Abstract
Exercise is believed to be beneficial for skeletal muscle functions across all ages. Regimented exercise is often prescribed as an effective treatment/prophylaxis for age-related loss of muscle mass and function, known as sarcopenia, and plays an important role in the maintenance of mobility and functional independence in the elderly. However, response to exercise declines with aging, resulting in limited gain of muscle strength and endurance. These changes likely reflect age-dependent alterations in transcriptional response underlying the muscular adaptation to exercise. The exact changes in gene expression accompanying exercise, however, are largely unknown, and elucidating them is of a great clinical interest for understanding and optimizing the exercise-based therapies for sarcopenia. In order to characterize the exercise-induced transcriptomic changes in aged muscle, a paired-end RNA sequencing was performed on rRNA-depleted total RNA extracted from the gastrocnemius muscles of 24 months-old mice after 8 weeks of regimented exercise (exercise group) or no formal exercise program (sedentary group). Differential gene expression analysis of aged skeletal muscle revealed upregulations in the group of genes involved in neurotransmission and neuroexcitation, as well as equally notable absence of anabolic gene upregulations in the exercise group. In particular, genes encoding the transporters and receptor components of glutaminergic transmission were significantly upregulated in exercised muscles, as exemplified by Gria 1, Gria 2 and Grin2c encoding glutamate receptor 1, 2 and 2C respectively, Grin1 and Grin2b encoding N-methyl-d-aspartate receptors (NMDARs), Nptx1 responsible for glutaminergic receptor clustering, and Slc1a2 and Slc17a7 regulating synaptic uptake of glutamate. These changes were accompanied by an increase in the post-synaptic density of NMDARs and acetylcholine receptors (AChRs), as well as their innervation at neuromuscular junctions (NMJs). These results suggest that neural responses predominate the adaptive response of aged skeletal muscle to exercise, and indicate a possibility that glutaminergic transmission at NMJs may be present and responsible for synaptic protection and neural remodeling accompanying the exercise-induced functional enhancement in aged skeletal muscle. In addition, the absence of upregulations in the anabolic pathways highlights them as the area of potential pharmacological targeting for optimizing exercise-led sarcopenia therapy.