Anti-diabetic drug canagliflozin hinders skeletal muscle regeneration in mice

A new research paper about something to watch for / consider (and perhaps another good reason to pulse dosing with the SGLT2 inhibitors):

Our data suggest that canagliflozin directly impairs ischemic skeletal muscle recovery in mice by downregulating LARS2 expression in muscle stem cells, and that LARS2 may be a promising therapeutic target for injured skeletal muscle regeneration.

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I hope we can get ahold of the full text when it’s published. It’s hard to tell from the abstract if, for instance, this is a class effect (i.e. all SGLT2 inhibitors or just canagliflozin) and if this applies to skeletal muscle “regeneration/recovery” after an exercise stimulus such as resistance training.

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Muscle growth is an extremely complex mechanism. Looking at one narrow pathway, especially in mice, might not translate to humans.

I am a high daily exerciser, both resistance and aerobic. Before diving into Rapamycin, I read much prevailing literature on mTOR blunting muscle synthesis, including muscle specific HUMAN studies. As building and maintaining muscle as we age, avoiding sarcopenia/frailty, is a hugely anti-aging intervention, it was concerning that Rapamycin might be blunting mTOR and muscle growth.

I stumbled on a post by Blagosklonny, and exchanged a few messages with him, where he confirmed that Rapamycin should not blunt, and his interesting senescence theory on this.

Further research, and further communications with leading muscle and rapamycin researchers around the world. In summary, it was communicated to me that there are Rapamycin INDEPENDENT and mTOR INDEPENDENT pathways to muscle synthesis!

Extremely complex indeed. So I marched forward.

My experience after 1 yr on Rapamycin (I am currently taking 10 mg/week with GFJ the day of), is I can see NO noticeable impact on my free weight load and rep stamina, recovery, or muscle growth. And neither on aerobic…I posted a PB on a 10k a few months ago.

I cannot say that if you’re not doing ANY resistance exercise to build muscle, whether Rapamcyin might reduce your total free muscle mass. Blagosklonny thinks not.

YMMV, but certainly, do NOT be afraid to try.

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I got the PDF of the full text of the article, but can’t upload it because it exceeds the 4 mb attachment size limit for this website (the article PDF is just under 10 mb)

Anti-diabetic drug canagliflozin hinders skeletal muscle regeneration in mice.pdf (9.1 MB)

Here is the full research paper.

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Thanks Brandy! :grin: Can’t wait to read it!

Ok, the first important thing is that they’re looking at ischemic injury to the muscle from cutting the femoral artery (trying to mimic ischemic injury seen in chronic diabetics, not trying to mimic microtrauma to muscle tissue as would be seen from resistance exercise). The second important thing is that the effect they saw was NOT a class effect and was only seen with canagliflozin, not empagliflozin or dapagliflozin.

It does shed light on why cana has the amputation risk warning, and the other SGLT2 inhibitors don’t, and I’ll bet based on this data that cana actually does inhibit muscular adaptations to an exercise stimulus since it appears to be somewhat toxic to mitochondria. It also makes me wonder just how mitotoxic might be the combination of metformin and canagliflozin.

Based on the data to date, I’m sticking with empagliflozin/Jardiance and never going back to canagliflozin.

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I definitely understand this perspective, Davin8r. But, I wonder whether this unique property of canagliflozin may actually be contributing to the longevity benefit it demonstrated in the ITP research study.

A good question for the researchers… good point.

That’s certainly possible in theory, but since canagliflozin has this mitotoxicity due exclusively to its off-target effects (LARS2 inhibition) and not from SGLT2 inhibition, I doubt it’s the case unless inhibition of LARS2 is beneficial in some way, which seems unlikely since it’s hard to imagine that preventing muscle cell repair/regeneration would be helpful except perhaps in the case of a muscle cell tumor i.e. sarcoma, perhaps? Hopefully someone will test one or more of the “pure” SGLT2 inhibitors for longevity enhancement in the near future.

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A study came from the town of wenzhou, china, i would not worry too much😆