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Muscle atrophy and weakness are among the most detrimental consequences of disuse, microgravity, hospitalisation and ageing. Oxidative modifications of myofibrillar proteins generated by oxidative stress may contribute to the reduced force- and power-generating capacity of skeletal muscles. As part of the 60-day AGBRESA bed rest (BR) study, we studied (1) how microgravity-induced disuse affected markers of systemic and muscle oxidative stress, (2) how these related to muscle function and (3) to what extent artificial gravity (AG) attenuated these changes. Since the myokine irisin may protect against muscle deterioration in disuse, we additionally assessed serum irisin levels. Sixteen men and eight women (33 ± 9 years) participated in the AGBRESA study. Participants were pseudorandomly assigned to a control group (BR only), or a continuous or intermittent centrifugation group (n = 8 in each group) to assess the efficacy of daily 30-min AG in attenuating the adverse effects of BR-induced disuse. Muscle function, muscle protein carbonyls, serum irisin and key modulators of oxidative stress and cell protection in muscle and blood were assessed before, on Day 6, and at the end of BR. BR caused a reduction in peak torque during maximal voluntary isometric knee extension and knee flexion (p < 0.001) that was greater in women than in men (knee extension, w: -39.7 ± 3.5%, m: -25.1 ± 2.4%; knee flexion, w: -32.9 ± 4.5%, m: -10.2 ± 3.5%, p ≤ 0.002) and faster electrically evoked twitch muscle contractions of plantar flexor and knee extensor muscles (half relaxation time and % peak rate of relaxation, p ≤ 0.003). AG attenuated the BR-induced increase in evoked twitch contraction speed in the knee extensors (group × time interactions: half relaxation time, p = 0.009; % peak rate of relaxation, p = 0.030), and the loss of evoked twitch peak torque of plantar flexors (AG - 25%, Controls -48%, group × time interactions, p = 0.020). Neither BR nor AG affected the circulating levels of systemic oxidative stress and muscle carbonyl concentration and serum irisin levels. However, participants with the highest serum irisin and brain-derived neurotrophic factor levels showed lower levels of 8-iso-PGF2α, a marker of systemic oxidative stress (r = -0.486, p = 0.019; r = -0.512, p = 0.012, respectively) and circulating levels of the C-terminal agrin fragment, a biomarker of neuromuscular junction fragmentation. AG exposure attenuated some of the BR-induced changes in twitch contractile properties. Neither BR nor AG induced significant alterations in systemic oxidative stress, or muscle protein carbonylation, suggesting that the main contribution to the BR-induced loss of muscle strength during the AGBRESA study was not oxidative stress. Show less

Sciatic nerve injury represents a prevalent and incapacitating condition characterized by denervation, muscular atrophy, and compromised functionality. The Protein Kinase B (PKB)/ Akt signaling cascade serves as a vital modulator of skeletal muscle hypertrophy, metabolic processes, and regenerative capabilities. Subsequent to sciatic nerve injury, the PI3K/Akt signaling pathway exhibits dysregulation, exacerbating muscle atrophy and hindering recovery processes due to feedback inhibition of PKB/Akt phosphorylation by mTORC1, which consequently increases the expression of E3 ubiquitin ligases and causes muscle atrophy. Additionally, a multitude of other variables, encompassing neurotrophic factors, intracellular calcium ion concentrations, carboxyl-terminal modulator proteins, connexins, and tumor necrosis factor-α, either exert regulatory influences on Akt or are subject to regulation by Akt in a multifaceted manner. Hence, this review discusses the complex role of the PI3K/Akt signaling pathway in skeletal muscle dynamics following sciatic nerve injury, emphasizing its regulatory mechanisms and downstream effectors, and highlights strategies to target this pathway to enhance muscle regeneration and restore functional capabilities. Show less