Glucose 6‐P dehydrogenase delays the onset of frailty by protecting against muscle damage

Abstract

Background Frailty is a major age‐associated syndrome leading to disability. Oxidative damage plays a significant role in the promotion of frailty. The cellular antioxidant system relies on reduced nicotinamide adenine dinucleotide phosphate (NADPH) that is highly dependent on glucose 6‐P dehydrogenase (G6PD). The G6PD‐overexpressing mouse (G6PD‐Tg) is protected against metabolic stresses. Our aim was to examine whether this protection delays frailty. Methods Old wild‐type (WT) and G6PD‐Tg mice were evaluated longitudinally in terms of frailty. Indirect calorimetry, transcriptomic profile, and different skeletal muscle quality markers and muscle regenerative capacity were also investigated. Results The percentage of frail mice was significantly lower in the G6PD‐Tg than in the WT genotype, especially in 26‐month‐old mice where 50% of the WT were frail vs. only 13% of the Tg ones (P < 0.001). Skeletal muscle transcriptomic analysis showed an up‐regulation of respiratory chain and oxidative phosphorylation (P = 0.009) as well as glutathione metabolism (P = 0.035) pathways in the G6PD‐Tg mice. Accordingly, the Tg animals exhibited an increase in reduced glutathione (34.5%, P < 0.01) and a decrease on its oxidized form (−69%, P < 0.05) and in lipid peroxidation (4‐HNE: −20.5%, P < 0.05). The G6PD‐Tg mice also showed reduced apoptosis (BAX/Bcl2: −25.5%, P < 0.05; and Bcl‐xL: −20.5%, P < 0.05), lower levels of the intramuscular adipocyte marker FABP4 (−54.7%, P < 0.05), and increased markers of mitochondrial content (COX IV: 89.7%, P < 0.05; Grp75: 37.8%, P < 0.05) and mitochondrial OXPHOS complexes (CII: 81.25%, P < 0.01; CIII: 52.5%, P < 0.01; and CV: 37.2%, P < 0.05). Energy expenditure (−4.29%, P < 0.001) and the respiratory exchange ratio were lower (−13.4%, P < 0.0001) while the locomotor activity was higher (43.4%, P < 0.0001) in the 20‐month‐old Tg, indicating a major energetic advantage in these mice. Short‐term exercise training in young C57BL76J mice induced a robust activation of G6PD in skeletal muscle (203.4%, P < 0.05), similar to that achieved in the G6PD‐Tg mice (142.3%, P < 0.01). Conclusions Glucose 6‐P dehydrogenase deficiency can be an underestimated risk factor for several human pathologies and even frailty. By overexpressing G6PD, we provide the first molecular model of robustness. Because G6PD is regulated by pharmacological and physiological interventions like exercise, our results provide molecular bases for interventions that by increasing G6PD will delay the onset of frailty.

Effect of Physical Activity/Exercise on Oxidative Stress and Inflammation in Muscle and Vascular Aging

“…Frailty is the consequence of the interaction between the aging process and some chronic diseases and conditions that are prevalent in the elderly [ 7 ]. This clinical syndrome is characterized by a progressive decline in multiple body systems that are associated with high vulnerability to stressors, which results in a dysregulation of multiple physiological systems [ 8 ], including skeletal muscle and the cardiovascular system [ 9 , 10 ]. The musculoskeletal system plays a key role in the decline in muscle strength and functional capacity in the older people.…”

G6PD Deficiency Is Crucial for Insulin Signaling Activation in Skeletal Muscle

“…All these results illustrated that even though the expression of G6PD decreased during myogenesis, it is not a necessary factor for skeletal muscle formation. To date, the role of G6PD deficiency in skeletal muscle is unclear, and most research focused on skeletal muscle damage [34,35]. Our study provides explicit evidence for the function of G6PD on myogenic formation.…”

Glucose 6-P Dehydrogenase Overexpression Improves Aging-Induced Endothelial Dysfunction in Aorta from Mice: Role of Arginase II

“…The overexpression of G6PD has been reported to be protective in the development of some age-associated conditions in mice, such as insulin resistance, neuromuscular impairment, lower DNA oxidation levels and frailty [ 48 , 49 ]. G6PD is the first and rate-limiting enzyme of the pentose phosphate pathway.…”