Genes & Nutrition · 6 authors, 1 centre
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This study in Drosophila shows that exercise reverses high-salt-induced age-related decline in muscle and heart function by upregulating FOXO gene expression. Muscle-specific FOXO knockdown blocks the protective effects of exercise, while FOXO overexpression enhances them, primarily through FOXO/SOD and FOXO/PGC-1α/SDH pathways. The muscle FOXO gene is essential for exercise to counteract high-salt-induced mortality and age-related defects in skeletal muscle and heart.
**Background:** FOXO transcription factors are known regulators of aging, exercise adaptation, and tissue homeostasis. High-salt intake (HSI) accelerates age-related decline in skeletal muscle and heart function, while exercise (E) delays these effects. However, the specific role of muscle FOXO in mediating exercise's protective effects against HSI-induced damage was unclear. This study investigated whether muscle FOXO is required for exercise to counteract HSI-induced age-related defects in skeletal muscle, heart, and mortality in Drosophila.
**Methods:** The authors used the Mhc-GAL4/UAS system to generate muscle-specific FOXO overexpression (FOXO-OE) and FOXO RNAi (FOXO-RNAi) flies. Flies were fed either normal food or high-salt food (2% NaCl) starting at 2 days old. Exercise groups underwent 1.5 hours of daily exercise (5 days/week) for 5 weeks using a rotating vial system that leveraged negative geotaxis. Climbing ability was assessed by time to fatigue (TTF) and climbing index (CI) at 1, 3, 5, and 7 weeks. Heart function was measured via high-speed video recordings of exposed hearts, quantifying diastolic interval (DI), systolic interval (SI), heart period (HP), and fractional shortening (FS). ELISA assays measured FOXO, PGC-1α, SDH, SOD, and ROS levels. qRT-PCR quantified gene expression. Transmission electron microscopy (TEM) assessed myofibrillar and mitochondrial structure. Lifespan was tracked daily with 200–210 flies per group.
**Key Results:** In w1118 wild-type flies, HSI significantly decreased TTF and CI at 5 and 7 weeks (P<0.05 or P<0.01), while exercise significantly improved these measures in HSI flies (P<0.05 or P<0.01). HSI downregulated FOXO expression in skeletal muscle (P<0.01), and exercise upregulated it (P<0.01). In FOXO-RNAi flies, at 5 and 7 weeks, FOXO-RNAi significantly decreased TTF (P<0.05, P<0.01) and CI (P<0.05). Exercise did not significantly improve TTF or CI in aged (5-7 week) FOXO-RNAi-HSI flies (P>0.05). FOXO-RNAi significantly decreased FOXO, PGC-1α, SDH, SOD, and Mhc levels while increasing ROS (P<0.05 or P<0.01). In FOXO-RNAi-HSI flies, exercise did not significantly change any of these molecular markers (P>0.05). TEM showed FOXO-RNAi increased myofibrillary damage, and exercise did not reduce this damage. For heart function, FOXO-RNAi significantly reduced DI, HP, FS, FOXO, PGC-1α, SDH, and SOD (P<0.05 or P<0.01), and exercise did not significantly improve these parameters in FOXO-RNAi-HSI flies (P>0.05).
In FOXO-OE flies, FOXO-OE significantly increased TTF and CI at 5 and 7 weeks (P<0.05). HSI did not significantly change TTF or CI in FOXO-OE flies at any age (P>0.05). Exercise further significantly increased TTF and CI in FOXO-OE and FOXO-OE-HSI flies (P<0.05 or P<0.01). FOXO-OE significantly increased FOXO, PGC-1α, SDH, SOD, and Mhc levels while decreasing ROS (P<0.05 or P<0.01). In FOXO-OE-HSI flies, exercise significantly increased FOXO, PGC-1α, SDH, SOD, and Mhc and decreased ROS (P<0.05 or P<0.01). TEM showed FOXO-OE reduced myofibrillary damage and exercise provided additional protection. For heart function, FOXO-OE significantly increased FS, FOXO, PGC-1α, SDH, and SOD (P<0.05 or P<0.01). HSI did not significantly change these parameters in FOXO-OE flies (P>0.05). Exercise significantly improved cardiac parameters in FOXO-OE and FOXO-OE-HSI flies (P<0.05 or P<0.01).
Lifespan analysis showed FOXO-RNAi significantly shortened lifespan vs. controls (P<0.01), and HSI further shortened it (P<0.001). Exercise did not significantly improve lifespan in FOXO-RNAi-HSI flies (P>0.05). FOXO-OE significantly prolonged lifespan (P<0.05), but HSI still shortened it (P<0.001). Exercise significantly extended lifespan in FOXO-OE-HSI flies (P<0.05).
**Clinical Implications:** This study demonstrates that muscle FOXO is a critical molecular mediator of exercise's protective effects against high-salt-induced aging of skeletal muscle and heart. The FOXO/SOD and FOXO/PGC-1α/SDH pathways are identified as key mechanisms. These findings suggest that interventions targeting FOXO activation in muscle could potentially counteract the detrimental effects of high dietary salt on muscle and cardiac aging. However, as a Drosophila study, direct translation to human clinical practice requires further investigation. The finding that FOXO overexpression alone could not resist HSI-induced lifespan shortening, but exercise combined with FOXO overexpression did, highlights the importance of systemic exercise adaptations beyond local FOXO activation.