Skip to main page content
U.S. flag
See More

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2009 Dec 1;106(48):20405-10.
doi: 10.1073/pnas.0911570106. Epub 2009 Nov 16.

Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging

Tina Wenz  1 , Susana G Rossi, Richard L Rotundo, Bruce M Spiegelman, Carlos T Moraes
Affiliations

Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging

Tina Wenz et al. Proc Natl Acad Sci U S A. .

Erratum in

  • Proc Natl Acad Sci U S A. 2014 Nov 4;111(44):15851

Retraction in

Abstract

Aging is a major risk factor for metabolic disease and loss of skeletal muscle mass and strength, a condition known as sarcopenia. Both conditions present a major health burden to the elderly population. Here, we analyzed the effect of mildly increased PGC-1alpha expression in skeletal muscle during aging. We found that transgenic MCK-PGC-1alpha animals had preserved mitochondrial function, neuromuscular junctions, and muscle integrity during aging. Increased PGC-1alpha levels in skeletal muscle prevented muscle wasting by reducing apoptosis, autophagy, and proteasome degradation. The preservation of muscle integrity and function in MCK-PGC-1alpha animals resulted in significantly improved whole-body health; both the loss of bone mineral density and the increase of systemic chronic inflammation, observed during normal aging, were prevented. Importantly, MCK-PGC-1alpha animals also showed improved metabolic responses as evident by increased insulin sensitivity and insulin signaling in aged mice. Our results highlight the importance of intact muscle function and metabolism for whole-body homeostasis and indicate that modulation of PGC-1alpha levels in skeletal muscle presents an avenue for the prevention and treatment of a group of age-related disorders.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Increased PGC-1α expression in skeletal muscle prevents age-associated weight gain and improves exercise capacity during aging. (A) Comparison of mice expressing the PGC-1α transgene in skeletal muscle (MCK-PGC-1α) and wild-type littermates (control) at different ages. (B and C) Lean and fat mass of 22-month-old wild-type and PGC-1α animals as determined by DEXA scans (n = 6 for each group). *, P > 0.05. (D) Relative hindlimb mass of 22-month-old wild-type and PGC-1α animals (n = 6 for each group). *, P > 0.001. (E) Treadmill performance test at different ages for wild-type and PGC-1α animals (n = 9 for each group). *, P > 0.001. In this and all subsequent figures, error bars represent SD.
Fig. 2.
Fig. 2.
Increased PGC-1α expression in skeletal muscle preserves OXPHOS function on organelle basis and increases overall OXPHOS capacity. (A and B) Relative COX activity in skeletal muscle mitochondria (A) and muscle homogenates (B) at different ages (n = 9 for each mouse group). *, P < 0.05, **, P < 0.001. (C and D) Western blot of NDUFA9, flavoprotein (Fp), COXI, ATPase β, VDAC1, and α-tubulin in skeletal muscle mitochondria (C) and muscle homogenates (D) of 3- and 22-month-old mice. (E) Histology of biceps femoris muscle from MCK-PGC-1α and wild-type control mice at 3 and 22 months showing succinate dehydrogenase (SDH), COX, and combined COX/SDH activity staining. (F and G) Levels of serum lactate and skeletal muscle ATP before and after exercise (n = 3 for each mouse group). *, P < 0.05, **, P < 0.001.
Fig. 3.
Fig. 3.
Increased PGC-1α expression during aging results in increased anti-oxidant response, lowered inflammatory markers, and preserved muscular structure. (A) Immunohistochemistry of mice biceps femoris using anti-8-OH-guanosine antibody to detect oxidative damage to nucleic acids. (B) Western blot of SOD2, HSP70, and VDAC1 in skeletal muscle mitochondria. (C) Catalase activity in muscle mitochondria (n = 9 for each group). *, P < 0.001. (D) Quantification of regenerating fibers in biceps femoris based on the number of fibers with centered nuclei (Fig. S3C) (n = 6 for each group). *, P < 0.05. (E) Level of inflammatory markers in skeletal muscle (n = 9 for each group). *, P < 0.01. (F) Western blot of p65-NFκB and α-tubulin in skeletal muscles homogenates of 3- and 22-month-old mice. (G) NMJs stained with Alexa-555 α-bungarotoxin to label AChR and Alexa-488 Fasciculin2 to label AChE to visualize the NMJ. (H) Sucrose gradient profiles of AChE activity show the different oligomeric forms of AChE expressed in young and older animals. G1, G2, and G4 are the globular monomeric, dimeric, and tetrameric AChE forms, respectively. A8 and A12 indicate the positions of the asymmetric collagen tailed synaptic forms.
Fig. 4.
Fig. 4.
Increased PGC-1α levels in aging muscle prevent degradative processes (A) Immunohistochemistry of biceps femoris using anti-active caspase 3 antibody to detect apoptosis. (B) Apoptotic index in skeletal muscle homogenates of wild-type and MCK-PGC-1α of different age-groups based on nucleosome fragmentation (n = 6 for each group). *, P < 0.05, **, P < 0.01, ***, P < 0.001. (C) Western blot of Bax and Bcl-2 in skeletal muscle homogenates. (D) Western blot of the 20S subunit of the proteasome and tubulin in skeletal muscle homogenates. (E) Western blot of LC3-I and LC3-II in skeletal muscle homogenates.
Fig. 5.
Fig. 5.
Increased PGC-1α expression in skeletal muscle during aging improves insulin signaling and vascularization, resulting in improved glucose and insulin tolerance. (A) Glucose tolerance test in 22-month-old wild-type and MCK-PGC-1α animals (n = 9 for each group). *, P < 0.05, **, P < 0.01. (B) Insulin tolerance test in 22-month-old animals (n = 9 for each group). *, P < 0.05, **, P < 0.01, ***, P < 0.001. (C) Quantification of circulating triglyceride levels (n = 9 for each group). *, P < 0.01. (D) Western blot of pAkt/Akt, pmTOR/mTOR, and tubulin in skeletal muscle homogenates.
See this image and copyright information in PMC

References

    1. Dela F, Kjaer M. Resistance training, insulin sensitivity and muscle function in the elderly. Essays Biochem. 2006;42:75–88. - PubMed
    1. Rolland Y, et al. Sarcopenia: Its assessment, etiology, pathogenesis, consequences and future perspectives. J Nutr Health Aging. 2008;12:433–450. - PMC - PubMed
    1. Marcell TJ. Sarcopenia: Causes, consequences, and preventions. J Gerontol A Biol Sci Med Sci. 2003;58:M911–M916. - PubMed
    1. Marzetti E, Anne Lees H, Eva Wohlgemuth S, Leeuwenburgh C. Sarcopenia of aging: Underlying cellular mechanisms and protection by calorie restriction. Biofactors. 2009;35:28–35. - PMC - PubMed
    1. Taaffe DR. Sarcopenia—Exercise as a treatment strategy. Aust Fam Physician. 2006;35:130–134. - PubMed

Publication types

Substances