Sarcolipin overexpression impairs myogenic differentiation in Duchenne muscular dystrophy. 2019

Nandita Niranjan, and Satvik Mareedu, and Yimin Tian, and Kasun Kodippili, and Nadezhda Fefelova, and Antanina Voit, and Lai-Hua Xie, and Dongsheng Duan, and Gopal J Babu
Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers University, Newark, New Jersey.

Reduction in the expression of sarcolipin (SLN), an inhibitor of sarco(endo)plasmic reticulum (SR) Ca2+-ATPase (SERCA), ameliorates severe muscular dystrophy in mice. However, the mechanism by which SLN inhibition improves muscle structure remains unclear. Here, we describe the previously unknown function of SLN in muscle differentiation in Duchenne muscular dystrophy (DMD). Overexpression of SLN in C2C12 resulted in decreased SERCA pump activity, reduced SR Ca2+ load, and increased intracellular Ca2+ () concentration. In addition, SLN overexpression resulted in altered expression of myogenic markers and poor myogenic differentiation. In dystrophin-deficient dog myoblasts and myotubes, SLN expression was significantly high and associated with defective cycling. The dystrophic dog myotubes were less branched and associated with decreased autophagy and increased expression of mitochondrial fusion and fission proteins. Reduction in SLN expression restored these changes and enhanced dystrophic dog myoblast fusion during differentiation. In summary, our data suggest that SLN upregulation is an intrinsic secondary change in dystrophin-deficient myoblasts and could account for the mishandling, which subsequently contributes to poor myogenic differentiation. Accordingly, reducing SLN expression can improve the cycling and differentiation of dystrophic myoblasts. These findings provide cellular-level supports for targeting SLN expression as a therapeutic strategy for DMD.

UI MeSH Term Description Entries
D009124 Muscle Proteins The protein constituents of muscle, the major ones being ACTINS and MYOSINS. More than a dozen accessory proteins exist including TROPONIN; TROPOMYOSIN; and DYSTROPHIN. Muscle Protein,Protein, Muscle,Proteins, Muscle
D011510 Proteolipids Protein-lipid combinations abundant in brain tissue, but also present in a wide variety of animal and plant tissues. In contrast to lipoproteins, they are insoluble in water, but soluble in a chloroform-methanol mixture. The protein moiety has a high content of hydrophobic amino acids. The associated lipids consist of a mixture of GLYCEROPHOSPHATES; CEREBROSIDES; and SULFOGLYCOSPHINGOLIPIDS; while lipoproteins contain PHOSPHOLIPIDS; CHOLESTEROL; and TRIGLYCERIDES.
D002118 Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Coagulation Factor IV,Factor IV,Blood Coagulation Factor IV,Calcium-40,Calcium 40,Factor IV, Coagulation
D002454 Cell Differentiation Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs. Differentiation, Cell,Cell Differentiations,Differentiations, Cell
D004285 Dogs The domestic dog, Canis familiaris, comprising about 400 breeds, of the carnivore family CANIDAE. They are worldwide in distribution and live in association with people. (Walker's Mammals of the World, 5th ed, p1065) Canis familiaris,Dog
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D016189 Dystrophin A muscle protein localized in surface membranes which is the product of the Duchenne/Becker muscular dystrophy gene. Individuals with Duchenne muscular dystrophy usually lack dystrophin completely while those with Becker muscular dystrophy have dystrophin of an altered size. It shares features with other cytoskeletal proteins such as SPECTRIN and alpha-actinin but the precise function of dystrophin is not clear. One possible role might be to preserve the integrity and alignment of the plasma membrane to the myofibrils during muscle contraction and relaxation. MW 400 kDa.
D053498 Sarcoplasmic Reticulum Calcium-Transporting ATPases Calcium-transporting ATPases that catalyze the active transport of CALCIUM into the SARCOPLASMIC RETICULUM vesicles from the CYTOPLASM. They are primarily found in MUSCLE CELLS and play a role in the relaxation of MUSCLES. Calcium-Transporting ATPases, Sarcoplasmic Reticulum,Sarcoplasmic Reticulum Calcium ATPase,SERCA Calcium ATPase,SERCA1 Calcium ATPase,SERCA2 Calcium ATPase,SERCA2a Calcium ATPase,SERCA3 Calcium ATPase,SR Ca(2+)-ATPase 1,SR Ca(2+)-ATPase 2,SR Ca(2+)-ATPase 3,Sarco-Endoplasmic Reticulum Ca2+-ATPase,Sarcoplasmic Reticulum Ca(2+)-ATPase,Sarcoplasmic Reticulum Calcium-Transporting ATPase 1,Sarcoplasmic Reticulum Calcium-Transporting ATPase 2,Sarcoplasmic Reticulum Calcium-Transporting ATPase 2a,Sarcoplasmic Reticulum Calcium-Transporting ATPase 3,Sarcoplasmic-Endoplasmic Reticulum Calcium ATPase 2,Sarcoplasmic-Endoplasmic Reticulum Calcium ATPase 2a,Sarcoplasmic-Endoplasmic Reticulum Calcium ATPase 3,Sarcoplasmic-endoplasmic Reticulum Calcium ATPase 1,Ca2+-ATPase, Sarco-Endoplasmic Reticulum,Calcium Transporting ATPases, Sarcoplasmic Reticulum,Reticulum Ca2+-ATPase, Sarco-Endoplasmic,Sarco Endoplasmic Reticulum Ca2+ ATPase,Sarcoplasmic Endoplasmic Reticulum Calcium ATPase 2,Sarcoplasmic Endoplasmic Reticulum Calcium ATPase 2a,Sarcoplasmic Endoplasmic Reticulum Calcium ATPase 3,Sarcoplasmic Reticulum Calcium Transporting ATPase 1,Sarcoplasmic Reticulum Calcium Transporting ATPase 2,Sarcoplasmic Reticulum Calcium Transporting ATPase 2a,Sarcoplasmic Reticulum Calcium Transporting ATPase 3,Sarcoplasmic Reticulum Calcium Transporting ATPases,Sarcoplasmic endoplasmic Reticulum Calcium ATPase 1
D018345 Mice, Knockout Strains of mice in which certain GENES of their GENOMES have been disrupted, or "knocked-out". To produce knockouts, using RECOMBINANT DNA technology, the normal DNA sequence of the gene being studied is altered to prevent synthesis of a normal gene product. Cloned cells in which this DNA alteration is successful are then injected into mouse EMBRYOS to produce chimeric mice. The chimeric mice are then bred to yield a strain in which all the cells of the mouse contain the disrupted gene. Knockout mice are used as EXPERIMENTAL ANIMAL MODELS for diseases (DISEASE MODELS, ANIMAL) and to clarify the functions of the genes. Knockout Mice,Mice, Knock-out,Mouse, Knockout,Knock-out Mice,Knockout Mouse,Mice, Knock out
D018482 Muscle, Skeletal A subtype of striated muscle, attached by TENDONS to the SKELETON. Skeletal muscles are innervated and their movement can be consciously controlled. They are also called voluntary muscles. Anterior Tibial Muscle,Gastrocnemius Muscle,Muscle, Voluntary,Plantaris Muscle,Skeletal Muscle,Soleus Muscle,Muscle, Anterior Tibial,Muscle, Gastrocnemius,Muscle, Plantaris,Muscle, Soleus,Muscles, Skeletal,Muscles, Voluntary,Skeletal Muscles,Tibial Muscle, Anterior,Voluntary Muscle,Voluntary Muscles

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