The sarcoplasmic reticulum (SR) is the main intracellular calcium store in skeletal muscle, an ion whose finely tuned redistribution governs each contraction and relaxation cycle. Following membrane depolarization, calcium is massively released through the ryanodine receptor to trigger contraction, then taken back up into the SR lumen by the SERCA pump (sarco/endoplasmic reticulum calcium ATPase), enabling relaxation and a new cycle. This balance is disrupted in myopathies, particularly Duchenne muscular dystrophy (DMD), one of the most common forms, which is characterized by chronically elevated cytosolic calcium concentrations and decreased SERCA activity. Despite advances in gene therapy, DMD remains an unmet medical need, justifying the search for new strategies to limit muscle degeneration.
The authors investigated whether the nuclear receptor NR1D1 (also known as REV-ERBα), a transcriptional repressor for which the team had previously reported a beneficial effect on muscle function and exercise capacity, regulates SR calcium homeostasis. In NR1D1-deficient mice, SERCA-dependent calcium uptake was found to be impaired. Mechanistic analysis showed that NR1D1 acts by repressing myoregulin, a transmembrane micropeptide that inhibits SERCA, through direct binding to its promoter — as demonstrated by chromatin immunoprecipitation. Restoring myoregulin expression abolished the effects of NR1D1 overexpression on SR calcium content, confirming that this micropeptide is the central effector of the identified pathway.
The experimental approaches combined mouse models (deficient mice and muscle-specific mutants), immortalized human myoblasts derived from DMD patients, calcium uptake measurements on microsomal fractions, calcium imaging, and in situ contractile property assays of the gastrocnemius. Myoblasts from DMD patients displayed reduced NR1D1 expression. Conversely, pharmacological activation of NR1D1 with the synthetic agonist SR9009 improved SR calcium homeostasis as well as muscle structure and function in dystrophic mdx/Utr+/– mice, with the assessment notably addressing fibrosis, circulating creatine phosphokinase activity, and contractile force.
This work establishes that NR1D1 controls calcium homeostasis of the skeletal muscle sarcoplasmic reticulum through repression of myoregulin, and highlights its therapeutic potential for alleviating myopathies.