Study: Acteoside Improves Muscle Atrophy and Motor Function by Inducing New Myokine Secretion in Chronic Spinal Cord Injury

I found a study on acteoside (verbascoside) from Cistanche that is really interesting!

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599386/

I'll copy the abstract below, and some highlights I found particularly cool.

Chronic spinal cord injury (SCI) is difficult to cure, even by several approaches effective at the acute or subacute phase. We focused on skeletal muscle atrophy as a detrimental factor in chronic SCI and explored drugs that protect against muscle atrophy and activate secretion of axonal growth factors from skeletal muscle. We found that acteoside induced the secretion of axonal growth factors from skeletal muscle cells and proliferation of these cells. Intramuscular injection of acteoside in mice with chronic SCI recovered skeletal muscle weight reduction and motor function impairment. We also identified pyruvate kinase isoform M2 (PKM2) as a secreted factor from skeletal muscle cells, stimulated by acteoside. Extracellular PKM2 enhanced proliferation of skeletal muscle cells and axonal growth in cultured neurons. Further, we showed that PKM2 might cross the blood–brain barrier. These results indicate that effects of acteoside on chronic SCI might be mediated by PKM2 secretion from skeletal muscles. This study proposes that the candidate drug acteoside and a new myokine, PKM2, could be used for the treatment of chronic SCI.

Two major issues in chronic SCI are the untreatable axonal disruption and the severe atrophy of skeletal muscle; our study showed that both may be improved by acteoside, via PKM2 secretion. In this study, we found that acteoside injection into skeletal muscle at the chronic phase of SCI recovers locomotor dysfunction and skeletal muscle atrophy in mice, despite the fact that our contusion model was quite severe; less than grade 2 at 30 days post-injury. A series of similar experiments by our group have shown that acteoside injection, starting at 43 days post-injury, also significantly improves hindlimb motor function (data not shown). Further, acteoside injection enhanced axonal growth in 5-HT–positive cells and synaptogenesis at the caudal side of the lesion center.

Importantly, we showed that acteoside stimulates the secretion of PKM2 from skeletal muscle and that PKM2 promotes proliferation of skeletal muscle cells and axonal growth. Our results indicate that PKM2 is a new myokine that activates skeletal muscle and neurons and that its secretion is enhanced by acteoside stimulation.

Further, we found that PKM2 might cross the BBB and BSCB despite its large molecular weight. After exercise, transcription of several myokines is increased in the brain.\17\,\34\ However, there is no clear evidence on whether myokines transfer to the brain. PKM2 may be a new type of myokine that reaches the brain and potentially the spinal cord. The advantages and significance of PKM2 penetration in the central nervous system should be clarified in future. The mechanism by which PMK2 crosses the BBB and BSCB might be similar to that in the case of IGF-1 (MW: 8.5 kDa), which crosses the BBB by transcytosis.

acteoside-mediated neuroprotection against amyloid β-induced cell death in PC12 cells is mediated by ERK and PI3K/Akt pathways.\23\ In cancer cells, acteoside directly binds to and inhibits protein kinase C.\38\ Moreover, binding to and inhibition of caspase-3 of acteoside were found in neurons.\39\ In inflammatory cells stimulated with lipopolysaccharide, acteoside promotes nuclear factor κB inhibition.\21\ Inhibition of calcium influx by acteoside has also been reported.

In conclusion, we found that acteoside improves skeletal muscle atrophy and locomotor dysfunction caused by chronic SCI, suggesting that it might be a promising therapeutic drug candidate for SCI. We also demonstrated that acteoside promotes the secretion of PKM2 from skeletal muscle cells, and that extracellular PKM2 induces axonal growth in cortical neurons and increases proliferation of skeletal muscle cells (\Fig. 10\). A strategy involving skeletal muscle-mediated therapy is a novel approach for chronic SCI, which might be effective in combination with other treatments.

A lot to unpack here, but I will keep it short. This is showing that acteoside (verbascoside) from Cistanche can help improve chronic spinal cord injury, by protecting against muscle atrophy and secreting axonal growth factors. In addition, they found a new myokine called PKM2, or pyruvate kinase isoform M2, which promotes proliferation of skeletal muscle cells and the growth of axons in the brain. It crosses the blood-brain-barrier, potentially in a similar way to IGF-1, or insulin-like growth factor 1. The acteoside from Cistanche stimulates the release of PKM2. This is a really cool new mechanism for Cistanche that I was unaware of. After working on a bunch of different extraction methods, we found that supercritical CO2 was the best way to concentrate the highest amount of acteoside. The more we learn about Cistanche, the cooler of a supplement it becomes!