Molecular basis for an attenuated mitochondrial adaptive plasticity in aged skeletal muscle

Vladimir Ljubicic,Giulia Uguccioni,Anna-Maria Joseph,David A Hood,Ayesha Saleem,Peter J Adhihetty,Julianna H Huang

doi:10.18632/aging.100083

Abstract

Our intent was to investigate the mechanisms driving the adaptive potential of subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria in young (6 mo) and senescent (36 mo) animals in response to a potent stimulus for organelle biogenesis. We employed chronic electrical stimulation (10 Hz, 3 h/day, 7 days) to induce contractile activity of skeletal muscle in 6 and 36 mo F344XBN rats. Subsequent to chronic activity, acute stimulation (1 Hz, 5 min) in situ revealed greater fatigue resistance in both age groups. However, the improvement in endurance was significantly greater in the young, compared to the old animals. Chronic muscle use also augmented SS and IMF mitochondrial volume to a greater extent in young muscle. The molecular basis for the diminished organelle expansion in aged muscle was due, in part, to the collective attenuation of the chronic stimulation-evoked increase in regulatory proteins involved in mediating mitochondrial protein import and biogenesis. Furthermore, adaptations in mitochondrial function were also blunted in old animals. However, chronic contractile activity evoked greater reductions in mitochondrially-mediated proapoptotic signaling in aged muscle. Thus, mitochondrial plasticity is retained in aged animals, however the magnitude of the changes are less compared to young animals due to attenuated molecular processes regulating organelle biogenesis.

Highlights

Adult skeletal muscle is a highly malleable tissue which can respond positively to pharmacological, environmental, and mechanical stimuli with remarkable adaptations
The TET/TAW was decreased by chronic contractile activity by approximately 20% in both age groups, while the +dF/dt was reduced by 40-50% in the young and old animals
We evaluated whether impaired adaptations in mitochondrial protein import machinery components in old animals would coincide with reduced functional rates of protein import into the organelle

Summary

Introduction

Adult skeletal muscle is a highly malleable tissue which can respond positively to pharmacological, environmental, and mechanical stimuli with remarkable adaptations. A characteristic example of adaptive muscle plasticity is mitochondrial biogenesis. Increased organelle synthesis occurs as the result of the functional coordination between nuclear, cytosolic, as well as mitochondrial domains [1]. During the induction of organelle biogenesis, stress-sensitive signaling molecules, such as AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK), communicate with downstream effectors including peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) that results in the transcriptional upregulation of nuclear genes encoding mitochondrial proteins [2,3,4]. Newly-synthesized proteins which are destined for the organelle, such as mitochondrial DNA (mtDNA) transcription factor A (Tfam) and apoptosisinducing factor (AIF), are directed to their specific mitochondrial sub-compartments by the mitochondrial protein import machinery (PIM). The PIM is comprised of translocase proteins of the outer mitochondrial membrane (TOM), as well as a similar complex within the inner membrane (TIM proteins).

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Conclusion