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Abstract
Physical exercise can improve age-dependent decline in cognition, which in rodent is partly mediated by restoration of an age-dependent decline in neurogenesis. Exercise-inducible myokines in the circulation present a link in muscle-brain crosstalk. The transcription factor PGC-1α regulates the release of such myokines with neurotrophic properties into the circulation. We study how chronic muscular overexpression of PGC-1α could contribute to exercise-induced effects on hippocampal neurogenesis and if this effect could be enhanced in a running wheel paradigm. We used 3- and 11-month-old transgenic mice with overexpression of PGC-1α under the control of muscle creatinine kinase promoter (MCK-PGC-1α), which have a constitutively developed endurance muscle phenotype. Wild-type and MCK-PGC-1α mice were single housed with free access to running wheels. Four weeks of running in female animals increased the levels of newborn cells, immature neurons, and, for young animals, new mature neurons, compared to sedentary controls. However, no difference in these parameters was observed between wild-type and transgenic mice under sedentary or running conditions. Multiplex analysis of serum cytokines, chemokines, and myokines suggested several differences in serum protein concentrations between genotypes with musclin found to be significantly upregulated 4-fold in male MCK-PGC-1α animals. We conclude that constitutive muscular overexpression of PGC-1α, despite systemic changes and difference in serum composition, does not translate into exercise-induced effects on hippocampal neurogenesis, independent of the age of the animal. This suggests that chronic activation of PGC-1α in skeletal muscle is by itself not sufficient to mimic exercise-induced effects or to prevent decline of neurogenesis in aging.
Highlights
Physical exercise, especially aerobic exercise, can prevent and treat health conditions in many organs in the body
To determine if chronic PGC-1α activation in skeletal muscle could prevent age-dependent decline in neurogenesis or enhance levels of exercise-induced neurogenesis in aging, we study hippocampal neurogenesis in young and middle-aged MCK-PGC-1α female mice subjected to a running wheel paradigm
Western blot on gastrocnemius homogenate of middle-aged (7–10-month-old) sedentary animals show that MCK-PGC1α animals have around 4-fold increased PGC-1α levels in comparison to wild-type animals (t test with Welch correction, n = 3, p = 0.043; all female animals except for one male individual in WT sedentary; see Fig. 1 and Online Resource Supplementary Figure S1), whereas no difference was detected in gastrocnemius PGC-1α protein levels between genotypes after 4 weeks of voluntary running (t test with Welch correction, n = 3, p = 0.17)
Summary
Especially aerobic exercise, can prevent and treat health conditions in many organs in the body. Synaptic plasticity, and angiogenesis in the dentate gyrus of the hippocampus [3], in part mediated by an exercise-induced increase in neurotrophic factors in the brain It is still unclear how exercise can exert effects on the central nervous system (CNS), through signaling by factors in the circulation [4]. Adipose tissue, and liver secrete various molecules and vesicles into the circulation during exercise with systemic effects on metabolism [9] The effects of these secreted molecules have been thoroughly studied in peripheral tissues, but the effects of exercise-induced metabolic changes on structural and functional changes in the CNS as well as underlying signaling mechanisms are yet to be elucidated
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