1186/s13293-021-00394-z.