Aberrant mitochondrial homeostasis in the skeletal muscle of sedentary older adults

Abstract

The role of mitochondrial dysfunction and oxidative stress has been extensively characterized in the aetiology of sarcopenia (aging-associated loss of muscle mass) and muscle wasting as a result of muscle disuse. What remains less clear is whether the decline in skeletal muscle mitochondrial oxidative capacity is purely a function of the aging process or if the sedentary lifestyle of older adult subjects has confounded previous reports. The objective of the present study was to investigate if a recreationally active lifestyle in older adults can conserve skeletal muscle strength and functionality, chronic systemic inflammation, mitochondrial biogenesis and oxidative capacity, and cellular antioxidant capacity. To that end, muscle biopsies were taken from the vastus lateralis of young and age-matched recreationally active older and sedentary older men and women (N = 10/group; female symbol = male symbol). We show that a physically active lifestyle is associated with the partial compensatory preservation of mitochondrial biogenesis, and cellular oxidative and antioxidant capacity in skeletal muscle of older adults. Conversely a sedentary lifestyle, associated with osteoarthritis-mediated physical inactivity, is associated with reduced mitochondrial function, dysregulation of cellular redox status and chronic systemic inflammation that renders the skeletal muscle intracellular environment prone to reactive oxygen species-mediated toxicity. We propose that an active lifestyle is an important determinant of quality of life and molecular progression of aging in skeletal muscle of the elderly, and is a viable therapy for attenuating and/or reversing skeletal muscle strength declines and mitochondrial abnormalities associated with aging.

Figure 1. A sedentary lifestyle exacerbates functional decline and systemic inflammation in the elderly.

(A) Maximal isometric torque (N.m) in young, AO, and SO subjects. Each point represents an individual who underwent strength testing as described in the methods. (B) Walk test and timed stair-climb test in AO and SO subjects as described in the methods. (C) CRP levels (ng.mg of protein⁻¹) in the vastus lateralis of young, AO, and SO subjects (N = 10/group; ♀  =  ♂). Asterisk denotes significant changes vs. young, and dagger denotes significant changes vs. AO (P≤0.05).

Figure 2. Mitochondrial biogenesis and COX activity are impaired in frail old.

(A) PGC-1α, CS, COX subunits- I, II, and IV, and phospho-GSK3β (Ser⁹) protein content, (B) citrate synthase and (C) mitochondrial complex IV activity (nmol.min⁻¹.mg of protein⁻¹) in the vastus lateralis of young, AO, and SO subjects (N = 10/group; ♀  =  ♂). (D) Mitochondrial complex IV activity (nmol.min⁻¹.mg of protein⁻¹) positively correlates (r = 0.77) with maximal isometric torque (N.m). Asterisk denotes significant changes vs. young, dagger denotes significant changes vs. AO, and double dagger denotes significant changes vs. both young and AO (P≤0.05).

Figure 3. Mitochondrial Mn-SOD activity is reduced in frail old.

(A) Mn-SOD protein content and (B) total- and Mn- SOD activity (U.mg of protein⁻¹) in the vastus lateralis of young, AO, and SO subjects (N = 10/group; ♀  =  ♂). Asterisk denotes significant changes vs. young, and dagger denotes significant changes vs. AO (P≤0.05).

Figure 4. Reduced Mn-SOD activity is due to tyrosine nitration in frail old.

(A) Mn-SOD was immunoprecipitated (IP) followed by immunoblotting (IB) for Mn-SOD nitrotyrosine content and (B) nNOS protein content in the vastus lateralis of young, AO, and SO subjects (N = 10/group; ♀  =  ♂). Asterisk denotes significant changes vs. young, and dagger denotes significant changes vs. AO (P≤0.05).