During the COVID-19 pandemic, diabetic and obese patients experienced higher rates of hospital admissions, severe illness, and mortality. However, vaccinations failed to provide those vulnerable populations the same level of protection against COVID-19 severity as those without diabetic and obese phenotypes. Our study aimed to investigate how diabetes mellitus (DM) impacts the immune response following vaccination including the artificially designed trimeric SARS-CoV-2 spike (S)-protein. By using two diabetic mouse models, ob/ob mice (obese, hyperglycemic, and insulin-resistant) and STZ-treated mice (insulin-deficient and hyperglycemic), we observed a significant reduction in S-protein-specific IgG antibody titer post-vaccination in both diabetic models compared to wild-type (WT) mice. Both diabetic mouse models exhibited significant abnormalities in spleen tissue, including marked reductions in splenic weight and the size of the white pulp regions. Furthermore, the splenic T-cell and B-cell zones were notably diminished, suggesting an underlying immune dysfunction that could contribute to impaired antibody production. Notably, vaccination with the S-protein, when paired with an optimal adjuvant, did not exacerbate diabetic cardiomyopathy, blood glucose levels, or liver function, providing reassurance about the vaccine′s safety. These findings offer valuable insights into potential mechanisms responsible for the decreased persistence of antibody production in diabetic patients.

Skeletal muscle atrophy underlies sarcopenia, frailty, and muscular dystrophies, but the molecular mechanisms linking oxidative stress to muscle degeneration remain incompletely understood. We previously identified protein complex formation between transient receptor potential canonical 3 (TRPC3) and NADPH oxidase 2 (Nox2) as a key driver of anthracycline-induced myocardial atrophy. Here, we investigated whether this complex also contributes to skeletal muscle wasting. In skeletal muscle from sciatic nerve transection model mice and Duchenne muscular dystrophy (mdx) mice, TRPC3-Nox2 complex formation was enhanced. TRPC3 deletion significantly attenuated denervation-induced soleus atrophy and reduced reactive oxygen species (ROS) production. TRPC3-Nox2 complex formation was upregulated in the soleus muscle (SM) of mdx mice. Pharmacological disruption of the TRPC3-Nox2 interaction improved muscle size and strength and reduced plasma creatine kinase in mdx mice. A recombinant adeno-associated virus (AAV) encoding a TRPC3 C-terminal peptide was used to suppress TRPC3-Nox2 complex formation in vivo. AAV-mediated expression of TRPC3 C-terminal peptide mitigated muscle wasting (CSA) in mdx mice, while muscle strength and plasma CK were not significantly improved. Thus, TRPC3-Nox2 complex formation may be a pivotal driver of oxidative stress-mediated skeletal muscle atrophy. Targeting this protein–protein interaction represents a promising therapeutic strategy for Duchenne muscular dystrophy (DMD) and other intractable muscle-wasting disorders.