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How could we modulate basal skeletal muscle metabolism on demand?

Image credit: Photo by astronaut Don Pettit (https://blogs.nasa.gov/letters/2012/06/22/post_1340397037344/)

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J. Nikola
J. Nikola Dec 14, 2021
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The aim of the session:
  • To find and determine the role of key players in basal skeletal muscle metabolism control.
  • To find new ways how basal skeletal muscle metabolism could be modulated.
  • To find new applications of the basal skeletal muscle metabolism modulations.

Introduction
Modulation of basal metabolism of skeletal muscles is not a new thing. It's how mammals advanced in the evolutionary tree and "got warmer", which enabled them to live in cold areas and hunt during cold nights. But the food itself cannot warm us up. It is broken down into much smaller molecules that are used by cell mitochondria to generate ATP. Every organ and tissue uses ATP to function properly, which also creates heat. Thus proportionally, bigger organs create more heat. That's why we feel hot and sweat during exercise.
The intriguing part
Recently, scientists wanted to see if see otters can heat themselves up by muscle activity, without physical activity or shivering, so they observed their muscle mitochondria. It seems that they are extremely "leaky" (also called "proton leakage", described in the video), providing sea otters with less of energy, but greater heat, even when they are doing nothing. That's what keeps them warm - muscle inneficiency.
The question
What if we found a way how we could reversibly change the basal metabolism of the muscle and make them inefficient in creating energy --> increase the heat generation?
The benefit
Imagine having a tumor and feeling really sick. Your body gives up on you and you fight for every breath. Then you receive chemotherapy and need to rest and let your body fight the disease. The outcome could be much higher if your basal skeletal muscle metabolism was lower, or, in other words, your muscles used less energy. The same could be beneficial for the astronauts in the space, if their bodies demanded lower food intake. On the other hand, if you want to burn more fat and get slim faster, you could raise the basal muscle metabolism and shorten the time to get back in shape. Not to mention, Raymond Pearl proposed in 1926 the "rate of living" hypothesis that explains how longevity varies inversely with basal metabolic rate. That way, lower basal skeletal muscle metabolism could contribute to the human battle for longevity.
Where else can it be used:
  • to heat soldiers during cold nights
  • to heat homeless people during cold nights

Call to action
  • Can you think of any molecule that could have an important role in metabolism regulation and could also be easily modulated? Do you have any papers in mind?
  • Is there an existing way how basal muscle metabolism can be increased without physical activity or shivering?
  • Can you think of any other application of this modulations which save energy or increase the energy "burn"?

[1]https://www.the-scientist.com/news-opinion/sea-otters-demonstrate-that-there-is-more-to-muscle-than-just-movement-it-can-also-bring-the-heat-69520

2
Creative contributions

Practice the Wim Hof breathing technique

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Shubhankar Kulkarni
Shubhankar Kulkarni Dec 21, 2021
The Wim Hof Method breathing method includes the following steps:
  1. Take a deep breath through the nose
  2. Exhale through the mouth
  3. Perform 30 such breaths
  4. When on your 30th breath, exhale up to 90 percent and hold for as long as you can
  5. When you feel you really need to take a breath, inhale completely and hold for 15 sec, and then release
This constitutes one round of the Wim Hof breathing method. Three such rounds constitute the basic technique. While performing this technique the lower part of the lungs should also be filled. When your lower lungs get filled, your belly produces. Use this as a sign.
Wim Hof uses this method to survive in the cold or ice water without any clothes. The method boosts your metabolism, activates the oxidation of brown fat in your body, and helps lose excess weight. Although it helps immensely in surviving in cold environments and high altitudes, it also helps with improving sleep, immune regulation, mental peace, increasing willpower, improving focus, and reducing stress.

[1]https://www.healthline.com/health/wim-hof-method#benefits

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Povilas S
Povilas S6 months ago
I don't want to sound discouraging, but I think people should take the method with a grain of salt. It might not be good for everyone, and I think one should be a bit careful when trying it. Wim Hof breathing techniques involve hyperventilation and holding breath for quite long periods of time. This is not a very safe thing to do. You might even pass out. That's where my concern lies.
I tried Wim Hof practices myself and stopped after a week or so because I noticed negative effects on my mental health, namely - my thoughts became more chaotic and my memory worsened. I'm not saying that Wim Hof exercises were the main cause of this (I don't know the cause), but it started exactly at the time when I was doing them, so it might have at least contributed to it.
There's another breathing practice called rebirthing which also involves hyperventilation and is often criticized by the scientific community. An acquaintance of mine reported an overly emotional sensitivity after rebirthing practices, which was lasting and something he wanted to get rid of.
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Shubhankar Kulkarni
Shubhankar Kulkarni6 months ago
Povilas S Wim Hof conducts training sessions himself, indicating that they are not to be performed on your own without proper supervision. Also, modulating your basal metabolism, for whatever reason, is not advisable for common folk like us. This technique is not an exercise to be performed daily. It is for those who require that kind of capacity for their work or mountaineers desiring to achieve new heights. Of course, it comes with consequences. Wim Hof has written five books on the technique, suggesting that there is more to it than the few lines I wrote in my contribution. So yes, I agree with you but modulating one's metabolism, using whichever method, is going to have consequences.
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J. Nikola
J. Nikola6 months ago
Really cool! Sounds fun, I'll try it.
Also, I agree it's "increasing skeletal muscle basal metabolism on demand", but only in a specific area of the body, right? Plus, it's not passive, which makes it difficult to implement as an addition for therapies (as mentioned in the session text). Nevertheless, I will check the physiological effect it has on the body and if anyone discovered which molecules play the main role in regulations during the Wim Hof technique. Thank you for the insight!
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Sarcopilin could be our best candidate!

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J. Nikola
J. Nikola Dec 29, 2021
Introduction
Sarcopilin (SLN) is a protein that regulates sarcoplasmic reticulum Ca2+ ATPase (SERCA) in muscles by uncoupling Ca2+ transport from ATP hydrolysis. It was shown that SLN plays an important role in the cold- and diet-induced thermogenesis, but the researchers couldn't depict how. The general premise was that reduced expression of SLN results in a higher rate of obesity.
Recently, researchers used three mice systems to describe the role of SLN: SLN knockout mice (Sln−/−), skeletal muscle-specific SLN overexpression mice (SlnOE), and wild-type mice (WT). They fed them with fixed calories diet and a high-fat diet. These were the results:
While being on fixed calory diet:
  • SlnOE mice exhibited a significant loss in body weight compared with WT mice
  • Sln−/− mice showed a significant gain in body weight compared with WT
  • SlnOE mice showed greater energy expenditure (likely due to a higher energy cost for muscle work (Figure 1A) and lower caloric efficiency (Figure 1C))
  • the increased energy expenditure was further supported by a decrease in fat mass (Figure 1B and 1D)
Figure 1. Results of a fixed-calory diet experiments
While being on high-fat diet:
  • SlnOE mice gained significantly less weight compared with WT littermates
  • SlnOE mice gained significantly less weight per calorie consumed
  • studies using isolated soleus muscle from SlnOE mice showed 57% higher oxygen consumption in the resting state
  • oxygen consumption and fatty acid oxidation were increased markedly in SlnOE mice
  • an increase in both mitochondrial number and size in SlnOE muscle

The ideas
Therefore, the idea is to manipulate basal muscle metabolism by sarcolipin, or sarcolipin activators to treat obesity (like mentioned here, too).
As shown in the the paper , SERCA activators have been used to treat acute and chronic heart failures, diabetes or metabolic dysfunctions, but not directly obesity.
  1. So, the first idea would be to test (or find research on) some of the SERCA activators to find if they can affect obesity development, thermoregulation and basal muscle metabolism
  2. If these don't work, I would then test luteolin, suberanilohydroxamic acid or pyridone derivative mentioned in another paper . They should also increase the SERCA activity.
  3. If none of the above-mentioned existing solutions work, I would then try to directly inoculate, absorb, consume or innoculate sarcolipin
  4. If this don't work, I would try to enhance its expression by CRISPR-Cas or mRNA "vaccines".
  5. On the other hand, if it works (or partially works), I would try to modify sarcolipin structure in terms of biochemical properties to make it even more effective, potent and safe
What do you think? Is it convincing enough?

Additional benefits and uses
Papers shown that SNL overexpression could be protective in cases of muscular dystrophy and atrophy

[1]https://www.nature.com/articles/nm.2897

[2]https://www.cell.com/cell-reports/pdfExtended/S2211-1247(18)31307-X

[3]https://www.sciencedirect.com/science/article/pii/S0021925820426146

[4]https://www.frontiersin.org/articles/10.3389/fmolb.2018.00036/full

[5]https://onlinelibrary.wiley.com/doi/full/10.1111/cbdd.13620

[6]https://www.frontiersin.org/articles/10.3389/fphys.2021.633058/full#:~:text=SLN%20deletion%20worsens%20dystrophic%20phenotype%20of%20the%20MDX%20mice%2C%20suggesting%20SLN%20upregulation%20as%20protective

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Shubhankar Kulkarni
Shubhankar Kulkarni6 months ago
Great find. Thank you for the in-depth explanation. The specific tissue knock-out experiment made me think about whether we need similar location- or tissue-specific drugs/ therapies to regulate metabolism for specific purposes. For example, if you are battling cold, you may require muscle-specific metabolism upregulation or brown-adipose tissue-targetted therapy. However, as you mentioned in the session text, if you want to burn fat, you may require white adipose-specific therapy. This adds another layer of complexity we need to take into consideration when we set out to find appropriate therapies. Also, some drugs might be potent in achieving a certain effect (for example, either for temperature regulation or fat oxidation, but not both) and not for others. Drugs that have a local effect could also be useful in certain cases.
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