Functional effects of muscle PGC-1alpha in aged animals

Springer Science and Business Media LLC - Tập 10 Số 1 - 2020
Steven Yang1, Emanuele Loro2, Shogo Wada1, Boa Kim1, Wei‐Ju Tseng3, Kristina Li1, Tejvir S. Khurana2, Zoltàn Arany1
1Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
2Department of Physiology and Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
3Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Tóm tắt

AbstractPGC-1 (peroxisome-proliferator-activated receptor-γ coactivator-1) alpha is a potent transcriptional coactivator that coordinates the activation of numerous metabolic processes. Exercise strongly induces PGC-1alpha expression in muscle, and overexpression of PGC-1alpha in skeletal muscle activates mitochondrial oxidative metabolism and neovascularization, leading to markedly increased endurance. In light of these findings, PGC-1alpha has been proposed to protect from age-associated sarcopenia, bone loss, and whole-body metabolic dysfunction, although these findings have been controversial. We therefore comprehensively evaluated muscle and whole-body function and metabolism in 24-month-old transgenic mice that over-express PGC-1alpha in skeletal muscle. We find that the powerful effects of PGC-1alpha on promoting muscle oxidative capacity and protection from muscle fatigability persist in aged animals, although at the expense of muscle strength. However, skeletal muscle PGC-1alpha does not prevent bone loss and in fact accentuates it, nor does it have long-term benefit on whole-body metabolic composition or insulin sensitivity. Protection from sarcopenia is seen in male animals with overexpression of PGC-1alpha in skeletal muscle but not in female animals. In summary, muscle-specific expression of PGC-1alpha into old age has beneficial effects on muscle fatigability and may protect from sarcopenia in males, but does not improve whole-body metabolism and appears to worsen age-related trabecular bone loss.

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Tài liệu tham khảo

Kelly DP, Scarpulla RC. Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev Cold Spring Harbor Laboratory Press. 2004;18:357–68.

Puigserver P, Spiegelman BM. Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α): transcriptional coactivator and metabolic regulator. Endocr Rev Narnia. 2003;24:78–90.

Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell Cell Press. 1999;98:115–24.

Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM. A Cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell Cell Press. 1998;92:829–39.

Koo S-H, Satoh H, Herzig S, Lee C-H, Hedrick S, Kulkarni R, et al. PGC-1 promotes insulin resistance in liver through PPAR-α-dependent induction of TRB-3. Nat Med Nature Publishing Group. 2004;10:530–4.

Arany Z, He H, Lin J, Hoyer K, Handschin C, Toka O, et al. Transcriptional coactivator PGC-1α controls the energy state and contractile function of cardiac muscle. Cell Metab Cell Press. 2005;1:259–71.

Lin J, Wu P-H, Tarr PT, Lindenberg KS, St-Pierre J, Zhang C-Y, et al. Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell Elsevier. 2004;119:121–35.

Baar K, Wende AR, Jones TE, Marison M, Nolte LA, Chen M, et al. Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. FASEB J Federation of American Societies for Experimental Biology. 2002;16:1879–86.

Koves TR, Li P, An J, Akimoto T, Slentz D, Ilkayeva O, et al. Peroxisome proliferator-activated receptor-γ co-activator 1α-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency. J Biol Chem American Society for Biochemistry and Molecular Biology. 2005;280:33588–98.

Norrbom J, Sundberg CJ, Ameln H, Kraus WE, Jansson E, Gustafsson T. PGC-1α mRNA expression is influenced by metabolic perturbation in exercising human skeletal muscle. J Appl Physiol American Physiological Society. 2004;96:189–94.

Lin J, Wu H, Tarr PT, Zhang C-Y, Wu Z, Boss O, et al. Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres. Nature Nature Publishing Group. 2002;418:797–801.

Calvo JA, Daniels TG, Wang X, Paul A, Lin J, Spiegelman BM, et al. Muscle-specific expression of PPARγ coactivator-1α improves exercise performance and increases peak oxygen uptake. J Appl Physiol American Physiological Society. 2008;104:1304–12.

Arany Z, Foo S-Y, Ma Y, Ruas JL, Bommi-Reddy A, Girnun G, et al. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1α. Nature Nature Publishing Group. 2008;451:1008–12.

Chinsomboon J, Ruas J, Gupta RK, Thom R, Shoag J, Rowe GC, et al. The transcriptional coactivator PGC-1α mediates exercise-induced angiogenesis in skeletal muscle. Proc Natl Acad Sci National Academy of Sciences. 2009;106:21401–6.

Rowe GC, Raghuram S, Jang C, Nagy JA, Patten IS, Goyal A, et al. PGC-1α induces SPP1 to activate macrophages and orchestrate functional angiogenesis in skeletal muscle. Circ Res NIH Public Access. 2014;115:504.

Chan MC, Rowe GC, Raghuram S, Patten IS, Farrell C, Arany Z. Post-natal induction of PGC-1α protects against severe muscle dystrophy independently of utrophin. Skelet Muscle. 2014;4:2.

Wenz T, Rossi SG, Rotundo RL, Spiegelman BM, Moraes CT. Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging. Proc Natl Acad Sci U S A National Academy of Sciences. 2009;106:20405–10.

Gill JF, Santos G, Schnyder S, Handschin C. PGC-1α affects aging-related changes in muscle and motor function by modulating specific exercise-mediated changes in old mice. Aging Cell. 2018;17:e12697.

Glatt V, Canalis E, Stadmeyer L, Bouxsein ML. Age-related changes in trabecular architecture differ in female and male C57BL/6 J Mice. J Bone Miner Res. John Wiley & Sons, Ltd; 2007;22:1197–1207.

Loro E, Ramaswamy G, Chandra A, Tseng W-J, Mishra MK, Shore EM, et al. IL15RA is required for osteoblast function and bone mineralization. Bone NIH Public Access. 2017;103:20–30.

Kim H, Wrann CD, Jedrychowski M, Vidoni S, Kitase Y, Nagano K, et al. Irisin mediates effects on bone and fat via αV integrin receptors. Cell. Elsevier; 2018;175:1756-1768.e17.

Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature Nature Publishing Group. 2012;481:463–8.

Choi CS, Befroy DE, Codella R, Kim S, Reznick RM, Hwang Y-J, et al. Paradoxical effects of increased expression of PGC-1 on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism. Proc Natl Acad Sci. 2008;105:19926–31.

Summermatter S, Shui G, Maag D, Santos G, Wenk MR, Handschin C. PGC-1α improves glucose homeostasis in skeletal muscle in an activity-dependent manner. Diabetes American Diabetes Association. 2013;62:85–95.

Colaianni G, Cuscito C, Mongelli T, Pignataro P, Buccoliero C, Liu P, et al. The myokine irisin increases cortical bone mass. Proc Natl Acad Sci U S A National Academy of Sciences. 2015;112:12157–62.

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