Key result
LMCD1 increases skeletal muscle mass and fatigue resistance through a calcineurin-dependent mechanism.
Why the study?
Skeletal muscle mass loss is associated with weakness, fatigue, and insulin resistance, and controlling muscle atrophy may reduce morbidity and mortality in diseases such as cancer cachexia and sarcopenia.
Does LMCD1 expression regulate skeletal muscle mass, calcium handling, and force in mouse models?
Does LMCD1 expression regulate skeletal muscle mass, calcium handling, and force in mouse models?
LMCD1 is a positive regulator of skeletal muscle mass and function, acting via a calcineurin-dependent pathway to repress myoregulin, presenting a potential therapeutic target for muscle wasting diseases.
LMCD1 modulation may target muscle wasting; animal data leave open human translation and require clinical validation.
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.
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Ferreira et al. (2019) studied Skeletal muscle hypertrophy and function. LMCD1 overexpression or silencing vs. Control adenovirus (GFP or scrambled shRNA) was evaluated on Muscle protein synthesis, fiber size, specific force, and calcium handling. LMCD1 acts as a positive regulator of skeletal muscle mass, increasing protein synthesis, fiber size, specific force, and fatigue resistance through a calcineurin-dependent mechanism.
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