Skeletal Muscle Mitochondria Dysfunction in Genetic Neuromuscular Disorders with Cardiac Phenotype

Abstract

Mitochondrial dysfunction is considered the major contributor to skeletal muscle wasting in different conditions. Genetically determined neuromuscular disorders occur as a result of mutations in the structural proteins of striated muscle cells and therefore are often combined with cardiac phenotype, which most often manifests as a cardiomyopathy. The specific roles played by mitochondria and mitochondrial energetic metabolism in skeletal muscle under muscle-wasting conditions in cardiomyopathies have not yet been investigated in detail, and this aspect of genetic muscle diseases remains poorly characterized. This review will highlight dysregulation of mitochondrial representation and bioenergetics in specific skeletal muscle disorders caused by mutations that disrupt the structural and functional integrity of muscle cells.

Effect of the Non-Immunosuppressive MPT Pore Inhibitor Alisporivir on the Functioning of Heart Mitochondria in Dystrophin-Deficient mdx Mice

“…Currently, cyclophilin D is the only mitochondrial protein that, on the one hand, has been proven to be involved in initiating pore opening, and, on the other hand, specific agents blocking its activity have been selected that prevent MPTP initiation [ 31 , 32 ]. The first such compound was CsA exhibiting a desensitizing effect on MPT pore opening in vitro, as well as in some in vivo models [ 3 ], but it has no positive effect on the state of DMD patients [ 33 ], which seems to be associated with the immunosuppressive effect of this agent, as well as the ability to inhibit calcineurin signaling secondarily reducing myotube differentiation and muscle regeneration. Promising effects were shown for the non-immunosuppressive CsA analog alisporivir, which fails to inhibit calcineurin signaling and also partially rescues the dystrophic phenotype in mdx mice [ 9 , 10 , 11 ], a zebrafish model of DMD [ 12 ], and muscle biopsies from DMD patients [ 12 ].…”

“…The cause of the disease is mutations in the gene encoding a set of dystrophin proteins, the largest of which reaches 427 kDa and is involved in the formation of the dystrophin–glycoprotein complex in cardiac and skeletal muscle cells. This complex provides the connection of the cytoskeleton of muscle cells with the extracellular matrix, maintaining the structural integrity of the tissue and its functional activity, and its absence is accompanied by progressive destabilization of the muscle fiber [ 3 ]. The main and primary clinical manifestations of DMD are associated with skeletal muscle weakness; however, the development of severe cardiac dysfunction by the third decade of life in patients is known [ 4 ].…”

“…It is believed that the rapid progression of destructive processes in muscle tissue is associated with significant dysfunction of intracellular organelles—the sarcoplasmic reticulum and mitochondria [ 3 ]. Indeed, it is known that in Duchenne dystrophy, skeletal muscle mitochondria show a decrease in the intensity of oxidative phosphorylation, ROS overproduction, as well as impairment of the ability to accumulate a large amount of Ca 2+ in the matrix due to a decrease in the resistance of organelles to the induction of mitochondrial permeability transition (MPT) pore and rearrangements of calcium-transporting systems [ 5 , 6 , 7 ].…”

Alisporivir Improves Mitochondrial Function in Skeletal Muscle of mdx Mice but Suppresses Mitochondrial Dynamics and Biogenesis

“…This protein provides a link between the cytoskeleton and the sarcolemma, as well as other muscle proteins, by forming the dystrophin-associated glycoprotein complex, playing a key role in muscle contraction. Disorganization of this structure leads to dysfunction of muscle tissue, the development of progressive muscle wasting and weakness, and in the later stages is also associated with heart failure [ 1 ].…”

“…It is known that the structural instability of myocytes in DMD is accompanied by an increase in the permeability of the sarcolemma for calcium ions and a significant increase in the concentration of this ion in muscle fibers, which is accompanied by the activation of proteases and lipases and subsequent degradation of muscle tissue [ 1 , 2 ]. Normally, the calcium level in the cell is regulated due to the functional interaction of the sarcoplasmic reticulum and mitochondria, the main calcium depots of skeletal muscles [ 1 , 3 ].…”