Acute rimonabant treatment promotes protein synthesis in C2C12 myotubes through a CB1-independent mechanism.

Publisher: Wiley-Liss Country of Publication: United States NLM ID: 0050222 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4652 (Electronic) Linking ISSN: 00219541 NLM ISO Abbreviation: J Cell Physiol Subsets: MEDLINE

Publication: New York, NY : Wiley-Liss
Original Publication: Philadelphia, Wistar Institute of Anatomy and Biology.

Cannabinoid Receptor Antagonists/*pharmacology ; Muscle Fibers, Skeletal/*drug effects ; Protein Biosynthesis/*drug effects ; Receptor, Cannabinoid, CB1/*antagonists & inhibitors ; Rimonabant/*pharmacology; Animals ; Calcium/metabolism ; Dexamethasone/toxicity ; Dose-Response Relationship, Drug ; HEK293 Cells ; Humans ; Mice ; Muscle Fibers, Skeletal/metabolism ; Muscle Fibers, Skeletal/pathology ; Muscular Atrophy/chemically induced ; Muscular Atrophy/metabolism ; Muscular Atrophy/pathology ; Muscular Atrophy/prevention & control ; Receptor, Cannabinoid, CB1/genetics ; Receptor, Cannabinoid, CB1/metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism ; Time Factors

Sarcopenia is an age-related loss of muscle mass associated with changes in skeletal muscle protein homeostasis due to lipid accumulation and anabolic resistance; changes that are also commonly described in obesity. Activation of the endocannabinoid system is associated with the development of obesity and insulin resistance, and with the perturbed skeletal muscle development. Taken together this suggests that endocannabinoids could be regulators of skeletal muscle protein homeostasis. Here we report that rimonabant, an antagonist for the CB1 receptor, can prevent dexamethasone-induced C2C12 myotube atrophy without affecting the mRNA expression of atrogin-1/MAFbx (a marker of proteolysis), which suggests it is involved in the control of protein synthesis. Rimonabant alone stimulates protein synthesis in a time- and dose-dependent manner through mTOR- and intracellular calcium-dependent mechanisms. CB1 agonists are unable to modulate protein synthesis or prevent the effect of rimonabant. Using C2C12 cells stably expressing an shRNA directed against CB1, or HEK293 cells overexpressing HA-tagged CB1, we demonstrated that the effect of rimonabant is unaffected by CB1 expression level. In summary, rimonabant can stimulate protein synthesis in C2C12 myotubes through a CB1-independent mechanism. These results highlight the need to identify non-CB1 receptor(s) mediating the pro-anabolic effect of rimonabant as potential targets for the treatment of sarcopenia, and to design new side-effect-free molecules that consolidate the effect of rimonabant on skeletal muscle protein synthesis.
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Keywords: CB1 receptor; endocannabinoids; protein anabolism; sarcopenia; skeletal muscle

0 (CNR1 protein, mouse)
0 (Cannabinoid Receptor Antagonists)
0 (Receptor, Cannabinoid, CB1)
7S5I7G3JQL (Dexamethasone)
EC 2.7.1.1 (mTOR protein, mouse)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RML78EN3XE (Rimonabant)
SY7Q814VUP (Calcium)

Date Created: 20200905 Date Completed: 20210920 Latest Revision: 20211204

20240829

10.1002/jcp.30034

32885412