Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I.

[pattismith]

Myotonic Dystrophy (1 or 2) are multisystemic genetic spliceopathies, and I wonder if ME/CFS may share similar mechanism.

AICAR and Rapamycin are promising treatment in MD1:


J Clin Invest. 2017
Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I.
Brockhoff M, Rion N, Chojnowska K, Wiktorowicz T, Eickhorst C, Erne B, Frank S, Angelini C, Furling D, Rüegg MA, Sinnreich M, Castets P.
Abstract
Myotonic dystrophy type I (DM1) is a disabling multisystemic disease that predominantly affects skeletal muscle. It is caused by expanded CTG repeats in the 3'-UTR of the dystrophia myotonica protein kinase (DMPK) gene. RNA hairpins formed by elongated DMPK transcripts sequester RNA-binding proteins, leading to mis-splicing of numerous pre-mRNAs. Here, we have investigated whether DM1-associated muscle pathology is related to deregulation of central metabolic pathways, which may identify potential therapeutic targets for the disease. In a well-characterized mouse model for DM1 (HSALR mice), activation of AMPK signaling in muscle was impaired under starved conditions, while mTORC1 signaling remained active. In parallel, autophagic flux was perturbed in HSALR muscle and in cultured human DM1 myotubes. Pharmacological approaches targeting AMPK/mTORC1 signaling greatly ameliorated muscle function in HSALR mice.

AICAR, an AMPK activator, led to a strong reduction of myotonia, which was accompanied by partial correction of misregulated alternative splicing.

Rapamycin, an mTORC1 inhibitor, improved muscle relaxation and increased muscle force in HSALR mice without affecting splicing.

These findings highlight the involvement of AMPK/mTORC1 deregulation in DM1 muscle pathophysiology and may open potential avenues for the treatment of this disease.

 

[pattismith]

I have clinical delayed muscle relaxation (like in myotonic dystrophy), muscle pain and weakness.
I also have skin microvascular damages, that got worse after my 4 RNA COVID vaccines.

I am currently doing a rapamycin trial, and yes it does help my muscle.
I take it once a week.
I got toxicity at 4 mg (drop of my blood red and white cells, rise of my liver parameter), but I am ok at 2 mg.
It helps with my muscles, but also with my skin vessels: I have some signs of perfusion improvment;

 

[Violeta]

I was just led to looking at AMPK through reading about berberine. Very interesting.

 

[pattismith]

I was just led to looking at AMPK through reading about berberine. Very interesting.

I wish I could try some AICAR, unfortunately it's a doping agent not available for health issue...

Life extension sells a supplement with Hesperidin and Actiponin for AMPK activation.

Here a 2023 study on the same topic, from Canada

Combinatorial treatment with exercise and AICAR potentiates the rescue of myotonic dystrophy type 1 mouse muscles in a sex-specific manner

Abstract​

Targeting AMP-activated protein kinase (AMPK) is emerging as a promising strategy for treating myotonic dystrophy type 1 (DM1), the most prevalent form of adult-onset muscular dystrophy.

We previously demonstrated that 5-aminomidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) and exercise, two potent AMPK activators, improve disease features in DM1 mouse skeletal muscles.

Here, we employed a combinatorial approach with these AMPK activators and examined their joint impact on disease severity in male and female DM1 mice.

Our data reveal that swimming exercise additively enhances the effect of AICAR in mitigating the nuclear accumulation of toxic CUGexp RNA foci.

In addition, our findings show a trend towards an enhanced reversal of MBNL1 sequestration and correction in pathogenic alternative splicing events. Our results further demonstrate that the combinatorial impact of exercise and AICAR promotes muscle fiber hypertrophy in DM1 skeletal muscle.

Importantly, these improvements occur in a sex-specific manner with greater benefits observed in female DM1 mice.

Our findings demonstrate that combining AMPK-activating interventions may prove optimal for rescuing the DM1 muscle phenotype and uncover important sex differences in the response to AMPK-based therapeutic strategies in DM1 mice.

 

[Violeta]

Patti, are you able to exercise? Do you cramp up frequently? Is it worse at night? Have you tried berberine?

Swimming is a great exercise, but I wish it weren't so expensive to do. Also, probably almost impossible to find a pool that has salt instead of chlorine.