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. 2022 Jul 30;13(8):1368.
doi: 10.3390/genes13081368.

Ablation of Ghrelin Receptor Mitigates the Metabolic Decline of Aging Skeletal Muscle

Colleen O'Reilly  1 , Ligen Lin  2   3 , Hongying Wang  4 , James Fluckey  1 , Yuxiang Sun  2   4
Affiliations

Ablation of Ghrelin Receptor Mitigates the Metabolic Decline of Aging Skeletal Muscle

Colleen O'Reilly et al. Genes (Basel). .

Abstract

The orexigenic hormone ghrelin has multifaceted roles in health and disease. We have reported that ablation of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), protects against metabolic dysfunction of adipose tissues in aging. Our further observation interestingly revealed that GHS-R deficiency phenocopies the effects of myokine irisin. In this study, we aim to determine whether GHS-R affects the metabolic functions of aging skeletal muscle and whether GHS-R regulates the muscular functions via irisin. We first studied the expression of metabolic signature genes in gastrocnemius muscle of young, middle-aged and old mice. Then, old GHS-R knockout (Ghsr-/-) mice and their wild type counterparts were used to assess the impact of GHS-R ablation on the metabolic characteristics of gastrocnemius and soleus muscle. There was an increase of GHS-R expression in skeletal muscle during aging, inversely correlated with the decline of metabolic functions. Remarkedly the muscle of old GHS-R knockout (Ghsr-/-) mice exhibited a youthful metabolic profile and better maintenance of oxidative type 2 muscle fibers. Furthermore, old Ghsr-/- mice showed improved treadmill performance, supporting better functionality. Also intriguing to note was the fact that old GHS-R-ablated mice showed increased expression of the irisin precursor FNDC5 in the muscle and elevated plasma irisin levels in circulation, which supports a potential interrelationship between GHS-R and irisin. Overall, our work suggests that GHS-R has deleterious effects on the metabolism of aging muscle, which may be at least partially mediated by myokine irisin.

Keywords: GHS-R; aging; irisin; skeletal muscle.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Relative mRNA expression in gastrocnemius muscle during aging. Young (4–5 m), middle-aged (12–14 m) and old (18–26 m) male C57BL/6 J mice were used. (a) Relative mRNA expression of mitochondrial functional markers of UCP3, SIRT1 and PGC-1α; (b) relative gene expression of glucose transporter marker GLUT and insulin signaling marker IRS1; (c) relative gene expression of GHS-R. 18s and β-actin house-keeping genes were used as internal controls in qPCR analysis. One-way ANOVA analysis was used to compare middle-aged or old mice to young mice. Data are presented as means ± standard error. (n = 6). * p < 0.05, ** p < 0.001, middle-aged or old mice vs. young mice.
Figure 2
Figure 2
Effects of GHS-R ablation on metabolic dysfunction of aging muscle. Gastrocnemius muscle was from old (18–26 m) WT (open bar) and Ghsr−/− (black bar) mice. (a) UCP3, PGC-1α and ACC1 mRNA expression. (b) Lipid content in gastrocnemius muscle. (c) Relative expression of IRS1 and GLUT4 in gastrocnemius muscle. 18s and β-actin house-keeping genes were used as internal controls in qPCR analysis. Two-tailed Student’s t-tests were completed, and data are presented as means ± standard error (n = 9). * p < 0.05, ** p < 0.001, Ghsr−/−. vs. WT.
Figure 3
Figure 3
Effects of GHS-R ablation on protein markers of metabolic functions in aging muscle. Gastrocnemius muscle of old (18–26 m) WT (open bar, n = 4) and Ghsr−/− (black bar, n = 3) mice is shown. (a) Activation of AMPK and ACC expressed as phosphorylated to total protein ratios. (b) Total Protein expression of UCP3 and Glut 4 in gastrocnemius muscle. (c) Representative images for AMPK, ACC, UCP3 and Glut 4. Two-tailed Student’s t-tests were performed, and data are presented as means ± standard error.
Figure 4
Figure 4
Expression of myosin heavy chain subtypes and treadmill work output of old Ghsr−/− mice. Old (16–24 m) WT (open bar) and Ghsr−/− (closed bar) mice were used in this set of experiments. (a) Relative mRNA expression of myosin heavy chain in gastrocnemius (n = 9). (b) Relative mRNA expression of myosin heavy chain in soleus muscle (n = 6). (c) Protein expression of myosin heavy chain isoforms of MHC-IIa and MHC-IIb relative to total Myosin heavy chain expression in old WT (n = 4) and Ghsr−/− (n = 3) mice. (d) Treadmill test—time, distance and work of old WT and Ghsr−/− mice (n = 10). S: seconds of time; m: meters of distance; mxg: work performed during treadmill. 18s and β-actin house-keeping genes were used as internal controls in qPCR analysis. Two-tailed Student’s t-test were performed, and data are presented as means ± standard error. * p < 0.05, ** p < 0.001, Ghsr−/−. vs. WT.
Figure 5
Figure 5
FNDC5 expression in gastrocnemius muscle and plasma irisin in the circulation. (a) FNDC5 mRNA expression in young (4–5 m), middle-aged (12–14 m) and old (18–26 m) WT mice (n = 6). (b) FNDC5 mRNA expression in gastrocnemius muscle of old WT (open bar) and Ghsr−/− (filled bar) mice. (c) Plasma irisin levels in old WT (open bar) and Ghsr−/− (filled bar) mice. 18s and β-actin house-keeping genes were used as internal controls in qPCR analysis. One-way ANOVA was performed in (a) and Student’s t-tests were performed for (b) and (d). Data are presented as means ± standard error. * p < 0.05, ** p < 0.001, middle-aged or old mice vs. young mice, or Ghsr−/−. vs. WT.
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