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

Duarte M.S. Ferreira, Arthur J. Cheng, Leandro Z. Agudelo, Igor Cervenka, Thomas Chaillou, Jorge C. Correia, Margareta Porsmyr-Palmertz, Manizheh Izadi, Alicia Hansson, Vicente Martínez-Redondo, Paula Valente-Silva, Amanda T. Pettersson-Klein, Jennifer L. Estall, Matthew M. Robinson, K. Sreekumaran Nair, Johanna T. Lanner, Jorge L. Ruas

Research output: Contribution to journalArticle

Abstract

Background: 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. Methods: 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 Ca2+ 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. Results: 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. Conclusions: Our gain- and loss-of-function studies show that LMCD1 controls protein synthesis, muscle fiber size, specific force, Ca2+ 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.

Original languageEnglish (US)
Article number26
JournalSkeletal Muscle
Volume9
Issue number1
DOIs
StatePublished - Oct 31 2019

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Hypertrophy
Cysteine
Skeletal Muscle
Calcium
Muscles
Calcineurin
Fatigue
Muscle Fatigue
Muscle Proteins
Muscle Cells
Cyclosporine
Sarcopenia
Gene Expression
Protein Array Analysis
Cachexia
Muscular Atrophy
Muscle Strength
Sarcoplasmic Reticulum
Luciferases
Cell Size

Keywords

  • Calcineurin
  • Calcium
  • Force
  • Hypertrophy
  • LMCD1
  • Skeletal muscle

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Molecular Biology
  • Cell Biology

Cite this

Ferreira, D. M. S., Cheng, A. J., Agudelo, L. Z., Cervenka, I., Chaillou, T., Correia, J. C., ... Ruas, J. L. (2019). LIM and cysteine-rich domains 1 (LMCD1) regulates skeletal muscle hypertrophy, calcium handling, and force. Skeletal Muscle, 9(1), [26]. https://doi.org/10.1186/s13395-019-0214-1

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

In: Skeletal Muscle, Vol. 9, No. 1, 26, 31.10.2019.

Research output: Contribution to journalArticle

Ferreira, DMS, Cheng, AJ, Agudelo, LZ, Cervenka, I, Chaillou, T, Correia, JC, Porsmyr-Palmertz, M, Izadi, M, Hansson, A, Martínez-Redondo, V, Valente-Silva, P, Pettersson-Klein, AT, Estall, JL, Robinson, MM, Nair, KS, Lanner, JT & Ruas, JL 2019, 'LIM and cysteine-rich domains 1 (LMCD1) regulates skeletal muscle hypertrophy, calcium handling, and force', Skeletal Muscle, vol. 9, no. 1, 26. https://doi.org/10.1186/s13395-019-0214-1
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. / LIM and cysteine-rich domains 1 (LMCD1) regulates skeletal muscle hypertrophy, calcium handling, and force. In: Skeletal Muscle. 2019 ; Vol. 9, No. 1.
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T1 - LIM and cysteine-rich domains 1 (LMCD1) regulates skeletal muscle hypertrophy, calcium handling, and force

AU - Ferreira, Duarte M.S.

AU - Cheng, Arthur J.

AU - Agudelo, Leandro Z.

AU - Cervenka, Igor

AU - Chaillou, Thomas

AU - Correia, Jorge C.

AU - Porsmyr-Palmertz, Margareta

AU - Izadi, Manizheh

AU - Hansson, Alicia

AU - Martínez-Redondo, Vicente

AU - Valente-Silva, Paula

AU - Pettersson-Klein, Amanda T.

AU - Estall, Jennifer L.

AU - Robinson, Matthew M.

AU - Nair, K. Sreekumaran

AU - Lanner, Johanna T.

AU - Ruas, Jorge L.

PY - 2019/10/31

Y1 - 2019/10/31

N2 - Background: 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. Methods: 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 Ca2+ 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. Results: 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. Conclusions: Our gain- and loss-of-function studies show that LMCD1 controls protein synthesis, muscle fiber size, specific force, Ca2+ 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.

AB - Background: 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. Methods: 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 Ca2+ 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. Results: 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. Conclusions: Our gain- and loss-of-function studies show that LMCD1 controls protein synthesis, muscle fiber size, specific force, Ca2+ 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.

KW - Calcineurin

KW - Calcium

KW - Force

KW - Hypertrophy

KW - LMCD1

KW - Skeletal muscle

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