Role of muscle FOXO gene in exercise against the skeletal muscle and cardiac age-related defects and mortality caused by high-salt intake in Drosophila

Abstract

FOXO has long been associated with aging, exercise, and tissue homeostasis, but it remains unclear what the role is of the muscle FOXO gene in E against high-salt intake(HSI)-induced age-related defects of the skeletal muscle, heart, and mortality. In this research, overexpression and RNAi of the FOXO gene in the skeletal and heart muscle of Drosophila were constructed by building Mhc-GAL4/FOXO-UAS-overexpression and Mhc-GAL4/FOXO-UAS-RNAi system. The skeletal muscle and heart function, the balance of oxidation and antioxidant, and mitochondrial homeostasis were measured. The results showed that exercise reversed the age-related decline in climbing ability and downregulation of muscle FOXO expression induced by HSI. Muscle-specific FOXO-RNAi (FOXO-RNAi) and -overexpression (FOXO-OE) promoted or slowed the age-related decline in climbing ability, heart function, and skeletal muscle and heart structure damage, which was accompanied by the inhibition or activation of FOXO/PGC-1α/SDH and FOXO/SOD pathway activity, and oxidative stress (ROS) increased or decreased in both skeletal muscle and heart. The protective effect of exercise on the skeletal muscle and heart was blocked by FOXO-RNAi in aged HSI flies. FOXO-OE prolonged its lifespan, but it did not resist the HSI-induced lifespan shortening. Exercise did not improve HSI-induced lifespan shortening in FOXO-RNAi flies. Therefore, current results confirmed that the muscle FOXO gene played a vital role in exercise against age-related defects of the skeletal muscle and heart induced by HSI because it determined the activity of muscle FOXO/SOD and FOXO/PGC-1α/SDH pathways. The muscle FOXO gene also played an important role in exercise against HSI-induced mortality in aging flies.

Xbp1 targets canonical UPRER and non-canonical pathways in separate tissues to promote longevity

“… 25 , 28 Indeed, Xbp1 s induction causes a transcriptome change similar to that caused by Aop activation and Pnt inhibition in the fat body ( Data S1 ). Our current work, as well as that of others, 29 , 30 , 44 adds Srl as another TF whose activity in the fat body promotes longevity, and which is transcriptionally activated by Xbp1 s and dFOXO. These 5 TFs are likely engaged in a transcriptional network in the Drosophila fat body, one that can impact whole animal longevity and whose further study may contribute to our understanding of regulatory networks that underly the plasticity of animal physiology.…”

Physical exercise ameliorates age‐related deterioration of skeletal muscle and mortality by activating Pten‐related pathways in Drosophila on a high‐salt diet

“…For instance, long‐term HSD is associated with an increase in age‐related hypertension, 22,23 an increase in age‐related cardiac hypertrophy, 24,25 and a significantly increased risk of stroke in older adults 26 . In flies, a HSD can lead to age‐related decline in climbing and cardiac function, and the molecular mechanism is related to increased oxidative stress, up‐regulated salt gene expression, and inhibition of Sir2/FOXO related pathways 27–29 . However, it remains unclear whether the Pten gene and its related pathways are involved in exercise against age‐related deterioration in skeletal muscle induced by a HSD.…”

“…Sirt1 is the upstream regulator of PGC‐1α, and its deacetylation can activate PGC‐1α protein 34 . Overexpression or knockdown of Sirt1 and PGC‐1α gene delayed or promoted cardiac aging and muscle aging by reducing or increasing age‐related oxidative stress and contractility debility 28,35–38 . Excessive oxidative stress impaired the function of skeletal muscle and heart, and it promoted age‐related deterioration of skeletal muscle and heart and reduced the lifespan of Drosophila 39–41 .…”

“…Exercise as a health promotion strategy can effectively improve aging and a HSD‐induced sarcopenia, high blood pressure, and heart disease 3,16,44–46 . In flies, a HSD induces the age‐related decline in climbing ability, heart function, and skeletal muscle and heart structure damage, and it also reduces the lifespan of flies, and its molecular mechanism is related to FOXO pathway, salt gene expression, and oxidative stress 16,27,28 . However, the molecular mechanism of salt‐induced age‐related sarcopenia and the mechanism of exercise against salt‐induced age‐related sarcopenia remain unclear.…”

“…Normal expression and overexpression of CG9940 have positive effects on cardiac function, motor capacity, and life‐adaptive exercise of aging flies, while low expression of CG9940 has negative effects on motor capacity and life‐adaptive exercise of aging flies 55 . Exercise reverses the age‐related decline in climbing ability and downregulation of muscle FOXO expression induced by a HSD via upregulating FOXO/PGC‐1α/SDH and FOXO/SOD pathway activity and decreasing ROS in both skeletal muscle and heart, but the protective effect of exercise on the skeletal muscle and heart was blocked by FOXO knockout in aged flies 28 . Moreover, miR‐17‐3p promotes cardiomyocyte hypertrophy, proliferation, and survival.…”