E01 Short term step-reduction induces mitochondrial impairments which are not restored after reambulation, in habitually active adults

Abstract

Inactivity causes physiological impairments to skeletal muscle mitochondria and disrupts metabolic homeostasis, which has predominantly been investigated through models of severe disuse. The impacts of less-restrictive inactivity through step-reduction (SR) suggests a decline in markers of mitochondrial content without a loss of function (Edwards et al. [2021]. J Appl Physiol, 131, 1653-1662). However, the impact of varying durations of SR and reambulation (RA) on skeletal muscle oxidative capacity are poorly understood. Therefore, this study aimed to investigate the effects of 14 days of SR, followed by 14 days of RA on markers of mitochondrial content and function, and also explore correlations between these markers. A cohort of 12 habitually active adults were studied from previous research (Bowden Davies et al. [2018]. Diabetologica, 61, 1282-1294), for which ethical approval was obtained from NRES Committee North West – Liverpool Central (REC:14/NW/1147). Skeletal muscle biopsy samples from the vastus lateralis were obtained at baseline (BSL), after SR and following RA, which were analysed through immunoblotting/calorimetric assays for markers of mitochondrial content (citrate synthase (CS) activity) and function (OXPHOS, PDH and CPT1A). In vivo mitochondrial function tests using 31P magnetic resonance spectroscopy (31P-MRS) was conducted in a subset of 7 participants. Markers of mitochondrial content and function were significantly reduced following SR (15-34% lower; low to medium effect size 0.3-0.5; COX I (P = 0.009), COX III (P = 0.03), COX IV (P = 0.03), 31P-MRS (P = 0.04)). COX III (P = 0.01) and 31P-MRS (P = 0.03) were lower after RA when compared to BSL. Although not significant, other markers of mitochondrial content and enzymes involved in glucose and fatty acid oxidation were numerically lower after SR (CS activity 17% lower, PDH 23% lower, CPT1A 15% lower). The changes in several complexes of OXPHOS, PDH and CPT1A were positively correlated with CS activity (r2= 0.35 to 0.53, P < 0.05) and 31P-MRS (r2 = 0.46 to 0.76, P < 0.05). The results suggest that a short term reduction in physical activity causes impairments to both mitochondrial content and function which are not completely restored after RA, although further studies are needed to understand the mechanisms that underpin these changes. The findings highlight the deleterious physiological consequences of just reducing physical activity, which manifests as metabolic diseases such as type 2 diabetes in the long run. This prompts for the revision of physical activity guidelines to include the importance of minimising sedentary time.