ADNP differentially interact with genes/proteins in correlation with aging: a novel marker for muscle aging

Abstract

Activity-dependent neuroprotective protein (ADNP) is essential for embryonic development with ADNP mutations leading to syndromic autism, coupled with intellectual disabilities and motor developmental delays. Here, mining human muscle gene-expression databases, we have investigated the association of ADNP transcripts with muscle aging. We discovered increased ADNP and its paralogue ADNP2 expression in the vastus lateralis muscle of aged compared to young subjects, as well as altered expression of the ADNP and the ADNP2 genes in bicep brachii muscle of elderly people, in a sex-dependent manner. Prolonged exercise resulted in decreased ADNP expression, and increased ADNP2 expression in an age-dependent manner in the vastus lateralis muscle. ADNP expression level was further correlated with 49 genes showing agedependent changes in muscle transcript expression. A high degree of correlation with ADNP was discovered for 24 genes with the leading gene/protein being NMNAT1 (nicotinamide nucleotide adenylyl transferase 1). Looking at correlations differentiating the young and the old muscles and comparing protein interactions revealed an association of ADNP with the cell division cycle 5-like protein (CDC5L), and an aging-muscle-related interactive pathway in the vastus lateralis. In the bicep brachii, very high correlation was detected with genes associated with immune functions as well as mitochondrial structure and function among others. Taken together, the results suggest a direct association of ADNP with muscle strength and implicate ADNP fortification in the protection against age-associated muscle wasting.

Age and Sex-Dependent ADNP Regulation of Muscle Gene Expression Is Correlated with Motor Behavior: Possible Feedback Mechanism with PACAP

“…Akap6, Foxp2 , and Myl9 showed the most abundant correlations across tissues, age, and sex ( Figure 2 A). Interestingly Nmnat1 , which was correlated before with ADNP expression in human muscle [ 19 ], showed a highly significant correlation with Adnp in the GC muscle in the youngest group of males ( Figure 2 A). Comparing males to females suggested a more significant Adnp transcript correlation effect in males.…”

“…Further referring to the mechanism, our original studies identified a high degree of correlation between ADNP and NMNAT1 in the human muscle [ 19 ]. Here, a high correlation was discovered between Adnp and Nmnat1 expression in the young male mouse muscle.…”

“…Thus, in the vastus lateralis ADNP is increased with aging in males and females, while ADNP2 is increased with aging in females only. In the bicep brachii muscles, ADNP is increased with aging only in males and not in females, while ADNP2 is increased with aging exclusively in females [ 19 ]. ADNP expression was highly correlated with 24 genes, with nicotinamide nucleotide adenylyl (NAD) transferase 1 (NMNAT1) being the leading gene/protein [ 19 ].…”

“…In the bicep brachii muscles, ADNP is increased with aging only in males and not in females, while ADNP2 is increased with aging exclusively in females [ 19 ]. ADNP expression was highly correlated with 24 genes, with nicotinamide nucleotide adenylyl (NAD) transferase 1 (NMNAT1) being the leading gene/protein [ 19 ]. As such, NMNAT1-associated regulation of NAD + salvage capacity in human skeletal muscle declines with aging, suggesting a causative or a compensatory role for ADNP content [ 20 ].…”

Tau, ADNP, and sex

“…Looking at neuromuscular diseases, those may be more prevalent in males, with tauopathy/ADNP and microtubule disruption playing a role (Ivashko-Pachima, Seroogy, et al, 2021;Kapitansky & Gozes, 2019;Kapitansky, Karmon, et al, 2020;.…”