Review Mitochondrial innate immune signaling in skeletal muscle adaptation to exercise, 2025, Ma, Hwang et al.

[SNT Gatchaman]

Mitochondrial innate immune signaling in skeletal muscle adaptation to exercise
Jin Ma; Annie Yujin Son; Youlim Son; Ping-yuan Wang; Paul M. Hwang

Exercise-induced inflammation is regarded as a response to muscle damage from mechanical stress, but controlled immune signaling can be beneficial by promoting metabolic adaptation which, for example, decreases obesity and lowers the risk of diabetes. In addition to oxidative metabolism, mitochondria play a central role in initiating innate immune signaling.

We review recent work that has identified the cGAS-STING–NF-κB signaling pathway, activated by the downregulation of mitochondrial proteins CHCHD4 and TRIAP1, as mediating skeletal muscle adaptation to exercise training as well as potentially promoting cellular resilience to environmental stresses. Notably, CHCHD4 haploinsufficiency prevents obesity in aging mice; therefore, this innate immune signaling pathway could be targeted to achieve some of the health benefits of exercise.

Link | PDF (Trends in Endocrinology & Metabolism) [Paywall]

 

[SNT Gatchaman]

Contrary to the previous ‘open-window’ hypothesis, which proposed a period of immune suppression and increased infection risk following acute exercise, current evidence suggests otherwise . It would be counterintuitive for the body to dramatically increase circulating effector cells only to become immunosuppressed. Instead, studies show that NK cell cytotoxic function is actually enhanced shortly after exertion. Acute exercise even preferentially mobilizes highly-differentiated T cells, and this rapid increase in circulating lymphocytes is being explored as a strategy to enrich T cells for adoptive immunotherapies like CAR T-cell production.

Although the effect of exercise on health is generally beneficial, individual responses to physical activity may be different depending on their pre-existing condition. Fatigue and immune aberrancies are characteristics of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a well-studied disorder estimated to affect up to 1% of the population and now may be even more prevalent as it has been likened to long COVID . A recommendation for individuals with fatigue may be to improve fitness by exercise training, but clinical experience for patients with ME/CFS suggests otherwise. Individuals with ME/CFS, and possibly those with long COVID, can experience post-exertional malaise (PEM), a debilitating exacerbation of fatigue symptoms following minimal physical or cognitive exertion. While the mechanism of this phenomenon remains unclear, mitochondrial dysfunction and dysregulated immune activation have been suggested to contribute to this deleterious response to exercise. Such subgroups of patients highlight the importance of targeted prescription of physical activity.

(Not well studied enough.)

In the course of examining the role of p53 regulation of mitochondrial respiration and exercise endurance, it was observed that acute exercise decreases the expression of mitochondrial protein import carrier Coiled-coil-Helix-Coiled-coil-Helix Domain 4 (CHCHD4, mammalian homolog of yeast Mia40) through the transcriptional repressor FOXO3, known to be induced by exercise stimulation. CHCHD4 plays a critical role in the import of a subset of proteins within the mitochondrial intermembrane space (IMS). Unlike some of the other mitochondrial protein import pathways, CHCHD4 serves as carrier in the mitochondrial disulfide relay system, working in concert with other components such as GFER and TOM40 to facilitate the proper import of substrates with specific cysteine motifs. CHCHD4 substrates are involved in various aspects of mitochondrial biogenesis including cardiolipin biosynthesis, cristae modeling, and respiratory complex assembly.

In investigating the molecular mechanism of CHCHD4-regulated muscle fiber switching using proteomics profiling, TP53-regulated inhibitor of apoptosis 1 (TRIAP1) was found to be a top candidate reciprocally affected by CHCHD4 in both transgenic and knockout mice, consistent with its known dependence on CHCHD4 for mitochondrial import. TRIAP1 transports the lipid precursor for the biosynthesis of cardiolipins which are enriched in the inner mitochondrial membrane and essential for normal mitochondrial structure and function.

Targeting CHCHD4–TRIAP1 signaling could be a potential strategy against obesity with its associated metabolic disorders, but the long-term consequences of modulating mitochondrial immune signaling will need to be carefully considered for safety and tolerability. Beyond the immediate concern about the potential side effects of pharmacologic targeting, it could be fruitful to consider the potential role of this immune pathway in disease pathogenesis. For example, in disorders associated with immune and exercise tolerance abnormalities such as ME/CFS, it could be speculated that the innate immune activation caused by exercise stress may contribute to the clinical symptom of post-exertional malaise. With this insight, a drug with STING antagonist properties could be considered as part of the treatment strategy]. The discovery of the CHCHD4–TRIAP1 pathway provides a fresh perspective on exercise biology, positioning mitochondria as a central hub that integrates innate immune signaling – one of the critical components driving skeletal muscle adaptation and metabolic resilience.

 

[SNT Gatchaman]

See —

CHCHD4-TRIAP1 regulation of innate immune signaling mediates skeletal muscle adaptation to exercise (2023)
Jin Ma; Ping-yuan Wang; Jie Zhuang; Annie Y. Son; Alexander K. Karius; Abu Mohammad Syed; Masahiro Nishi; Zhichao Wu; Mateus P. Mori; Young-Chae Kim; Paul M. Hwang

Spoiler: Abstract

Exercise training can stimulate the formation of fatty-acid-oxidizing slow-twitch skeletal muscle fibers, which are inversely correlated with obesity, but the molecular mechanism underlying this transformation requires further elucidation.

Here, we report that the downregulation of the mitochondrial disulfide relay carrier CHCHD4 by exercise training decreases the import of TP53-regulated inhibitor of apoptosis 1 (TRIAP1) into mitochondria, which can reduce cardiolipin levels and promote VDAC oligomerization in skeletal muscle.

VDAC oligomerization, known to facilitate mtDNA release, can activate cGAS-STING/NFKB innate immune signaling and downregulate MyoD in skeletal muscle, thereby promoting the formation of oxidative slow-twitch fibers. In mice, CHCHD4 haploinsufficiency is sufficient to activate this pathway, leading to increased oxidative muscle fibers and decreased fat accumulation with aging.

The identification of a specific mediator regulating muscle fiber transformation provides an opportunity to understand further the molecular underpinnings of complex metabolic conditions such as obesity and could have therapeutic implications.

Link | PDF (Cell Reports) [Open Access]

 

[V.R.T.]

To highlight this bit from the conclusion:

'For example, in disorders associated with immune and exercise tolerance abnormalities such as ME/CFS, it could be speculated that the innate immune activation caused by exercise stress may contribute to the clinical symptom of post-exertional malaise. With this insight, a drug with STING antagonist properties could be considered as part of the treatment strategy'

What drugs have STING antagonist properties?

It's good to see Hwang's team still thinking about ME/CFS

 

[SNT Gatchaman]

I excluded the reference numbers in the quote, but it's "With this insight, a drug with STING antagonist properties could be considered as part of the treatment strategy [85]"

[85] STING Agonists/Antagonists: Their Potential as Therapeutics and Future Developments (2022, Cells) [Open Access]

 

[Murph]

I"m excited that Hwang has his eye on ME/CFS all the time, even in papers on pre-existing research streams that needn't mention it. I feel we have him on our team now!

I remember that in his big paper he found weird issues in PERK and eif2-alpha., which are activated by endoplasmic reticulum stress. It was a bit of mystery. It is possible STING is part of his thinking about how to solve that mystery. There's lots of papers a bit like this one that link STING to PERK and eif2a:

The cGAS-STING/PERK-eIF2α: Individual or Potentially Collaborative Signaling Transduction in Cardiovascular Diseases ​

 

[jnmaciuch]

What drugs have STING antagonist properties?

In addition to the STING modulators that @SNT Gatchaman linked, it’s possible to target a few things upstream or downstream of it. For upstream, cyclosporine blocks the mPTP which is how mitochondrial DNA exits the mitochondria under homeostatic stress and triggers cGAS-STING.

There are also several type I interferon inhibitors which would be downstream of STING. I’ve been really been interested in those as I saw testimony in several lupus forums of people who were on conventional lupus therapies targetting the adaptive immune system but still reported ME/CFS-like symptoms leaving them homebound. They said that adding a type I interferon inhibitor on top of their other meds gave them their life back. It’s been making me wonder if there is some critical overlap between those lupus cases and ME/CFS that isnt related to the autoimmune component of lupus

 

[V.R.T.]

I’ve been really been interested in those as I saw testimony in several lupus forums of people who were on conventional lupus therapies targetting the adaptive immune system but still reported ME/CFS-like symptoms leaving them homebound. They said that adding a type I interferon inhibitor on top of their other meds gave them their life back. It’s been making me wonder if there is some critical overlap between those lupus cases and ME/CFS that isnt related to the autoimmune component of lupus

Facinating - is there anything we can do to bring this hypothesis to the point where we can do a clinical trial? Or falsify it so we know we don't need to?

Also, if those therapies are B cell depletion, does it follow that if it turns out Daratumumab works for ME/CFS perhaps non responders might need something like a type I interferon inhibitor in combination which dara?

 

[jnmaciuch]

Facinating - is there anything we can do to bring this hypothesis to the point where we can do a clinical trial? Or falsify it so we know we don't need to?

The hypothesis would be part of a muscle biopsy study I’ve been trying hard to arrange. Though like I’ve said elsewhere, it’s unfortunately slow going—all grants to my institution are halted due to the political situation in the US and the search for potential collaborators has not been fruitful despite my best efforts so far.

Also, if those therapies are B cell depletion, does it follow that if it turns out Daratumumab works for ME/CFS perhaps non responders might need something like a type I interferon inhibitor in combination which dara?

If my idea has any merit, then Daratumumab would be doing nothing for the non-responders anyways (my thought in lupus is not that anti-inferon therapies are enhancing B-cell therapies, but that it’s solving a different upstream problem). Fluge and Mella might be interested in trialing an anti-interferon therapy separately, but I’m sure they would need some justification for it first. My hope is that a mechanistic study on muscle cells might be able to provide that.

 

[V.R.T.]

The hypothesis would be part of a muscle biopsy study I’ve been trying hard to arrange. Though like I’ve said elsewhere, it’s unfortunately slow going—all grants to my institution are halted due to the political situation in the US and the search for potential collaborators has not been fruitful despite my best efforts so far.

That sounds very frustrating, and I'm sorry it hasn't been fruitful so far. I hope that things change on that front as it sounds like a very worthwhile study. If there is anything we on the forum can do to help facilitate some progress, do let us know.

If my idea has any merit, then Daratumumab would be doing nothing for the non-responders anyways (my thought in lupus is not that anti-inferon therapies are enhancing B-cell therapies, but that it’s solving a different upstream problem). Fluge and Mella might be interested in trialing an anti-interferon therapy separately, but I’m sure they would need some justification for it first. My hope is that a mechanistic study on muscle cells might be able to provide that.

Thanks for explaining further, that's very clear.

 

[jnmaciuch]

I"m excited that Hwang has his eye on ME/CFS all the time, even in papers on pre-existing research streams that needn't mention it. I feel we have him on our team now!

I remember that in his big paper he found weird issues in PERK and eif2-alpha., which are activated by endoplasmic reticulum stress. It was a bit of mystery. It is possible STING is part of his thinking about how to solve that mystery. There's lots of papers a bit like this one that link STING to PERK and eif2a:

The cGAS-STING/PERK-eIF2α: Individual or Potentially Collaborative Signaling Transduction in Cardiovascular Diseases ​

That's really interesting, I've also been trying to figure out how the unfolded protein response might be playing a role. On another thread (https://www.s4me.info/threads/malat...lation-of-inflammation-2024-chen-et-al.43873/) I was exploring other potential reasons why malic acid might be effective for me besides its role in the TCA cycle. That paper found that malate inhibits the interferon response, but only through BiP, which is a protein that gets released during UPR. If cGAS-STING activation by mtDNA during activity results in an unfolded protein response on its own, that might solve that mystery and potentially explain why malic acid prevents me from getting PEM.

 

[Jonathan Edwards]

I saw testimony in several lupus forums of people who were on conventional lupus therapies targetting the adaptive immune system but still reported ME/CFS-like symptoms leaving them homebound. They said that adding a type I interferon inhibitor on top of their other meds gave them their life back. It’s been making me wonder if there is some critical overlap between those lupus cases and ME/CFS that isnt related to the autoimmune component of lulupus

The caveat to that is there aren't any therapies that target the adaptive system in lupus effectively. There are steroids that block downstream for inflammatory antibody effects and ritux cuts some other antibodies like those giving low platelets. But there are no treatments for the antibodies that most go with fatigue like Ro, Sm and RNP.

I agree that interferon are a good bet but I don't see a need to invoke anything more than antibodies as drivers in lupus.

 

[jnmaciuch]

I agree that interferon are a good bet but I don't see a need to invoke anything more than antibodies as drivers in lupus

Perhaps, though I think there is additional evidence of high interferon levels in the circulation preceding positive ANA, debilitating fatigue as a side effect of interferon therapies for other conditions, and those interferon therapies resulting in higher rates of lupus (but the reported fatigue precedes positive ANA).

[Edit: also positive ANA being present without any sign of disease, even sometimes at higher levels than in disease. This speculation may not be the case for all, but certainly seems to be a driver of specific symptoms for some]

 

[Jonathan Edwards]

Perhaps, though I think in lupus there is additional evidence of high interferon levels in the circulation preceding positive ANA, debilitating fatigue as a side effect of interferon therapies for other conditions, and those interferon therapies resulting in higher rates of lupus (but the reported fatigue precedes positive ANA).

Not aware of data about interferon in lupus before antibodies. There was a fashion for blaming type 1 interferons at one time but it always seemed a bit speculative.

 

[jnmaciuch]

Not aware of data about interferon in lupus before antibodies. There was a fashion for blaming type 1 interferons at one time but it always seemed a bit speculative.

It was something I read a few weeks ago, I’ll see if I can dig it up from my history when I have a free moment. [edit: I’ll consider the point speculative until I can prove to myself I’m not misremembering]

I believe it’s also known that circulating levels seem to fall after several months corresponding to epigenetic changes in DCs. So later symptoms aren’t solely driven by circulating interferon (though that doesn’t necessarily rule out interferon in the tissues) and the tissue damage-specific symptoms are certainly mediated by adapative