Does Inflammation Influence Muscle Building?

Whenever we think about inflammation, a negative idea comes to mind: fever, pain, malaise, etc. Inflammation is also associated with diseases (especially chronic diseases, which can persist for weeks or years) such as heart disease, diabetes, and cancer. However, inflammation is a protective mechanism of our defense system (immune system), whose main objective is to eliminate an invading/aggressor agent (bacteria, viruses, fungus, heat, chemical substances, etc). Some inflammatory responses can be very intense and persistent, damaging our own organs and causing illness. Due to these possible deleterious effects, it can be difficult to accept the idea that inflammation could ever be considered beneficial. However, when it comes to building muscle, some believe that inflammation can in fact be a good thing.

The muscular system is the system formed by all the muscles in our body. They correspond to about 40% of our body's total weight, and the contraction of these structures is responsible for several bodily functions. Our body is made up of 3 types of muscle tissue: the skeletal muscle, responsible for the voluntary contraction of the muscles (its contraction is conscious), involved in locomotion and providing support and stability to the body; the cardiac muscle, of involuntary contraction, crucial for heartbeats; and the smooth muscle, with involuntary contraction and responsible for the contractions of visceral organs (Constantin-Teodosiu & Constantin, 2021). Skeletal and cardiac muscles are types of striated muscle tissue. The term striated is associated with the fact that these muscles have light and dark bands, which alternately appear when observed under optical microscopy (Figure 1).

Figure 1. The human body muscle tissues. (Nitty Gritty Science, n.d.).

The muscles are formed by elongated and multinucleated cells (cells that have more than one nucleus), which are called muscle fibers (Figure 2). Muscle fibers have myosin and actin filaments, which are proteins capable of contraction. Actin, along with other proteins (troponin and tropomyosin), constitutes the so-called thin filaments. Myosin forms thick filaments. Thin and thick filaments alternate, forming light and dark bands. During muscle contraction, the sarcomeres (structure formed by actin, myosin, and other proteins) and, consequently, the entire muscle fiber shorten. During contraction, an overlap of actin and myosin filaments is observed (Constantin-Teodosiu & Constantin, 2021).

Figure 2. Skeletal muscle organization and structures responsible for contraction. A skeletal muscle is made up of muscle fibers. The muscle fibers are, in turn, composed of myofibrils. The myofibrils are composed of overlapping, protein-made, thick (myosin) and thin (actin) myofilaments highly organized as sarcomere units, which are de facto the contractile units of the muscle. The sheaths are made of connective tissue that encapsulates the bundle of myofibrils, muscle fibers, and the outer side of the muscle are named endomysium, perimysium, and epimysium, respectively. (Constantin-Teodosiu & Constantin, 2021)

Skeletal muscle hypertrophy (increase in muscle size and volume due to overload) can be induced by multiple mechanisms. Hormones and growth factors can serve as positive regulators, stimulating muscle growth, while also counteracting the negative regulators that inhibit hypertrophy (Schiaffino, Reggiani, Akimoto, & Blaauw, 2021). The process of muscle growth operates at a microscopic level, involving the activation of specific genes that stimulate the production of muscle proteins. For this process to be effective, it is necessary to adopt a balanced diet rich in proteins, vitamins, minerals, and carbohydrates. Furthermore, mechanical signals play a crucial role, particularly in the context of strength training, as will be explained below.

A striking feature of skeletal muscle is its great ability to adapt to external environmental stimuli. An example of this adaptive capacity is the large increase in muscle mass that can be induced by mechanical loading, as in weightlifting exercises to increase strength. Strength training, also known as resistance training, is useful to increase the capacity of the mechanical load of human skeletal muscle, and such exercise causes responses that lead to muscle hypertrophy (Schiaffino et al., 2021).

Inflammation Vs. Skeletal Muscle Growth

After engaging in physical exercise, it is common for our muscles to experience soreness. This is called delayed onset muscle soreness (DOMS). This discomfort typically sets in approximately 24 hours after the workout. During this period, the muscles undergo an inflammatory response, leading to soreness and stiffness (Lewis, Ruby, & Bush-Joseph, 2012). The peak of DOMS and the inflammatory process usually occurs on the second day following the exercise and gradually subsides thereafter. But what is the relationship between inflammation and muscle growth?

Inflammation is an acute, vital reaction mechanism to threats, and it is part of a beneficial defense system that maintains tissue equilibrium. Mechanical loading of skeletal muscle can initiate an inflammatory response. This happens because, during intense physical activity, part of the muscle tissue is damaged, causing cell death. When a cell dies, it can release intracellular components that generate an "alarm" signal that is recognized by our defense system. In this way, some cells of the immune system, known as white blood cells, migrate from the circulation to the injured tissue. These cells are mainly neutrophils and macrophages (known also as inflammatory cells) that accumulate in skeletal muscle and release various inflammatory mediators, causing local soreness and pain (Howard, Pasiakos, Blesso, Fussell, & Rodriguez, 2020; Koh & Pizza, 2009).

Damaged skeletal muscle can regenerate and repair itself through a process called myogenesis (Figure 3). The myogenic response involves the activation, proliferation, and differentiation of muscle-resident stem cells, known as satellite cells. Satellite cells are normally quiescent, which means they are inactive or in a state of dormancy (non-dividing cells). Depending on the stimuli (such as mechanical loading), they can become activated, mediating self-renewal or myogenesis. Activated satellite cells generate myoblasts (precursors of muscle fibers) in response to injury-related signals by reentering the cell cycle and proliferating. Myoblasts subsequently differentiate and eventually fuse with each other, forming new muscle fibers to regenerate and repair the damaged tissue (Arnold et al., 2007; Isesele & Mazurak, 2021).

Figure 3. The steps of myogenic differentiation. Satellite cells (muscle-resident stem cells), can be activated by inflammatory signals, reentering the cell cycle, proliferating, and differentiating into myoblasts. Myoblasts subsequently differentiate and eventually fuse with each other, forming new muscle fibers. (Isesele & Mazurak, 2021)

Inflammatory mediators play a critical role in mediating the regenerative response to muscle damage. The release of inflammatory mediators following muscle fiber damage is a finely regulated response. A transient increase in local inflammatory mediators induces signals in muscle cells that aid in the repair, remodeling, and maintenance of healthy muscle tissue (Koh & Pizza, 2009; Munoz-Canoves, Scheele, Pedersen, & Serrano, 2013). Neutrophils and macrophages that were recruited after the tissue injury at first produced pro-inflammatory mediators but, as the inflammatory response progresses, they can help in the removal of damaged tissue via a process that is known as phagocytosis. Phagocytosis ("phago-" comes from the Greek meaning "to eat") is a cellular process for ingesting and eliminating particles and cell debris, removing microorganisms, foreign substances, and even damaged tissue (Figure 4). This clearance of dead cells plays a crucial role in promoting a shift from pro-inflammatory to anti-inflammatory mediators within days of muscle injury. All together, these events effectively reduce local inflammation and facilitate the subsequent phases of muscle regeneration and repair (Arnold et al., 2007; Juban & Chazaud, 2021; Koh & Pizza, 2009).

Figure 4. Phagocytosis during skeletal muscle regeneration. Upon muscle damage, pro-inflammatory macrophages exert various properties, such as stimulating the proliferation of muscle stem cells. Upon phagocytosis of muscle debris and dead cells (represented by red and pink circles), the activation of anti-inflammatory genes takes place, which further shifts into repairing macrophages that help in the restoration of the tissue. (Juban & Chazaud, 2021)

Other Factors Involving Inflammation That Can Affect Muscle Growth

There are some other factors that should be considered when it comes to muscle growth. In some situations when intramuscular inflammation persists, for example, due to an exceedingly high inflammatory response or a systemic inflammation, the regenerative capacity of the muscle is diminished. Chronic inflammation can cause muscle atrophy, limiting muscle recovery by preventing the repair of damaged tissue, and impairing the restoration of muscle function (Costamagna, Costelli, Sampaolesi, & Penna, 2015). Thus, the inflammatory process should be finely regulated. In addition, chronic inflammation associated with advanced age (for more details visit https://www.byarcadia.org/post/inflammaging-a-new-insight-for-age-associated-diseases), can impair the regenerative processes by disrupting the normal balance between inflammatory and reparative pathways, resulting in reduced muscle mass and strength (Suetta et al., 2013).

It’s believed that the use of NSAIDs (nonsteroidal anti-inflammatory drugs) might impair the repair of muscle tissue and reduce muscle growth. NSAIDs are a class of medications commonly used to reduce inflammation, relieve pain, and lower fever. Some examples are ibuprofen, aspirin, diclofenac and naproxen. Some studies have reported significant impairments in muscle growth following NSAID intake (Lilja et al., 2018), while others have found no substantial differences in muscle building (Krentz, Quest, Farthing, Quest, & Chilibeck, 2008). Based on the current body of research, it seems that long-term, high-dose use of NSAIDs may hinder maximal muscle growth, whereas low-dose usage, while still effective in fighting inflammation and pain may not have a significant impact. Therefore, the balance between the duration and dose of the treatment seems to be relevant. It is important to note that this topic remains of ongoing debate and further studies are needed to reach a conclusion.

Conclusions

A finely regulated inflammatory response can be beneficial for muscle growth. A self-limited inflammatory response can generate signals that will induce the proliferation and differentiation of muscle cells, facilitating the regeneration and repair of the tissue after mechanical loading exercises. However, studies on this topic are still being conducted to elucidate which inflammatory mediators are able to activate a pro-myogenic response in muscle tissue, in addition to other mediators and cells that may be involved. It is important to consider other factors that should be balanced and that contribute to muscle growth as well. Engaging in regular resistance training is crucial for promoting muscle hypertrophy. An adequate diet, such as proper intake of protein and carbohydrates, provides the necessary building blocks and energy for muscle synthesis and recovery. Additionally, allowing for sufficient rest and recovery periods is essential to support optimal muscle growth. By considering these factors in combination, individuals can enhance their potential for satisfactory muscle growth and overall fitness.

References

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Constantin-Teodosiu, D., & Constantin, D. (2021). Molecular Mechanisms of Muscle Fatigue. Int J Mol Sci, 22(21). doi:10.3390/ijms222111587

Costamagna, D., Costelli, P., Sampaolesi, M., & Penna, F. (2015). Role of Inflammation in Muscle Homeostasis and Myogenesis. Mediators Inflamm, 2015, 805172. doi:10.1155/2015/805172

Howard, E. E., Pasiakos, S. M., Blesso, C. N., Fussell, M. A., & Rodriguez, N. R. (2020). Divergent Roles of Inflammation in Skeletal Muscle Recovery From Injury. Front Physiol, 11, 87. doi:10.3389/fphys.2020.00087

Isesele, P. O., & Mazurak, V. C. (2021). Regulation of Skeletal Muscle Satellite Cell Differentiation by Omega-3 Polyunsaturated Fatty Acids: A Critical Review. Front Physiol, 12, 682091. doi:10.3389/fphys.2021.682091

Juban, G., & Chazaud, B. (2021). Efferocytosis during Skeletal Muscle Regeneration. Cells, 10(12). doi:10.3390/cells10123267

Koh, T. J., & Pizza, F. X. (2009). Do inflammatory cells influence skeletal muscle hypertrophy? Front Biosci (Elite Ed), 1(1), 60-71. doi:10.2741/E7

Krentz, J. R., Quest, B., Farthing, J. P., Quest, D. W., & Chilibeck, P. D. (2008). The effects of ibuprofen on muscle hypertrophy, strength, and soreness during resistance training. Appl Physiol Nutr Metab, 33(3), 470-475. doi:10.1139/H08-019

Lewis, P. B., Ruby, D., & Bush-Joseph, C. A. (2012). Muscle soreness and delayed-onset muscle soreness. Clin Sports Med, 31(2), 255-262. doi:10.1016/j.csm.2011.09.009

Lilja, M., Mandic, M., Apro, W., Melin, M., Olsson, K., Rosenborg, S., . . . Lundberg, T. R. (2018). High doses of anti-inflammatory drugs compromise muscle strength and hypertrophic adaptations to resistance training in young adults. Acta Physiol (Oxf), 222(2). doi:10.1111/apha.12948

Munoz-Canoves, P., Scheele, C., Pedersen, B. K., & Serrano, A. L. (2013). Interleukin-6 myokine signaling in skeletal muscle: a double-edged sword? FEBS J, 280(17), 4131-4148. doi:10.1111/febs.12338

Schiaffino, S., Reggiani, C., Akimoto, T., & Blaauw, B. (2021). Molecular Mechanisms of Skeletal Muscle Hypertrophy. J Neuromuscul Dis, 8(2), 169-183. doi:10.3233/JND-200568

Suetta, C., Frandsen, U., Mackey, A. L., Jensen, L., Hvid, L. G., Bayer, M. L., . . . Kjaer, M. (2013). Ageing is associated with diminished muscle re-growth and myogenic precursor cell expansion early after immobility-induced atrophy in human skeletal muscle. J Physiol, 591(15), 3789-3804. doi:10.1113/jphysiol.2013.257121

Visual Sources

Figure 1: Nitty Gritty Science. (n.d.). Human Body – Part 1, Section 2: The Muscular System. [image]. https://nittygrittyscience.com/textbooks/human-body-part-1/section-2-the-muscular-system/

Figure 2: Constantin-Teodosiu, D., & Constantin, D. (2021). Molecular Mechanisms of Muscle Fatigue. Int J Mol Sci, 22(21). [image]. doi:10.3390/ijms222111587

Figure 3: Isesele, P. O., & Mazurak, V. C. (2021). Regulation of Skeletal Muscle Satellite Cell Differentiation by Omega-3 Polyunsaturated Fatty Acids: A Critical Review. Front Physiol, 12, 682091. [image]. doi:10.3389/fphys.2021.682091

Figure 4: Juban, G., & Chazaud, B. (2021). Efferocytosis during Skeletal Muscle Regeneration. Cells, 10(12). [image]. doi:10.33 90/cells10123267