dFatp regulates nutrient distribution and long-term physiology in Drosophila.

Nutrient allocation and usage plays an important part in regulating the onset and progression of age-related functional declines. Here, we describe a heterozygous mutation in Drosophila (dFatp) that alters nutrient distribution and multiple aspects of physiology. dFatp mutants have increased lifespan and stress resistance, altered feeding behavior and fat storage, and increased mobility. Concurrently, mutants experience impairment of cardiac function. We show that endurance exercise reverses increased lipid storage in the myocardium and the deleterious cardiac function conferred by dFatp mutation. These findings establish a novel conserved genetic target for regulating lifespan and physiology in aging animals. These findings also highlight the importance of varying exercise conditions in assessing aging functions of model organisms.

Endurance training protocol and longitudinal performance assays for Drosophila melanogaster.

One of the most pressing problems facing modern medical researchers is the surging levels of obesity, with the consequent increase in associated disorders such as diabetes and cardiovascular disease (1-3). An important topic of research into these associated health problems involves the role of endurance exercise as a beneficial intervention. Exercise training is an inexpensive, non-invasive intervention with several beneficial results, including reduction in excess body fat (4), increased insulin sensitivity in skeletal muscle (5), increased anti-inflammatory and antioxidative responses (6), and improved contractile capacity in cardiomyocytes (7). Low intensity exercise is known to increase mitochondrial activity and biogenesis in humans (8) and mice, with the transcriptional coactivator PGC1-α as an important intermediate (9,10). Despite the importance of exercise as a tool for combating several important age-related diseases, extensive longitudinal genetic studies have been impeded by the lack of an endurance training protocol for a short-lived genetic model species. The variety of genetic tools available for use with Drosophila, together with its short lifespan and inexpensive maintenance, make it an appealing model for further study of these genetic mechanisms. With this in mind we have developed a novel apparatus, known as the Power Tower, for large scale exercise-training in Drosophila melanogaster (11). The Power Tower utilizes the flies' instinctive negative geotaxis behavior to repetitively induce rapid climbing. Each time the machine lifts, then drops, the platform of flies, the flies are induced to climb. Flies continue to respond as long as the machine is in operation or until they become too fatigued to respond. Thus, the researcher can use this machine to provide simultaneous training to large numbers of age-matched and genetically identical flies. Additionally, we describe associated assays useful to track longitudinal progress of fly cohorts during training.

The Drosophila PGC-1α homolog spargel modulates the physiological effects of endurance exercise.

Endurance exercise is an inexpensive intervention that is thought to provide substantial protection against several age-related pathologies, as well as inducing acute changes to endurance capacity and metabolism. Recently, it has been established that endurance exercise induces conserved alterations in physiological capacity in the invertebrate Drosophila model. If the genetic factors underlying these exercise-induced physiological alterations are widely conserved, then invertebrate genetic model systems will become a valuable tool for testing of genetic and pharmacological mimetics for endurance training. Here, we assess whether the Drosophila homolog of the vertebrate exercise response gene PGC-1α spargel (srl) is necessary or sufficient to induce exercise-dependent phenotypes. We find that reduction of srl expression levels acutely compromises negative geotaxis ability and reduces exercise-induced improvement in both negative geotaxis and time to exhaustion. Conversely, muscle/heart specific srl overexpression improves negative geotaxis and cardiac performance in unexercised flies. In addition, we find that srl overexpression mimics some, but not all, exercise-induced phenotypes, suggesting that other factors also act in parallel to srl to regulate exercise-induced physiological changes in muscle and heart.