Unraveling Muscle Impairment Associated With COVID-19 and the Role of 3D Culture in Its Investigation

Abstract

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been considered a public health emergency, extensively investigated by researchers. Accordingly, the respiratory tract has been the main research focus, with some other studies outlining the effects on the neurological, cardiovascular, and renal systems. However, concerning SARS-CoV-2 outcomes on skeletal muscle, scientific evidence is still not sufficiently strong to trace, treat and prevent possible muscle impairment due to the COVID-19. Simultaneously, there has been a considerable amount of studies reporting skeletal muscle damage in the context of COVID-19. Among the detrimental musculoskeletal conditions associated with the viral infection, the most commonly described are sarcopenia, cachexia, myalgia, myositis, rhabdomyolysis, atrophy, peripheral neuropathy, and Guillain-Barré Syndrome. Of note, the risk of developing sarcopenia during or after COVID-19 is relatively high, which poses special importance to the condition amid the SARS-CoV-2 infection. The yet uncovered mechanisms by which musculoskeletal injury takes place in COVID-19 and the lack of published methods tailored to study the correlation between COVID-19 and skeletal muscle hinder the ability of healthcare professionals to provide SARS-CoV-2 infected patients with an adequate treatment plan. The present review aims to minimize this burden by both thoroughly exploring the interaction between COVID-19 and the musculoskeletal system and examining the cutting-edge 3D cell culture techniques capable of revolutionizing the study of muscle dynamics.

Keywords: COVID-19; SARS-CoV-2; biomaterials; inflammation; skeletal muscle.

Figure 1

Inflammatory and immunological repercussions of SARS-CoV-2 infection. SARS-CoV-2 components such as the S protein, PAMPs and viral single-stranded RNA (ssRNA) are recognized by macrophages and other immunological cells through Toll-Like Receptors (TLR), triggering intracellular cascades responsible for initiating inflammatory gene expression and cytokine production. Cytokines from the innate immune response against COVID-19 also intensify inflammatory gene expression through different pathways, such as JAK-STAT signaling. Increased synthesis of IL-6, IL-10, IL-1ß, IFN-γ and other cytokines in response to viral infection enhance phagocytotic activity, B cell class differentiation into IgG synthesizing plasmocytes and tissue-specific T-cell recruitment. Phagocytotic activity is related to viral clearance and tissue remodeling as a response to chronic inflammation. Anti-spike IgG might cross-react with neuronal myelin, predisposing SARS-CoV-2 infected patients to GBS (Guillain-Barré Syndrome), a disease whose development is also associated with cytokines produced in the setting of SARS-CoV-2 infection. Lastly, T-cell recruitment is associated with increased production of cytokines, which not only enhance myotoxicity through decreased muscle protein synthesis and increased protein degradation, but also deplete circulating T cells, which can aggravate systemic immunological response to infection. Created with Biorender.com.

Figure 2

COVID-19 associated sarcopenia mechanisms. SARS-CoV-2 infection activates a series of mechanisms responsible for increasing the risk of sarcopenia development. COVID-19 induces ACE2 downregulation and hinders the ACE2 protective effect, predisposing skeletal muscle to sarcopenia. The inflammatory response in response to infection, mainly characterized by the production of IL-1, IL-6, IFN-γ, TNF-α, IL-12, IFN-α, CRP, and Ferritin, prompts muscle catabolism, reducing muscle protein synthesis and increasing its susceptibility to damage and death. Bedrest and physical inactivity in the context of patients with COVID-19 not only increases several inflammatory biomarkers (such as TNF-α, CRP, and IL-6) but also reduces muscle quantity, strength, anaerobic performance, and protein synthesis. Additionally, the inactivity state impairs glycemic control, which also contributes to a decrease in muscle protein synthesis and damages neuromuscular junctions. Interstitial pneumonia secondary to COVID-19 commonly triggers a state of hypoxia, which accounts for (1) a decrease in phosphorylation of p70S6K1 and 4E-BP1, (2) a switch from the IGF-1/Akt to IGF-1/ERK signaling pathway, (3) an increase in myostatin levels and (4) an inhibition of mTOR. The decrease in phosphorylation of p70S6K1 and 4E-BP1 suppresses protein synthesis. The switch from the IGF-1/Akt to IGF-1/ERK signaling pathway impairs myoblast differentiation. Elevated levels of myostatin activate catabolism and negatively regulate muscle growth. Inhibition of mTOR activity hampers the regulation of cell growth and proliferation, which augments the risk of damage within the skeletal muscle. Hypoxia, thus, makes the musculoskeletal system susceptible to sarcopenia. Created with adobe.com/illustrator.

Figure 3

Strategies to mitigate SARS-CoV-2 impact on the musculoskeletal system. Diet modifications, sunlight exposure and exercise have been indicated in the literature as potential strategies to minimize the impacts of SARS-CoV-2 on skeletal muscle. Meals rich in antioxidant plants likely boost defenses of the immune system, improving viral infections combat. At the same time, the production of vitamin D, triggered by exposure to sunlight, enhances the function of T cells. Physical activity, on the other hand, exerts a modulatory effect in the organism, mainly characterized by a state of increase in myokines, IL-6 and IL-10, which improves the body's immunovigilance. Augmented expression of antioxidant Extracellular Superoxide Dismutase enzyme (EcSOD) has also been detected during exercise, which contributes to both oxidative stress and tissue damage reduction. Angiotensin 1-7 also seems to be upregulated in the setting of physical activity, which plays a role in mitigating the deteriorating effects of SARS-CoV-2 in the organism. Created with Biorender.com.