Estrogen-related receptor signaling counters sarcopenia and preserves exercise fitness in naturally aged mice

Abstract

BackgroundEstrogen-related receptor gamma (ERR{gamma}) drives an exercise mimicking aerobic gene program in the skeletal muscle that could be beneficial in aging. We have investigated the effect of chronic ERR{gamma} activation on minimizing sarcopenia. MethodsExperiments were performed in muscle specific ERR{gamma} transgenic (TG) mice and wild type (WT) littermates, at young (4-5 months) and old (24-26 months) age. In the skeletal muscle, global gene expression changes, as well as myofiber histological changes in fiber type, size, vascular supply and neuromuscular junction (NMJ), and mitochondrial content were measured. Functional analysis was performed using in vivo muscle contraction assay. Exercise fitness was measured using treadmill sprint and endurance test. Gene and protein expression was measured using QPCR and Westerns, respectively. ResultsERR{gamma} activates a pan-ERR aerobic program in the skeletal muscle to increase expression of 574 genes including ERR, mitochondrial homeostasis (e.g. Mfn1, Opa1, Drp1, Fis1, and Tfam), vascularization (e.g. Vegfa, Angpt1, Fgf1), and neuromuscular junction (NMJ) (e.g. Nrp1, Aspa, Ptprm, Cxcr4), simultaneously suppressing the expression of atrophy related genes (e.g. Atrogin1, Traf6, Nedd4, Myd88, p21). ERR{gamma} increases mitochondrial content [Mitochondrial area: old TG vs. WT, 2.00 fold; young TG vs. WT, 1.32 fold], oxidative capacity [NADH-TR activity: old TG vs. WT, 1.20 fold; young TG vs. WT, 1.22 fold] and myofiber type [2a: old TG (687{+/-}258) vs. WT (252{+/-}71); young TG (797{+/-}168) vs. WT (440{+/-}76); 2x: old TG 1348{+/-}87 vs. WT 976{+/-}219; young TG 1131{+/-}135 vs. WT 936{+/-}84; 2b: old TG (798{+/-}103) vs. WT (1628{+/-}148); young TG (967{+/-}133) vs. WT (1623{+/-}189)], and capillarity [capillary-to-myofiber ratio: old TG (3.25{+/-}0.19) vs. WT (2.41{+/-}0.16); young TG (3.41{+/-}0.21) vs WT (2.59{+/-}0.2)] and [NMJ number [old TG (67{+/-}8) vs. WT (40{+/-}9); young TG (77{+/-}11) vs WT (77{+/-}7)], mitigating age-related loss of NMJ and myofiber cross-sectional area [old TG (1570{+/-}147{micro}m2) vs. WT (1692.5{+/-}208{micro}m2) WT; young TG (1828.15{+/-}132.8{micro}m2) vs. WT (2109.7{+/-}296.8{micro}m2)]. ERR{gamma} overexpression preserves muscle contractility with aging [Fatigue resistance: 22.72% reduction in force in old vs. young WT; 3.11% reduction in force between old vs. young TG]. Furthermore, ERR{gamma} maintains exercise fitness in old mice [Running: old TG (2964.52{+/-}405m) vs. old WT (910.75{+/-}6034m); young TG (2232.43{+/-}193.64m) vs. young WT (1366.76{+/-}60.76m)]. ConclusionsERR{gamma} drives a pan-ERR and counter sarcopenic gene program enhancing oxidative myofiber type, mitochondrial content, vasculature, and NMJ in aging muscle. Consequently, ERR{gamma} minimizes myofiber atrophy, preserves contractility, and improves exercise fitness in old mice. Therefore, ERRs are potential translational targets for combating sarcopenia.