Loss ofPgc-1αexpression in aging mouse muscle potentiates glucose intolerance and systemic inflammation

Abstract

Diabetes risk increases significantly with age and correlates with lower oxidative capacity in muscle. Decreased expression of peroxisome proliferator-activated receptor-γ coactivator-1α ( Pgc-1α) and target gene pathways involved in mitochondrial oxidative phosphorylation are associated with muscle insulin resistance, but a causative role has not been established. We sought to determine whether a decline in Pgc-1α and oxidative gene expression occurs during aging and potentiates the development of age-associated insulin resistance. Muscle-specific Pgc-1α knockout (MKO) mice and wild-type littermate controls were aged for 2 yr. Genetic signatures of skeletal muscle (microarray and mRNA expression) and metabolic profiles (glucose homeostasis, mitochondrial metabolism, body composition, lipids, and indirect calorimetry) of mice were compared at 3, 12, and 24 mo of age. Microarray and gene set enrichment analysis highlighted decreased function of the electron transport chain as characteristic of both aging muscle and loss of Pgc-1α expression. Despite significant reductions in oxidative gene expression and succinate dehydrogenase activity, young mice lacking Pgc-1α in muscle had lower fasting glucose and insulin. Consistent with loss of oxidative capacity during aging, Pgc-1α and Pgc-1β expression were reduced in aged wild-type mouse muscle. Interestingly, the combination of age and loss of muscle Pgc-1α expression impaired glucose tolerance and led to increased fat mass, insulin resistance, and inflammatory markers in white adipose and liver tissues. Therefore, loss of Pgc-1α expression and decreased mitochondrial oxidative capacity contribute to worsening glucose tolerance and chronic systemic inflammation associated with aging.

PGC‐1α affects aging‐related changes in muscle and motor function by modulating specific exercise‐mediated changes in old mice

“…Glucose intolerance and increased blood pressure represent hallmarks of the age‐related metabolic syndrome (Hildrum, Mykletun, Hole, Midthjell, & Dahl, 2007). In line with the aggravated glucose intolerance in old mKO animals described previously (Sczelecki et al., 2014), we observed that absence of muscle PGC‐1α accelerated glucose intolerance during aging. Even though no overt amelioration in glucose tolerance was observed in the mTG mice, overexpression of muscle PGC‐1α abolished the age‐associated increase in blood pressure.…”

“…The age of 21 months as starting point was chosen based on the presarcopenic state of mice at that age, and to avoid a potential reduction in lifespan of the PGC‐1α knockout mice. While a number of effects of muscle‐specific gene ablation of PGC‐1α on muscle metabolism in aging have been demonstrated (Sczelecki et al., 2014), we now observed that reduced and elevated PGC‐1α levels accelerate and delay, respectively, broader aspects of muscle aging. Interestingly however, we also show that PGC‐1α modulation is not sufficient to fully control muscle aging as some age‐related muscle dysfunctions are not altered by deletion or overexpression of this coactivator.…”

“…We show here that even when performed only at old age, exercise is sufficient to prevent or even improve many age‐related deteriorations. While evidence has been presented that demonstrate a role for PGC‐1α modulation in the muscle metabolism and inflammation of old muscle‐specific knockout animals (Sczelecki et al., 2014), we now have studied the role of this coactivator in muscle aging in the context of exercise as well as both gain of function and loss of function. Most surprisingly, we observed a strong involvement of muscle PGC‐1α in the control of motor coordination and balance.…”

Habitual physical activity protects against lipopolysaccharide-induced inflammation in mouse adipose tissue

“…Similarly, loss of PGC-1a, albeit in muscle, potentiates the pro-inflammatory environment of aging. 46 Therefore, as VWR increased PGC-1a in both iWAT and eWAT, it is possible that this may have mediated some of the protective effects we see against LPS induced inflammation. Clearly further work is needed to elucidate the mechanisms through which prior physical activity protects against LPS-induced inflammation.…”

CB1 receptor blockade counters age‐induced insulin resistance and metabolic dysfunction

“…Numerous studies have linked aging with development of insulin resistance (Rowe et al ., 1983; O'Shaughnessy et al ., 1992; Sczelecki et al ., 2013). In accord with this, we report a marked reduction in the ability of insulin to phosphorylate/activate PKB at its two key regulatory sites Thr 308 (by 1.7‐fold; P  < 0.05) and Ser 473 (by 1.6 fold; P  < 0.05) in aged versus young soleus tissue (Fig.…”