A Possible Association of Elevated Delta-Like Protein 4 Concentration With Low Walking Speed and Low Handgrip Strength in Japanese Older Adults

Background

A recent study using mice showed that delta-like protein 4 (Dll4), a ligand released from the impaired vascular endothelium, can activate Notch receptor 2 signals in skeletal muscles, leading to muscle atrophy and dysfunction. However, it remains unclear whether circulating Dll4 is associated with ageing-related physical dysfunction in humans and sarcopenia diagnosed by both low muscle mass and low muscle strength.

Methods

We investigated the associations of serum Dll4 level as the main outcome with physical performance, muscle strength and muscle mass in 283 Japanese older adults defined as ≥ 65 years of age (men/women: 125/158, mean age: 75 ± 6 years) who received annual health checkups in the Tanno–Sobetsu Study, a population-based cohort.

Results

Dll4 concentration was negatively correlated with levels of high-density lipoprotein cholesterol (HDL-C) (r = −0.17, p = 0.01) and fasting glucose (r = −0.12, p = 0.048) and with walking speed (r = −0.14, p = 0.02) but not with handgrip strength (r = −0.04, p = 0.47) or appendicular skeletal muscle mass index (ASMI) (r = 0.01, p = 0.85). When subjects were divided by sex, Dll4 level was inversely correlated with walking speed (r = −0.17, p = 0.03) and handgrip strength (r = −0.17, p = 0.04) in women but not in men. Multivariable regression analysis after adjustment of age, sex, body mass index and levels of HDL-C and fasting glucose showed that walking speed (β = −0.15, p = 0.04) or handgrip strength (β = −0.24, p = 0.03) was independently associated with Dll4 level. Conversely, Dll4 level was independently associated with walking speed (β = −0.12, p = 0.03) or handgrip strength (β = −0.09, p = 0.03) but not ASMI (β = 0.06, p = 0.22) after adjustment of age, sex and body mass index as consistent confounders in exploratory analyses. There was no significant interaction between sex and Dll4 level for walking speed and handgrip strength. Furthermore, the addition of Dll4 level into the consistent confounders significantly improved discriminatory capacity for predicting low walking speed, but not low handgrip strength and low ASMI, in the integrated discrimination improvement and continuous net reclassification improvement.

Conclusions

A high serum level of Dll4 is independently associated with low walking speed and low muscle strength, but not low muscle atrophy, in Japanese older adults. Measurement of Dll4 level might be useful for ageing-associated physical performance assessed by walking speed.