Lovastatin combined with ezetimibe induced liver cell senescence, lowered blood levels of the growth factor IGF-1 and reduced muscle fiber thickness in mice
Lovastatin combined with ezetimibe induced liver cell senescence, lowered blood levels of the growth factor IGF-1 and reduced muscle fiber thickness in mice
Korean researchers tested whether statins affect muscles through the liver. Mouse liver cells cultured with statins for nine weeks showed reduced IGF-1 gene expression, and muscle cells exposed to their secretions became thinner. Ezetimibe blocks cholesterol absorption in the intestine.
Muscle pain and weakness are common complaints among people taking statins: in a pooled analysis of 19 placebo-controlled trials, 27,1% of participants receiving a statin and 26,6% receiving a placebo reported muscle pain or weakness. The authors attributed fewer than a tenth of these complaints to statins. Research into the mechanism behind these symptoms has focused on muscle itself: in a 2017 study, simvastatin suppressed AKT signaling in muscle cells, while adding IGF-1 partially protected them.
In a paper published on October 10 in Cell Death Discovery, researchers at the Korea Research Institute of Bioscience and Biotechnology examined the liver's role. The liver metabolizes statins and releases IGF-1, insulin-like growth factor 1, into the blood. In muscle cells, IGF-1 activates the AKT/mTOR enzyme signaling pathway, which stimulates protein synthesis and inhibits protein breakdown mediated by Atrogin-1 and MuRF1, enzymes that mark proteins for destruction.
The authors propose a second pathway involving the liver: statins induce senescence in liver cells (atorvastatin had previously been shown to induce senescence in liver cancer cells). A senescent cell stops dividing and changes the mix of signaling molecules it releases. If blood IGF-1 levels fall, muscle receives less stimulation to make protein.
Mouse AML12 liver cells were cultured for nine weeks with 1 μM atorvastatin or 0,5 μM lovastatin. Senescence was assessed using blue staining for senescence-associated β-galactosidase, an enzyme active in senescent cells, and the expression of p21 and p16, genes that inhibit cell division. With lovastatin, the proportion of stained cells rose to about 27%, compared with 1% in the control group. Atorvastatin produced no significant change in this proportion, while both statins increased p21 and p16 expression.
Of the ten genes encoding signaling molecules that were measured, three showed significantly reduced expression: IGF-1 and the inflammatory mediators IL-1α and IL-1β. A senescent liver usually harms muscle through inflammatory signals. The authors attribute the decrease in these signals to the anti-inflammatory effects of statins, leaving IGF-1 as a potential mediator of the effect on muscle.
The effects of senescent liver cell secretions on muscle were tested in a two-chamber culture system. After nine weeks of statin exposure, liver cells were transferred to the upper chamber in statin-free medium, while C2C12 mouse muscle precursor cells were grown in the lower chamber. The membrane separating the chambers allows only dissolved substances to pass through. C2C12 cells develop into myotubes, elongated muscle cells. When cultured alongside senescent liver cells, these myotubes became thinner (about 10 μm compared with 12 in the control group), and their Atrogin-1 and MuRF1 levels increased.
The researchers also tested the effect in eleven-month-old mice given lovastatin combined with ezetimibe by gavage for three weeks. In the liver, the proportion of tissue section area staining positive for senescence-associated β-galactosidase increased, as did p21 and p16 protein levels. Blood IGF-1 levels fell by about a fifth, muscle fiber cross-sectional area in the lower leg decreased by almost the same proportion, and AKT/mTOR signaling in that muscle weakened.
In the cell experiments, statins alone induced liver cell senescence, reduced IGF-1 expression and caused muscle cells to become thinner. In mice, the combination of lovastatin and ezetimibe produced the same three changes, and the authors consider the statin a contributor to this sequence. They suggest that targeting the liver could protect muscle by slowing liver cell senescence or restoring IGF-1/AKT/mTOR signaling.