Mitochondrial Transplantation's Role in Rodent Skeletal Muscle Bioenergetics: Recharging the Engine of Aging

Abstract

Background: Mitochondria are the 'powerhouses of cells' and progressive mitochondrial dysfunction is a hallmark of aging in skeletal muscle. Although different forms of exercise modality appear to be beneficial to attenuate aging-induced mitochondrial dysfunction, it presupposes that the individual has a requisite level of mobility. Moreover, non-exercise alternatives (i.e., nutraceuticals or pharmacological agents) to improve skeletal muscle bioenergetics require time to be effective in the target tissue and have another limitation in that they act systemically and not locally where needed. Mitochondrial transplantation represents a novel directed therapy designed to enhance energy production of tissues impacted by defective mitochondria. To date, no studies have used mitochondrial transplantation as an intervention to attenuate aging-induced skeletal muscle mitochondrial dysfunction. The purpose of this investigation, therefore, was to determine whether mitochondrial transplantation can enhance skeletal muscle bioenergetics in an aging rodent model. We hypothesized that mitochondrial transplantation would result in sustained skeletal muscle bioenergetics leading to improved functional capacity.

Methods: Fifteen female mice (24 months old) were randomized into two groups (placebo or mitochondrial transplantation). Isolated mitochondria from a donor mouse of the same sex and age were transplanted into the hindlimb muscles of recipient mice (quadriceps femoris, tibialis anterior, and gastrocnemius complex).

Results: The results indicated significant increases (ranging between ~36% and ~65%) in basal cytochrome c oxidase and citrate synthase activity as well as ATP levels in mice receiving mitochondrial transplantation relative to the placebo. Moreover, there were significant increases (approx. two-fold) in protein expression of mitochondrial markers in both glycolytic and oxidative muscles. These enhancements in the muscle translated to significant improvements in exercise tolerance.

Conclusions: This study provides initial evidence showing how mitochondrial transplantation can promote skeletal muscle bioenergetics in an aging rodent model.

Keywords: endurance; energy production; exercise physiology.

Figure 1

Results of the incremental treadmill test, prior to, 3 weeks after, and 6 Weeks after mitochondrial transplantation (mean ± SEM; n = 7 to 8 mice per group). Note: MT: mitochondrial transplantation.

Figure 2

Basal cytochrome c oxidase activity and [ATP] in the quadriceps femoris muscle (A). High-resolution complex I-related in-gel activity assay reveals no significant changes in supercomplex composition in aged mouse quadriceps muscle following mitochondrial injection. The gel was incubated with a complex I substrate, and the violet bands indicate complex I in-gel activity (B). (C) is the quantitative representation of supercomplex from panel (B). SC denotes supercomplex, while I denotes monomeric complex I. Each lane represents an individual sample from a different mouse (mean ± SEM).

Figure 3

Representative western blots and quantification for key mitochondrial markers for the soleus and plantaris muscles. Loading control for target proteins were normalized to α-tubulin (mean ± SEM; n = 5–8 per group).

Figure 3

Representative western blots and quantification for key mitochondrial markers for the soleus and plantaris muscles. Loading control for target proteins were normalized to α-tubulin (mean ± SEM; n = 5–8 per group).

Figure 4

Epigenetic results for the quadriceps femoris muscles for NFe2L2, PPAGC-1β, SIRT3, and TFAM. No significant (p > 0.05) mean differences between groups (mean ± SEM; n = 7 to 8 mice per group).