Effects of oral γ-aminobutyric acid intake on muscle regeneration in diabetic mice

Abstract

Though γ-aminobutyric acid (GABA) serves as the primary inhibitory neurotransmitter in the brain, its numerous biological activities in the periphery, including anti-inflammatory and antidiabetic functions, have been documented. In addition, GABA may be a mediator underlying effects of ketone bodies/ketogenic diets on muscle regeneration. Here, we investigated the effects of GABA on muscle regeneration in type 1 diabetes mouse models. Akita and wild-type (WT) mice were treated with GABA in drinking water for 6 wk, followed by cardiotoxin (CTX)-induced muscle injury. At 5 days postinjury, GABA treatment exhibited no effects on regenerating myofiber size in both WT and Akita mice. Unexpectedly, regenerating GABA-treated Akita muscles exhibited significantly increased embryonic myosin heavy chain (eMHC) expression and higher intramuscular macrophage content, suggesting delays in muscle regeneration and in elevated macrophage infiltration in diabetic muscles. Next, we determined if GABA treatment delayed the inflammatory process during muscle regeneration. Providing GABA in the drinking water during the peak inflammatory period (days 0-5 postinjury) resulted in a significantly greater amount of small regenerating myofibers and higher expressions of TNFα and eMHC in regenerating streptozotocin (STZ)-diabetic muscles, indicating delays in inflammation process and muscle regeneration in diabetes. Plasma GABA levels were found higher in GABA-treated STZ mice than in WT mice and negatively correlated with regenerating myofiber size. This delay in muscle regeneration in STZ-diabetic mice was abolished by a lower dose of GABA water that did not raise plasma GABA levels. Together, high doses of GABA intake during the early phases of muscle repair may delay regeneration.NEW & NOTEWORTHY With increasing evidence that ketogenic diets improve aspects of muscle health (e.g., insulin sensitivity and mitochondrial function), we hypothesized that supplementation with GABA-a key metabolite changed with ketogenic diets-would improve muscle recovery from injury. Unexpectedly, GABA supplementation during the early inflammatory phases of muscle regeneration delayed muscle repair in type 1 diabetes mice, possibly due to inflammation suppression. Further work is needed to ascertain the effective use of GABA supplementation, particularly following intense or damaging exercise.

Keywords: GABA; diabetes; ketogenic diet; ketone bodies; muscle regeneration.