Cardiolipin Synthesis in Skeletal Muscle Is Rhythmic and Modifiable by Age and Diet

Area of Science:

• Mitochondrial biology
• Circadian rhythms
• Lipid metabolism

Background:

• Circadian clocks control tissue-specific metabolism, with function declining during aging.
• Skeletal muscle mitochondria's circadian regulation is crucial for healthy aging.
• The circadian regulation of cardiolipin (CL), vital for mitochondrial function, is poorly understood.

Purpose of the Study:

• To investigate the circadian regulation of cardiolipin (CL) synthesis in skeletal muscle.
• To determine the role of ROR nuclear receptors in CL rhythmic synthesis.
• To examine the impact of aging and Nobiletin on CL synthesis and its regulation.

Main Methods:

• Diurnal assessment of CL levels in C2C12 myotubes.
• Analysis of circadian gene expression in Ror-deficient C2C12 cells.
• In vivo studies in young and aged mice skeletal muscle.
• Effect of Nobiletin on CL synthesis genes in aged mouse muscle.

Main Results:

• CL levels oscillate diurnally in C2C12 myotubes.
• ROR nuclear receptors regulate rhythmic expression of CL synthesis genes (Taz, Ptpmt1).
• Aging alters CL gene expression rhythms and increases CL levels in skeletal muscle.
• Nobiletin partially restores CL synthesis gene expression in aged muscle.

Conclusions:

• Skeletal muscle exhibits rhythmic cardiolipin synthesis controlled by ROR nuclear receptors.
• Aging disrupts this circadian rhythm, leading to elevated CL levels.
• Dietary intervention with Nobiletin shows potential for modulating CL synthesis in aging muscle.