Differentiation-dependent susceptibility of human muscle cells to Zika virus infection

Abstract

Muscle cells are potential targets of many arboviruses, such as Ross River, Dengue, Sindbis, and chikungunya viruses, that may be involved in the physiopathological course of the infection. During the recent outbreak of Zika virus (ZIKV), myalgia was one of the most frequently reported symptoms. We investigated the susceptibility of human muscle cells to ZIKV infection. Using an in vitro model of human primary myoblasts that can be differentiated into myotubes, we found that myoblasts can be productively infected by ZIKV. In contrast, myotubes were shown to be resistant to ZIKV infection, suggesting a differentiationdependent susceptibility. Infection was accompanied by a caspase-independent cytopathic effect, associated with paraptosis-like cytoplasmic vacuolization. Proteomic profiling was performed 24h and 48h post-infection in cells infected with two different isolates. Proteome changes indicate that ZIKV infection induces an upregulation of proteins involved in the activation of the Interferon type I pathway, and a downregulation of protein synthesis. This work constitutes the first observation of primary human muscle cells susceptibility to ZIKV infection, and differentiation-dependent restriction of infection from myoblasts to myotubes. Since myoblasts constitute the reservoir of stem cells involved in reparation/regeneration in muscle tissue, the infection of muscle cells and the viral-induced alterations observed here could have consequences in ZIKV infection pathogenesis.

Skeletal Muscle Is an Early Site of Zika Virus Replication and Injury, Which Impairs Myogenesis

“…In agreement with our findings, it was recently demonstrated that undifferentiated myoblast cells were more susceptible to ZIKV infection than are differentiated fibers ( 31 ). In neural tissues, ZIKV preferentially replicates in neural progenitor cells disrupting neurogenesis ( 32 – 34 ).…”

Key concepts in muscle regeneration: muscle “cellular ecology” integrates a gestalt of cellular cross-talk, motility, and activity to remodel structure and restore function

“…Notably, muscle regeneration is impaired in autoimmune myopathies that result from inflammatory cell activation by antibodies against signal-recognition protein or HMG-CoA reductase; the impairment, a defect in myoblast fusion and fiber formation, was associated with deficient levels of IL-4 and IL-13 (Arouche-Delaperche et al 2017 ). Thus, inflammation, its resolution and its etiology including direct muscle infection by viruses such as Zika, arboviruses, and SARS-CoV-2 (COVID-19) (Disser et al 2020 ; Filippone et al 2020 ; Legros et al 2020 ; Paliwal et al 2020 ), are important during regeneration.…”

Effects of Low Doses of L-Carnitine Tartrate and Lipid Multi-Particulate Formulated Creatine Monohydrate on Muscle Protein Synthesis in Myoblasts and Bioavailability in Humans and Rodents

“…We first assessed the effect of 2 combinations of CARN/Cr at 0.05 mM/0.05 mM or 0.1 mM/0.1 mM on muscle protein synthesis in human primary myoblasts. Myoblasts, although not fully differentiated, are growth-factor responsive and have been used in similar experiments previously [19][20][21].These doses were chosen based on the reported plasma levels for these compounds. We found that both combinations led to a significant increase in protein synthesis (Figure 1).…”