Influenza A (H1N1) virus reduces anabolism and alters 2’O-rRNA methylation during the progression of muscle wasting

Influenza virus infections typically affect the respiratory system but can also cause weakness and muscle loss. Previous studies reported local muscle inflammation and increased proteasomal activity in Influenza A Virus (IAV) infected mice, but whether IAV infections compromise muscle anabolism remains undetermined. Propagating viruses need to hijack the host’s ribosomal machinery to preferentially translate viral mRNAs, therefore we determined whether systemic IAV infection-induced muscle wasting results in anabolic deficits by modifying ribosomal capacity and 2’O-rRNA methylation. Gastrocnemius muscle was collected from adult male and female C57BL/6 mice 3 or 8 days post infection (dpi) with a murine-adapted IAV. Expression of viral nucleocapsid proteins (NP), 45S pre-rRNA, variant-rDNA (v-rDNA), accessory factors of the RNA polymerase I (Pol I) regulon were assessed by qRT-PCR and vulnerable 2’O-methylation (2’O-me) sites were evaluated by RiboMethSeq. NP expression was detectable in both male and female IAV infected mice with significant expression as early as 3 dpi. Muscle atrophy was evident by loss in muscle mass at 3 and 8 dpi in males (20.8% and 33.8%, respectively, p< 0.05) and females (16.2% and 29.7%, respectively, p< 0.05) and was reflected in a corresponding 15.5% (males) and 31.2% (females) (p< 0.05) reduction in fCSA, at 8 dpi. Analysis of differentially expressed genes from bulk RNA-seq analysis revealed the upregulation of inflammatory and innate immune response genes at 3 dpi in both males and females (p< 0.05). At 8 dpi, the male and female networks displayed bidirectional regulation of genes involved in cytokine signaling, innate, and adaptive immune responses (p< 0.05). Reduction in rRNA demonstrate anabolic deficits in males at both 3 and 8 dpi (27.2% and 30.1%, respectively, p< 0.05), but a less dramatic loss in females (15.6% and 12.6%, effect sizes at 3 and 8 dpi (d=1.25 and 1.11), respectively). rDNA transcription was decreased in both males (44.6%) and females (45.6%) starting at 3 dpi (p< 0.05) and remained lower than respective control levels through 8 dpi (37.9% and 48.3%, respectively, p< 0.01). Expression of select Pol I accessory factors were upregulated in females at 8 dpi (p< 0.01), and v-rDNA expression showed divergent responses at both 3 and 8 dpi in males (p< 0.01) and females (p< 0.05). Profiling of 2’O-me sites revealed hypomethylation at 3 dpi (p< 0.05) in males and bidirectional alterations at 8 dpi (p< 0.05) near functional regions of the ribosome. Similarly, 2’O-me sites showed bidirectional changes at 3 dpi (p< 0.05) in females, but less sites were altered at 8 dpi (p< 0.05). Our study shows that systemic induction of IAV can productively infect skeletal muscle and cause atrophy. The resulting anabolic deficits suggest IAV disrupts ribosome homeostasis by reducing anabolism and by altering vulnerable 2’O-me in critical ribosomal regions. The present study was supported by the National Institutes of Health grant AR078430 to GAN. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.