Thesis Muscle at Risk: How Physical Inactivity and Systemic Inflammation Affect Skeletal Muscle Health, 2024, Eggelbusch

https://research.vu.nl/en/publicati...hysical-inactivity-and-systemic-inflammation-

Muscle at Risk: How Physical Inactivity and Systemic Inflammation Affect Skeletal Muscle Health


Moritz Eggelbusch

• Vrije Universiteit Amsterdam

Research output: PhD Thesis › PhD-Thesis - Research and graduation internal

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Abstract

Physical inactivity causes declines in various physiological systems and contributes to metabolic diseases. Skeletal muscle mass loss due to inactivity is linked to decreased insulin sensitivity and altered glucose metabolism, causing insulin resistance. However, the specific molecular and metabolic changes underlying these inactivity-induced effects remain unclear.

In Chapter 2, a human bed rest study explored body composition, insulin and glucose metabolism, and mitochondrial function. Results indicated that short-term bed rest causes intracellular glycogen and lipid accumulation (nutrient overload), while prolonged inactivity exacerbates lipid storage, linked to local and systemic inflammation and lipotoxicity, alongside reduced mitochondrial function. These findings suggest nutrient overload as a primary driver of metabolic adaptations, with insulin insensitivity potentially acting as a protective mechanism against further nutrient accumulation. Inactivity often coincides with chronic systemic inflammation, as seen in ageing, chronic disease, obesity, and post-surgery.

Chapter 3 investigated the role of the NLRP3 inflammasome in inflammation-related muscle alterations. Cultured myotubes exposed to lipopolysaccharide (LPS) exhibited NLRP3 inflammasome activation, leading to mitochondrial ROS production and impaired muscle growth. Prolonged LPS exposure further damaged cells via IL-1β production, likely reducing protein synthesis. Treating cells with MCC950, an NLRP3 inhibitor, mitigated these growth impairments, indicating a promising therapeutic approach for inflammation-driven muscle wasting. Systemic inflammation and physical inactivity may have compounding effects on muscle deterioration, yet this interaction is understudied.

In Chapter 4, a preclinical mouse model examined the combined effects of inactivity (hindlimb suspension) and inflammation (LPS injection). Results showed significant muscle and body mass loss, especially upon combined conditions. Muscle atrophy was shown by reduced fibre size, with an impaired anabolic response evident through reduced leucine-stimulated protein synthesis and decreased Akt phosphorylation. Combined unloading and LPS induced metabolic stress in skeletal muscle, leading to anabolic resistance, increased proteolysis, and heightened inflammation.

Chapter 5 focused on muscle alterations in acute COVID-19 and post-COVID-19 (PASC) patients. Severe COVID-19 and PASC patients often face muscle weakness, exercise intolerance, and muscle atrophy, alongside metabolic changes and immune cell infiltration. Contributing factors include systemic inflammation, inactivity, hypoxemia, and malnutrition, all common in ICU-acquired weakness. Muscle alterations in PASC may stem from direct viral invasion or an abnormal immune response, showing similarities with chronic fatigue syndrome and warranting further study.

In Chapter 6, a novel method for estimating vastus lateralis (VL) muscle volume was developed to assess muscle mass in critical illness myopathy associated with inactivity and inflammation. This method, using a constant “muscle shape factor” applied to VL muscle length and cross-sectional area, achieved high accuracy (5.3±3.4% relative difference, R²=0.99). Two practical approaches - ultrasound image stitching and muscle thickness measurement - proved effective and feasible for bedside use, providing a reliable, safe, and affordable tool for clinical and research settings to monitor muscle size changes over time.

Overall, this thesis delivers valuable insights into how inactivity and inflammation impact skeletal muscle from molecular to whole-body levels. Inactivity-induced nutrient overload contributes to insulin insensitivity, lipotoxicity, and mitochondrial dysfunction, with insulin insensitivity possibly serving as an adaptive response to limit further metabolic stress. The NLRP3 inflammasome emerges as a key player in inflammation-driven muscle wasting, presenting a potential therapeutic target. Furthermore, the combined effect of inactivity and systemic inflammation exacerbates muscle atrophy and metabolic dysfunction, resulting in anabolic resistance and diminished mitochondrial function. The new VL muscle volume estimation method aids muscle monitoring, especially relevant for vulnerable populations such as the elderly and critically ill. These findings highlight the need for interventions to preserve muscle function and metabolic health in at-risk populations. Future research should aim at developing targeted strategies to counter muscle atrophy and enhance metabolic function in conditions of inactivity and inflammation.

Original language English
Qualification PhD
Awarding Institution

• Vrije Universiteit Amsterdam

Supervisors/Advisors

• Jaspers, Richard, Supervisor
• Weijs, Peter, Supervisor, -
• Wust, Rob, Co-supervisor
• Tieland, Micheal, Co-supervisor, -

Award date 19 Dec 2024
Print ISBNs 9789493406216
Publication status Published - 19 Dec 2024

 

So much is made about the dangers of physical inactivity. But even in studies that look at severe ME patients, they find nothing that reflects any disease state other than a few vague immunological and inflammatory differences. In fact it often leads to insistence that we are perfectly healthy and advice for the patient to just get up and move. Yet it's basically promoted as if this will lead you to die quickly, or whatever.

All those things said about the consequences of inactivity. We generally don't find them when looking at us. Only small differences outside of looking for indicators of fitness, like muscle mass, VO2max and so on. Which would mean that those markers are markers of fitness, not health. Otherwise we would light up indicators of poor health like a giant Christmas tree. But it's actually problematic that we don't. Only a few things like how much energy we use for the effort, as noted by Todd Davenport out of the NIH intramural study, but it's been mostly ignored.

No doubt being fit is better, but other than the fact that there is a direct relation between being healthy and able to be active enough to be fit, there's basically nothing. But of course it's argued completely backwards, because of a weird obsession with health being a thing that people can control at will, hence why making fitness markers equal to health markers make 'sense'.

It's really remarkable that both 'truths' are accepted as is, despite being contradictory in our case. Like the authoritarians who rage against enemies who are both easy to defeat, yet so mighty they will bring down their whole society unless they are crushed. It's so mindless and weird.

 

Muscle at risk, we'll tell you all about it in june 2026.

 

The mention of inflammation seems disconnected from the study of inactivity and insulin resistance. The latter may be of interest to ME/CFS research. The Beentjes paper from Edinburgh picked out insulin resistance clues despite no increase in BMI. It may be that inactivity with shift in tissue mass from muscle to fat is enough to show an increased insulin resistance or that there are more subtle shifts going on. Either way it might make sense of the insulin resistance clues as downstream. They may have shown up as independent of activity level but I think there is a possibility that a change in activity patterns even without an absolute reduction may occur in people as part of pacing.

 

For me the biggest question regarding to our muscles is - we have strength but very bad stamina. I think this question has never been answered.
I can do regurally an exercise but I will not improve my stamina too much. For example I tried to do daily push ups. At first I was able to do 10 push ups and after 2 months of daily training I was able to do only 15 and my muscles always trumbled a lot already after few push ups. I stopped it because it was contraproductive but I could see that there is no way to improve too much even with a regular training. Just to compare, before ME/CFS I could do 100 push ups.