Persistent Muscle Symptoms in Long COVID: A Comprehensive Analysis


The global pandemic caused by the virus known as SARS-CoV-2, which led to the disease COVID-19, has affected the world in unprecedented ways since it began in March 2020. While the situation has significantly improved thanks to vaccines, better treatments, and the virus becoming less severe, COVID-19 is still a major concern with new cases and related deaths occurring daily around the world.

COVID-19 is not just an acute illness that one recovers from quickly. Many people continue to experience symptoms long after the initial infection has cleared, a condition known as post-COVID-19 syndrome or “long COVID.” This condition affects people of all ages and presents a variety of symptoms that can persist for weeks or even months. Managing these lingering symptoms has become a significant challenge for healthcare providers.

One of the most common and persistent symptoms of long COVID is muscle fatigue, which is a feeling of extreme tiredness and weakness in the muscles. This symptom can occur regardless of how severe the initial COVID-19 infection was. Unlike typical muscle fatigue experienced during other illnesses, the muscle fatigue associated with COVID-19 tends to be more severe and lasts much longer.

Researchers have found that muscle fatigue in long COVID is often accompanied by other symptoms such as myalgia (muscle pain), brain fog (difficulty thinking clearly), headaches, insomnia (trouble sleeping), and anxiety. These symptoms can greatly impact a person’s quality of life, making it difficult to perform daily activities.

Studies have shown that the muscle problems in long COVID are due to various changes in the muscles themselves. These changes include muscle atrophy (where the muscles shrink and weaken), inflammation (swelling and irritation), and problems with the mitochondria (the parts of the cells that produce energy). Mitochondrial abnormalities mean the muscles cannot produce energy efficiently, leading to feelings of fatigue and weakness.

To understand why these muscle problems occur and persist, scientists conducted detailed studies using animal models. One such model is the golden hamster, which is useful because it shows many of the same symptoms and disease patterns as humans with COVID-19. In these studies, scientists found that the virus does not directly attack the muscles but causes significant changes in how the muscles function. They discovered that the muscles of infected hamsters showed signs of atrophy and a persistent reduction in the ability to produce energy.

The studies also showed that the body’s immune response to the virus plays a crucial role in these muscle changes. During an acute infection, the body releases various immune molecules to fight the virus, but these same molecules can cause long-term damage to the muscles. For example, molecules like interferons and tumor necrosis factor-alpha (TNF-α) can impair the muscles’ ability to generate energy, leading to prolonged fatigue and weakness.

In summary, long COVID is a condition where symptoms, particularly muscle fatigue, continue long after the initial infection. This fatigue is due to lasting changes in muscle structure and function, triggered by the body’s immune response to the virus. Understanding these mechanisms is essential for developing treatments to help those suffering from long COVID regain their health and quality of life.

The study….

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of coronavirus disease 2019 (COVID-19) since March 2020. Although the situation has greatly improved, thanks to the development of vaccines, advances in the treatment of acute infections, and the evolution of less virulent strains, many new COVID-19 cases and related morbidity and mortality are encountered every day worldwide. COVID-19 impacts human health beyond acute infection. COVID-19 long-haul symptoms are relatively prevalent across different age groups, and managing these symptoms has become a challenge. The condition in which the symptoms persist beyond 12 weeks after an acute viral infection with no alternative diagnosis has been defined as post-COVID-19 syndrome.

Post-COVID-19 syndrome can manifest many symptoms, the majority of which are neurological and neuropsychiatric, including myalgia, fatigue, brain fog, headaches, insomnia, and anxiety, among others. Muscle fatigue represents the most prevalent symptom, as revealed by several large cohort studies, and it can occur regardless of the severity of the initial viral infection. Although myalgia and fatigue are common with acute respiratory viral infections such as influenza, the symptoms are often more severe and long-lasting when associated with SARS-CoV-2, implicating prolonged structural and functional abnormalities in skeletal muscle after acute respiratory SARS-CoV-2 infection.

There are several published histopathological examinations of the skeletal muscle of patients who suffered from long COVID-19. These studies showed a variety of pathological changes, including muscle atrophy, inflammation, mitochondrial abnormalities, and capillary injury. Recent studies have also shown reduced mitochondrial oxidative capacity in patients with long COVID.

To better understand the molecular mechanisms underlying the development and persistence of myalgia and fatigue associated with COVID-19, a longitudinal study was performed to characterize the histopathological and transcriptional responses of skeletal muscle to respiratory SARS-CoV-2 infection and benchmarked the findings to influenza A virus (IAV) infection, utilizing the golden hamster as a model system. The hamster model has been proven to largely phenocopy COVID-19 biology, and it displays severe lung morphology and a tropism that matches what is observed in human patients. The study showed no direct viral invasion but myofiber atrophy, which was accompanied by persistent suppression of the genes related to myofibers, ribosomal proteins, and mitochondrial oxidative metabolism in the SARS-CoV-2 group.

It downregulated both cytoplasmic and mitochondrial ribosome protein genes, likely impairing protein synthesis. It also downregulated many nuclear genes, but not mitochondrial genes, involved in fatty acid β-oxidation, the tricarboxylic acid (TCA) cycle, and all five oxidative phosphorylation (OXPHOS) complexes. In contrast, no myofiber atrophy or persistent gene expression changes were observed in the IAV-infected hamsters. In addition to the transient type I and type II interferon responses at the acute phase of either infection, only the SARS-CoV-2 infection induced TNF-α but not IL-6 response in skeletal muscle. In vitro co-treatment of differentiated C2C12 cells, a skeletal muscle cell line, with IFN-γ and TNF-α greatly impaired mitochondrial respiration and shifted energy metabolism from mitochondrial oxidative respiration to glycolysis. These findings suggest that the combined systemic interferon and TNF-α responses during acute respiratory SARS-CoV-2 infection might induce a long-lasting suppression of mitochondrial oxidative energy metabolism and myofiber atrophy, causing acute and persistent muscle symptoms.


Muscle fatigue represents the most common symptom that persists after COVID-19. By characterizing the longitudinal skeletal muscle histopathological and transcriptional changes after acute respiratory SARS-CoV-2 infection in the COVID-19 hamster model, several important findings have been generated that shed light on the potential mechanisms underlying muscle symptoms associated with COVID-19 and long COVID.

First, the study supports the notion that SARS-CoV-2 is unlikely to directly invade skeletal muscle after an acute respiratory infection. So far, there has been no convincing evidence that SARS-CoV-2 directly invades skeletal muscle in humans. In the COVID-19 hamster model, there is no evidence of direct SARS-CoV-2 infection of skeletal muscle, as SARS-CoV-2 RNA and protein expression, virus-like particles, and inflammatory cell infiltrates are all absent in skeletal muscle.

Second, despite the absence of direct viral invasion, skeletal muscle in the COVID-19 hamster model undergoes myofiber atrophy and long-lasting transcriptomic changes, which are not observed with acute respiratory IAV infection. Myofiber atrophy has also been reported in muscle biopsies of patients with long COVID. The study further shows that both oxidative and glycolytic myofibers undergo atrophy, which argues against immobilization being the sole cause of the atrophy, as disuse has a primary impact on glycolytic fibers. In parallel with this muscle atrophy, atrogenes are upregulated while many cytoplasmic ribosomal protein genes are downregulated, suggesting that the myofiber atrophy is likely a result of both accelerated protein degradation and impaired protein synthesis.

Another prominent transcriptional response detected in skeletal muscle after respiratory SARS-CoV-2 infection is the long-lasting suppression of genes related to mitochondrial energy metabolism, especially those involved in mitochondrial OXPHOS, fatty acid β-oxidation, and the TCA cycle. Consistent with the findings, reduced expression of OXPHOS proteins, impaired mitochondrial respiration, and altered muscle metabolism with a lower reliance on oxidative metabolism have been observed in patients with exercise intolerance associated with long COVID. The study further shows that the respiratory SARS-CoV-2 infection affects mitochondrial oxidative metabolism at the nuclear gene level, as the 13 protein-encoding mtDNA genes are not affected.

Third, the systemic cytokine response to acute respiratory SARS-CoV-2 infection is likely an important trigger of the persistent histopathological and transcriptional changes observed in skeletal muscle. While respiratory SARS-CoV-2 and IAV infections generate comparable acute and transient type I and II interferon responses in skeletal muscle, the inflammatory cytokine response is different, with the TNF-α/NF-κB signaling pathway being differentially upregulated in the former. SARS-CoV-2 can infect cells and bind to critical host mitochondrial proteins to inhibit mitochondrial function. The impaired mitochondrial functions can persist in a variety of non-muscle tissues, even after the virus is cleared. The study further shows that the respiratory SARS-CoV-2 infection can persistently suppress mitochondrial oxidative metabolism genes in skeletal muscle without direct infection, which suggests a role of the acute systemic responses in the pathogenesis of muscle abnormalities. There is no evidence of persistent viral pneumonia or a chronic systemic response in the model.

The host interferon response is critical for controlling viral infection, but it can also enhance the inflammatory cytokine response. An exuberant systemic inflammatory cytokine response is a prominent feature of acute respiratory SARS-CoV-2 infection. The plasma levels of type I and type II interferons as well as several inflammatory cytokines, including IFN-α, IFN-γ, IL-6, TNF-α, and IL-1β, are significantly increased in human patients during acute infection. While IL-6 signaling is strongly induced in the lungs following acute respiratory SARS-CoV-2 infection, the genes in this pathway are not coordinately regulated in skeletal muscle, as shown by the transcriptome study. Genes involved in TNF-α/NF-κB signaling, however, are coordinately upregulated in muscle at the acute phase. Given the finding that TNF-α ligand expression is extremely low in skeletal muscle, the circulating TNF-α may act on skeletal muscle to cause muscle abnormalities. The TNF-α/NF-κB signaling pathway is known to induce skeletal muscle atrophy by inhibiting muscle protein synthesis and increasing protein breakdown. Activation of TNF-α/NF-κB signaling can also lead to upregulation of Fbxo32, which is significantly upregulated in skeletal muscle at day 3 post-respiratory SARS-CoV-2 infection. Therefore, the enrichment of this signaling pathway likely contributes to muscle atrophy.

Myalgia and fatigue are common side effects of IFN-α treatment in patients with hepatitis C, which can lead to chronic fatigue. Comparing with healthy controls, one study reported that the patients who developed chronic fatigue after IFN-α treatment showed high serum levels of IL-6 and TNF-α during but not after the treatment. The findings lead to speculation that although the type I and type II interferon responses are transient in skeletal muscle after the respiratory SARS-CoV-2 infection, the combination of the systemic interferon and TNF-α responses during acute infection might exert a synergistic impact on skeletal muscle and set the stage for chronic muscle fatigue. Importantly, the simultaneous upregulation of IFN-α, IFN-γ, and TNF-α was observed only in SARS-CoV-2-infected hamsters but not in IAV-infected hamsters. This difference might contribute, in part, to the different impact on mitochondrial oxidative function and the persistency of the abnormality. In support of this notion, the in vitro study showed that the treatment of C2C12 myotubes with combined IFN-γ and TNF-α but not IFN-γ or TNF-α alone markedly impaired mitochondrial oxidative function. Although the in vitro study did not demonstrate a significant impact of IFN-α on mitochondrial oxidative function, IFN-α might still play a role in vivo, as this response was also significantly upregulated by the acute SARS-CoV-2 infection. Future studies are needed to further elucidate the mechanisms. The findings suggest that targeting TNF-α during acute SARS-CoV-2 infection may be beneficial to the prevention or mitigation of persistent muscle fatigue. Drugs that can boost mitochondrial functions, enhance protein

synthesis, and inhibit protein degradation, may also be useful for treating muscle fatigue associated with long COVID.

The study has several limitations. The cohort is relatively small and may not have sufficient statistical power to detect all the abnormalities in skeletal muscle. Since no fresh specimens could be withdrawn from the BSL-3 laboratory for serum or tissue protein assays such as ELISA and Western blot, it was unable to assess serum cytokines or muscle proteins to correlate with the transcriptional changes in the hamsters. Many proteins that regulate skeletal muscle atrophy and energy metabolism are activated at the translational and post-translational levels, alterations of which cannot be detected by the transcriptional study. Nevertheless, the study is informative and may help guide future studies and therapy development. The hamster model appears valuable for future studies of muscle abnormalities associated with COVID-19 and long COVID, given the significant histopathological and transcriptional changes detected.

Supplementary Materials

The following supporting information can be downloaded: Figure S1: Robust expression of SARS-CoV-2 protein in the lung of a SARS-CoV-2 respiratory infected hamster at 3-days post-infection (dpi), but no positive expression at 30 dpi; Figure S2: Respiratory infection with SARS-CoV-2 but not IAV-induced skeletal muscle fiber atrophy; Figure S3: Respiratory SARS-CoV-2 infection does not impact the relative amount of mitochondrial DNA, mitochondrial biogenesis genes, or fusion and fission genes, but downregulates some mitophagy genes; Figure S4: Respiratory SARS-CoV-2 infection has mild effects on the expression of genes involved in glycolysis and amino acid metabolism; Figure S5: Limited effects of respiratory SARS-CoV-2 or IAV infection on the morphology of subsarcolemmal mitochondria; Figure S6: Type I and Type II interferon responses, TNF-α/NF-κB, and IL6/JAK/STAT3 are induced by SARS-CoV-2 infection at acute phase but not post-recovery phase in lungs; Figure S7: Limited effects of inflammatory cytokine treatments on expressions of some OXPHOS complex and ribosomal proteins in C2C12 myotubes; Table S1: qRT-PCR primer sequences; Table S2: Comparisons of morphometric and shape descriptors of subsarcolemmal mitochondria; Table S3: Comparisons of morphometric and shape descriptors of intermyofibrillar mitochondria; Data S1: Summary of Gene Set Enrichment Analysis (GSEA) results.

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