Reduced Levels of NAD in Skeletal Muscle and Increased Physiologic Frailty Are Associated With Viral Coinfection in Asymptomatic Middle-Aged Adults

Abstract

Background: People living with HIV (PLWH) are disproportionately burdened with multimorbidity and decline in physiologic function compared with their uninfected counterparts, but biological mechanisms that differentially contribute to the decline in muscle function in PLWH compared with uninfected people remain understudied. Setting: The study site was Brigham and Women's Hospital, Harvard Medical School, Boston, MA. Methods: We evaluated skeletal muscle tissue for levels of total nicotinamide adenine dinucleotide (NAD), NAD + , and nicotinamide adenine dinucleotide (NADH) in middle-aged asymptomatic PLWH, coinfected with hepatitis C virus and/or cytomegalovirus and compared them with uninfected control participants. Results: Of the 54 persons with muscle biopsy data, the mean age was 57 years with 33% women. Total NAD levels declined in skeletal muscle in association with HIV infection and was exacerbated by hepatitis C virus and cytomegalovirus coinfection, with lowest levels of total NAD, NAD + , and NADH among persons who were coinfected with all 3 viruses ( P = 0.015, P = 0.014, and P = 0.076, respectively). Levels of total NAD, NAD + , and NADH in skeletal muscle were inversely associated with inflammation ( P = 0.014, P = 0.013, and P = 0.055, respectively). Coinfections were also associated with measures of inflammation (CD4/CD8 ratio: P < 0.001 and sCD163: P < 0.001) and immune activation (CD38 and human leukocyte antigen-DR expression on CD8 T cells: P < 0.001). In addition, coinfection was associated with increased physiologic frailty based on the Veteran Aging Cohort Study 1.0 index assessment ( P = 0.001). Conclusions: Further research is warranted to determine the clinical relevance of preclinical deficits in NAD metabolites in skeletal muscle in association with viral coinfection and inflammation, as well as the observed association between viral coinfection and physiologic frailty.

Macrodomain Mac1 of SARS-CoV-2 Nonstructural Protein 3 Hydrolyzes Diverse ADP-ribosylated Substrates

“…NAD + is a mediator of both anti-viral and anti-inflammatory responses, which is involved in protein-protein interactions and served as a marker of energy (38,39), play a crucial role in fueling enzymatic activity to support host immune regulation and responses (40). Lower concentrations of NAD + were found in human peripheral blood leukocytes infected with HIV-1 in vitro, human fibroblast herpes simplex virus 1, and skeletal muscle of patients with HIV-1 and hepatitis C (41)(42)(43). Parallel to these, there is increasing of evidence showing decreased concentration of nicotinamide mononucleotide (NMN), an NAD + precursor, in patients with severe COVID-19 symptoms compared to healthy subjects (44).…”

Emerging Role of Nicotinamide Riboside in Health and Diseases

“…Multiple independent lines of evidence point to NAD + metabolism as a potential target of intervention. Viral infections are known to cause cellular NAD + depletion [ 103 , 104 ]. Indeed, declined levels of NMN, an NAD + precursor, have been detected in the blood of COVID-19 patients [ 105 ].…”

NAD+ Precursors: A Physiological Reboot?

“…The burden of another severe syndrome caused by SARS-CoV-2 infection and associated with acute respiratory syndrome has also been related to disturbances in NAD+ metabolism. Supporting this, NAD+ depletion is a common feature in certain viral infections [14,15]. Sharma C. et al [11] also linked the NAD+ depletion in target SARS-CoV-2infected tissues to the overexpression of PARPs, a class of NAD+-consuming enzymes [16], and the potential benefits of emerging NAD+-increasing approaches as relevant adjuvant therapy to alleviate the severity of COVID-19.…”