Bile Acid Metabolism Affects Muscle Regeneration in Aging Skeletal Muscle in a Manner Associated with Regulation of ABCB1 Expression

TL;DR

This study shows how bile acid metabolism in aging muscle affects muscle regeneration through changes in ABCB1 transporter activity, offering a new target for treating sarcopenia.

Contribution

The study identifies a novel 'bile acid–MMEC–muscle' axis in sarcopenia involving miR-135a-5p and ABCB1 regulation.

Findings

Elevated DCA and LCA levels and reduced TUDCA levels in aging muscle correlate with downregulated ABCB1 expression.

ABCB1 inhibition in MMECs impairs bile acid efflux, promotes inflammation, and harms endothelial health.

miR-135a-5p directly regulates ABCB1 and mediates myoblast dysfunction through bile acid efflux impairment.

Abstract

The role of bile acid metabolism within the skeletal muscle microenvironment in sarcopenia remains unclear. This study investigated bile acid alterations and the function of the ATP Binding Cassette Subfamily B Member 1 (ABCB1) transporter in muscle microvascular endothelial cells (MMECs) during aging. Using a sarcopenic mouse model stratified by muscle density, we found elevated deoxycholic acid (DCA) and lithocholic acid (LCA) levels but reduced tauroursodeoxycholic acid (TUDCA) levels in muscle, correlating with downregulated ABCB1/P-glycoprotein expression. In vitro, inhibition of ABCB1 in MMECs impaired bile acid efflux, promoted inflammation, and compromised endothelial health. Conditioned medium from these MMECs reduced the viability, proliferation, and differentiation of C2C12 myoblasts, downregulated myogenic factors, and increased atrophy markers. Furthermore, we identified miR-135a-5p as a direct upstream regulator of ABCB1 in MMECs, and demonstrated that it mediates bile acid efflux impairment and subsequent myoblast dysfunction. Our findings reveal a novel “bile acid–MMEC–muscle” axis in sarcopenia, where miR-135a-5p-mediated ABCB1 downregulation in MMECs disrupts the local bile acid milieu and impairs muscle regeneration, highlighting ABCB1 as a potential therapeutic target for aging-related muscle loss.

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