Deletion of Neuronal CuZnSOD Accelerates Age-Associated Muscle Mitochondria and Calcium Handling Dysfunction That Is Independent of Denervation and Precedes Sarcopenia.

Yu Su,Meixiang Huang,Carol S Davis,Dennis R Claflin,Susan V Brooks,Holly Van Remmen,Arlan Richardson,Peter C D Macpherson

doi:10.3390/ijms221910735

Abstract

Skeletal muscle suffers atrophy and weakness with aging. Denervation, oxidative stress, and mitochondrial dysfunction are all proposed as contributors to age-associated muscle loss, but connections between these factors have not been established. We examined contractility, mitochondrial function, and intracellular calcium transients (ICTs) in muscles of mice throughout the life span to define their sequential relationships. We performed these same measures and analyzed neuromuscular junction (NMJ) morphology in mice with postnatal deletion of neuronal Sod1 (i-mn-Sod1-/- mice), previously shown to display accelerated age-associated muscle loss and exacerbation of denervation in old age, to test relationships between neuronal redox homeostasis, NMJ degeneration and mitochondrial function. In control mice, the amount and rate of the decrease in mitochondrial NADH during contraction was greater in middle than young age although force was not reduced, suggesting decreased efficiency of NADH utilization prior to the onset of weakness. Declines in both the peak of the ICT and force were observed in old age. Muscles of i-mn-Sod1-/- mice showed degeneration of mitochondrial and calcium handling functions in middle-age and a decline in force generation to a level not different from the old control mice, with maintenance of NMJ morphology. Together, the findings support the conclusion that muscle mitochondrial function decreases during aging and in response to altered neuronal redox status prior to NMJ deterioration or loss of mass and force suggesting mitochondrial defects contribute to sarcopenia independent of denervation.

Highlights

Aging is associated with loss of skeletal muscle mass and impairments in function that are major contributors to frailty in the elderly [1,2]
We recently showed that postnatal deletion of Sod1 from motor neurons (i-mn-Sod1-/mice) resulted in an acceleration of age-associated muscle atrophy such that most muscles examined showed reduced mass by middle age, while in old age, denervation was more extensive in i-mn-Sod1-/- mice than controls [14]
1B), muscles of i-mn-Sod1 mice showed an earlier decline, largely intact neuromuscular junctions (NMJ) morphology with unbroken pretzel-like arrangements of acetylcholine receptors and no significant loss of overlap between pre- and post-synaptic structures (Figure 6B–D). These findings indicate that the age-associated defects in mitochondrial function and calcium handling observed in middle-aged i-mn-Sod1-/- and control mice develop at an age when there was no evidence of NMJ deterioration or denervation

Summary

Introduction

Aging is associated with loss of skeletal muscle mass and impairments in function that are major contributors to frailty in the elderly [1,2]. Postnatal deletion of Sod from only neurons results in accelerated age-associated loss of muscle mass and force and more extensive denervation at advanced age compared with wild type (WT) mice [14]. These studies suggest a model in which loss of redox homeostasis in motor neurons triggers NMJ degeneration and denervation leading to impaired mitochondrial function and muscle atrophy and weakness, but this sequence of events has not been directly examined

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Discussion

Conclusion