Optimizing autophagy to counteract aging-induced muscle deterioration in mice - some pharmacological agents alleviate aging-induced loss of muscle mass and function (i.e., sarcopenia) when…

Optimizing autophagy to counteract aging-induced muscle deterioration in mice - some pharmacological agents alleviate aging-induced loss of muscle mass and function (i.e., sarcopenia) when prescribed as a single-mode therapy, but combining them with exercise has produced frustrating outcomes. Thus, identifying a pharmacological agent that enhances exercise benefits is an unmet need in this field. Our long-term goal is to uncover crucial mechanisms of sarcopenia to identify effective therapeutic strategies to prevent, stop, or reverse the progression of this muscle degenerative condition. IT is postulated that because there is an accumulation of autophagic substrates, including protein aggregates and dysfunctional mitochondria in aging muscles, autophagic activity is decreased. The mechanism by which autophagy is suppressed in aging muscles remains poorly understood. The golgi-associated plant pathogenesis-related protein 1 (gapr-1) is a potent negative regulator of autophagy. Gapr-1 suppresses autophagy by physically interacting with BECLIN1, a protein inducing autophagy. Since fine autophagy regulation is required for maintaining muscle mass and function, the central hypothesis is that combining TAT-BECLIN1, a specific autophagy agonist disrupting BECLIN1/gapr-1 interaction, may enhance endurance exercise benefits in aging muscles. The hypothesis will be tested with two specific aims. 1) define the role of gapr-1 in sarcopenia; and 2) determine the efficacy of combining TAT-BECLIN1 with endurance exercise in halting sarcopenia progression in aging mice. In aim 1, in vivo muscle gene transfer by electroporation to overexpress or knockdown gapr-1 into tibialis anterior will be applied to determine whether gapr-1 regulates sarcopenia in 24- month-old mice of both sexes. In vivo muscle contractility assays, comprehensive biochemical and morphology phenotype will be examined. Under aim 2, a combination of TAT-BECLIN1 with endurance exercise will be applied in 22-month-old mice of both sexes for four months. Functional, biochemical, morphological, and molecular (i.e., proteomics) will be assessed. This proposal is innovative because IT centers on uncovering a new molecular mechanism contributing to sarcopenia and testing TAT-BECLIN1 as a pharmacological agent enhancing exercise benefits in aging muscles by optimizing autophagy. The proposal is significant because IT addresses a relevant and poorly understood area of muscle biology, and IT could put into development a new therapeutic approach to tackle sarcopenia.