LIM and cysteine-rich domains 1 (LMCD1) regulates skeletal muscle hypertrophy, calcium handling, and force

Skeletal muscle mass and strength are crucial determinants of health. Muscle mass loss is associated with weakness, fatigue, and insulin resistance. In fact, it is predicted that controlling muscle atrophy can reduce morbidity and mortality associated with diseases such as cancer cachexia and sarcop...

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Published in:	Skeletal muscle Vol. 9; no. 1; p. 26
Main Authors:	Ferreira, Duarte M S, Cheng, Arthur J, Agudelo, Leandro Z, Cervenka, Igor, Chaillou, Thomas, Correia, Jorge C, Porsmyr-Palmertz, Margareta, Izadi, Manizheh, Hansson, Alicia, Martínez-Redondo, Vicente, Valente-Silva, Paula, Pettersson-Klein, Amanda T, Estall, Jennifer L, Robinson, Matthew M, Nair, K Sreekumaran, Lanner, Johanna T, Ruas, Jorge L
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 31-10-2019 BioMed Central BMC
Subjects:	Adenoviruses Amino acids Animals Biochemistry Cachexia Calcineurin Calcineurin - physiology Calcineurin Inhibitors - pharmacology Calcium Calcium - metabolism Cancer Care and treatment Cells, Cultured Co-Repressor Proteins - genetics Co-Repressor Proteins - physiology Cyclosporins Cysteine Cystine Development and progression Diabetes therapy Fatigue Force Gene expression Gene Expression Regulation Genes Genetic aspects Genotypes Health aspects Humans Hypertrophy Hypertrophy - genetics Hypertrophy - pathology Hypertrophy - physiopathology Insulin Insulin resistance LIM Domain Proteins - genetics LIM Domain Proteins - physiology LMCD1 Luciferase Medical research Medicin och hälsovetenskap Mice Mice, Inbred C57BL Mice, SCID Mice, Transgenic Morbidity Muscle Fibers, Skeletal - pathology Muscle Fibers, Skeletal - physiology Muscle Proteins - deficiency Muscle Proteins - genetics Muscle Proteins - physiology Muscle Strength - genetics Muscle Strength - physiology Muscle, Skeletal - pathology Muscle, Skeletal - physiology Muscle, Skeletal - physiopathology Muscular Diseases - genetics Muscular Diseases - pathology Muscular Diseases - physiopathology Musculoskeletal diseases Novels Protein synthesis RNA, Messenger - genetics RNA, Messenger - metabolism Sarcopenia Signal Transduction Skeletal muscle United States Calcium Force LMCD1 Calcineurin Skeletal muscle Hypertrophy
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Summary:	Skeletal muscle mass and strength are crucial determinants of health. Muscle mass loss is associated with weakness, fatigue, and insulin resistance. In fact, it is predicted that controlling muscle atrophy can reduce morbidity and mortality associated with diseases such as cancer cachexia and sarcopenia. We analyzed gene expression data from muscle of mice or human patients with diverse muscle pathologies and identified LMCD1 as a gene strongly associated with skeletal muscle function. We transiently expressed or silenced LMCD1 in mouse gastrocnemius muscle or in mouse primary muscle cells and determined muscle/cell size, targeted gene expression, kinase activity with kinase arrays, protein immunoblotting, and protein synthesis levels. To evaluate force, calcium handling, and fatigue, we transduced the flexor digitorum brevis muscle with a LMCD1-expressing adenovirus and measured specific force and sarcoplasmic reticulum Ca release in individual fibers. Finally, to explore the relationship between LMCD1 and calcineurin, we ectopically expressed Lmcd1 in the gastrocnemius muscle and treated those mice with cyclosporine A (calcineurin inhibitor). In addition, we used a luciferase reporter construct containing the myoregulin gene promoter to confirm the role of a LMCD1-calcineurin-myoregulin axis in skeletal muscle mass control and calcium handling. Here, we identify LIM and cysteine-rich domains 1 (LMCD1) as a positive regulator of muscle mass, that increases muscle protein synthesis and fiber size. LMCD1 expression in vivo was sufficient to increase specific force with lower requirement for calcium handling and to reduce muscle fatigue. Conversely, silencing LMCD1 expression impairs calcium handling and force, and induces muscle fatigue without overt atrophy. The actions of LMCD1 were dependent on calcineurin, as its inhibition using cyclosporine A reverted the observed hypertrophic phenotype. Finally, we determined that LMCD1 represses the expression of myoregulin, a known negative regulator of muscle performance. Interestingly, we observed that skeletal muscle LMCD1 expression is reduced in patients with skeletal muscle disease. Our gain- and loss-of-function studies show that LMCD1 controls protein synthesis, muscle fiber size, specific force, Ca handling, and fatigue resistance. This work uncovers a novel role for LMCD1 in the regulation of skeletal muscle mass and function with potential therapeutic implications.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2044-5040 2044-5040
DOI:	10.1186/s13395-019-0214-1