It is well known that the inflammation associated with rheumatoid arthritis (RA) leads to pain in the muscles and joints and is treatable with medication. However, muscle dysfunction, which is often associated with fatigue and weakness of the muscles, is a symptom of inflammation and leads to the increased production of reactive oxygen species (ROS) and has not yet been extensively studied as separately treatable. As anti-inflammatory medication primarily offsets the pain associated with RA, researchers believe there is a more direct route for targeting muscle dysfunction. Superoxide dismutase (SOD) 2/catalase mimetic (EUK-134), a targeted antioxidant, combined with physical exercise, has shown promising signs of becoming an effective treatment.
We spoke with Dr Johanna Lanner, of the Molecular Muscle Physiology and Pathophysiology Laboratory at the Karolinska Institute in Stockholm, Sweden, about her team’s publication on this topic, “Skeletal muscle redox signaling in rheumatoid arthritis.”
Does muscle dysfunction lead to symptoms other than increased weakness in patients with RA?
Dr Lanner: When it comes to a muscle, I would say that the weakness is 1 thing, but also, that will lead to a feeling of fatigue. If your muscles are weaker, then the effort it takes to do something will also make it feel that you don’t want to move, maybe. That could then indirectly be seen as fatigue. Since the muscles are weaker, they produce less force. You can maybe continue doing something with less force for a longer time, but the overall feeling for the mind and body would be fatigue. A patient may say that they feel fatigue, but we, as muscle researchers, see it more as weakness, because it just takes more effort to do the work.
Although they may not have the same contributing factors, do muscle dysfunction and loss of muscle mass in RA have a complementary relationship?
Dr Lanner: We have mostly looked at the intrinsic defects, normalizing it to the muscle size, but of course there is also a component of atrophy. Maybe you have increased protein degradation and less protein synthesis and that, of course, could come from the same source. That’s something we are looking into now in preclinical studies. Hopefully, a year or 2 from now, we can dissect out the mechanism for that, but it all originates from inflammation.
Can you briefly describe how oxidative stress, via increased ROS production, leads to muscle dysfunction in patients with RA?
Dr Lanner: We believe the inflammation is what leads to increased ROS production, or free radical species. They’re active molecules that can interact with anything, really, in their proximity. They interact with proteins and modify them, which makes the protein not able to generate force, and they sit where the protein should be. Also, these modifications are stable, so there’s no known way of removing them unless you make a new protein. And for some reason which is still unknown, even if you have a low grade of inflammation, you still have these modifications. We’ve even seen them in patients that have had RA for 10 years, although they have relatively low activity. These free radicals can stay in the muscle and remain on the contractile proteins, and that contributes to the weakness.
Why are disease-modifying anti-rheumatic drugs (DMARDs) for inflammation at times not sufficient for patients with RA?
Dr Lanner: When you have less inflammation, your joints as not as swollen and you have less pain. What we thought was interesting is that you still have muscle weakness, so that basically says that, even if you keep the inflammation low, you still get muscle problems as a comorbidity of the disease itself. So even though you have only low-grade inflammation, you have chronicity in the free radicals that are in your muscles, and that then contributes to the muscle weakness.
According to your paper, SOD 2/EUK-134 seems to prevent muscle weakness in rats. Do researchers have reason to believe that it may also be successful in treating patients with RA who also have pre-existing muscle weakness?
Dr Lanner: I think it’s a very promising compound. It’s one of the few that are targeted antioxidants. Typically, what people use are general antioxidants that couldn’t work as a treatment, like vitamin C and vitamin E, but this particular compound is more targeted to the mitochondria. We are super interested in studying it, but we haven’t been able to yet.
Your article explains that, although exercise is associated with some level of both inflammation and ROS, performing physical exercise has been shown to offset RA’s effects. Why is this?
Dr Lanner: If you can perform exercises, it’s definitely beneficial. When you do exercise, you get rapid, but intense, bursts of these free radicals and all types of signaling to the rest of the cell to increase your endogenous antioxidant defense. If you do endurance exercise, it sends positive signals, and you help your mitochondria function better. You also get an inflammatory signal, but that’s a transient signal that contributes to making the beneficial adaptation that you see with exercise. If you have rheumatoid arthritis, you have chronic, low-grade inflammation, but then also the same thing with free radicals. So, what we think is that exercise shocks the system with this type of stress and that beneficial signal. Any type of physiotherapy that you can perform without pain is good for you.
Is an exercise regimen a common recommendation for patients with RA?
Dr Lanner: Historically it’s been, “If you have pain, don’t stress the system, don’t exercise,” but now, what more and more people are showing is that exercise is good for overall health and also to boost your own antioxidant defense system. Physicians nowadays are definitely promoting exercise as a tool, as one component of treatment, combined with DMARDs or other medication.
What is your team currently working on?
Dr Lanner: Right now, what we are looking to do is understand the actual source of the free radicals. One major component of muscle function is, of course, our mitochondria, which is the powerhouse of the muscle, and we’re now trying to better understand how the mitochondria plays a part in muscle weakness as a comorbidity of inflammatory disease. We’re also looking into atrophic signaling, or rheumatoid cechexia.
Steinz MM, Santos-Alvess E, Lanner, JT. Skeletal muscle redox signaling in rheumatoid arthritis. Clin Sci. 2020 Nov 13;134(21):2835-2850. doi:10.1042/CS20190728