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

Author:

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

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.

Funder

National Institute on Aging

U.S. Department of Veterans Affairs

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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