PGC-1α (PPARGC1A)

PGC-1α is the master transcriptional coactivator for mitochondrial-biogenesis. It is intrinsically disordered, carries no enzymatic activity of its own, and instead functions as a scaffold that recruits HAT complexes and mediator components to nuclear-receptor target genes. Its activity is exquisitely tuned by post-translational modification — particularly the competing actions of SIRT1 (deacetylation; activating) and KAT2A (acetylation; repressing) — making it a central node where energy status is translated into mitochondrial gene expression. PGC-1α activity declines with age in muscle and brain, a change linked to accumulated acetylation as SIRT1 activity falls, and the resulting mitochondrial insufficiency contributes to the mitochondrial-dysfunction hallmark.

Identity

UniProt: Q9UBK2 (PRGC1_HUMAN), Swiss-Prot (manually curated), accessed 2026-05-05
Gene / HGNC symbol: PPARGC1A / HGNC:9237
NCBI Gene ID: 10891
Mouse ortholog: Ppargc1a (one-to-one ortholog)
GenAge entry: ID 256 — included on the basis of vascular aging acceleration in Ppargc1a knockout mice (telomere dysfunction, DNA damage, atherosclerosis)
Length: 798 amino acids (canonical isoform 1; human)
Molecular weight: ~91 kDa
Structure: Intrinsically disordered; no solved full-length crystal structure. The protein lacks a folded globular core; activity is mediated through linear binding motifs that dock onto ordered partner surfaces.

Isoforms: At least 10 isoforms arising from alternative promoter usage and alternative splicing. The most studied are:

Isoform	Distinguishing feature	Primary tissue
Isoform 1 (canonical)	Full-length, 798 aa	Broad; BAT, muscle, liver
PGC-1α2 / PGC-1α3	Exercise-specific alternative N-terminus	Skeletal muscle
PGC-1α4	Truncated; promotes hypertrophy, not mitochondrial biogenesis	Skeletal muscle
Liver-specific (isoform 9)	Alternative first exon	Liver

The isoform distinction matters for exercise biology: PGC-1α2, -3, and -4 are preferentially induced by exercise in mouse skeletal muscle and have distinct downstream programs. needs-human-replication — isoform-specific responses in human muscle are less fully characterized.

Domain architecture

PGC-1α has a modular organization that can be read left-to-right as “activation — regulatory — RNA processing”:

Region (approx.)	Name	Function
~1–200	N-terminal activation domain (AD)	Recruits [[cbp-p300
~144–148	LxxLL motif (NR box)	Nuclear receptor interaction interface (docks onto ligand-binding domains of PPARs, ERRs, etc.)
~200–400	Serine/arginine-rich regulatory region	Harbors many of the GCN5-targeted acetylation sites; conformational changes regulate partner access
~400–600	Central region	Additional regulatory elements; contains the major Akt phosphorylation site (S570 per Li 2007)
~677–753	RNA recognition motif (RRM)	RNA binding; role in splicing regulation of target pre-mRNAs
~753–798	RS-rich C-terminus	Splicing factor-like domain; connects to SR-protein network

Note on CBP/p300 as a PGC-1α HAT: The N-terminal AD recruits CBP/p300, and CBP/p300 binding to PGC-1α has been observed. However, direct acetylation of PGC-1α by CBP/p300 has not been demonstrated in the primary literature for the functionally defined acetylation sites (Rodgers 2005 identifies GCN5 as the writer; see PTM section below). This attribution should be treated as inferential ¹. See cbp-p300 for the verifier finding on this point (2026-05-05).

Discovery

PGC-1α was identified in 1998 by Puigserver et al. (Spiegelman lab, Dana-Farber Cancer Institute) in a yeast-two-hybrid screen for proteins interacting with PPARγ in brown adipose tissue (BAT) ². The original finding: PGC-1α was cold-inducible, strongly expressed in BAT, and its overexpression in white fat cells drove a broad thermogenic gene-expression program (UCP1, OXPHOS subunits, mtDNA replication machinery), establishing it as a master regulator of adaptive thermogenesis. The pathway from cold → β-adrenergic → cAMP → CREB → Pgc-1α transcription → NRF1/TFAM → mtDNA replication was worked out over subsequent years.

Substrate and coactivation network

PGC-1α does not bind DNA directly. It docks onto sequence-specific transcription factors already sitting at target promoters and amplifies their activity by recruiting HAT complexes and mediator. Key coactivation partners:

Partner TF	Downstream program	Primary tissue context
[[nrf1	NRF1]] / NRF2 (not the antioxidant NRF2/NFE2L2)	TFAM, OXPHOS subunit transcription, mtDNA replication
PPARα	Fatty acid oxidation (β-oxidation genes)	Liver, heart, muscle
PPARγ	Adipogenesis, thermogenesis	BAT, WAT
PPARδ/β	Fatty acid oxidation, slow-twitch fiber program	Skeletal muscle
ERRα / ERRβ / ERRγ	Expanded mitochondrial program, OXPHOS	Broad; particularly muscle and heart
HNF4α + [[foxo1	FoxO1]]	Gluconeogenic genes (PEPCK, G6Pase)
MEF2	Slow-twitch (Type I) muscle fiber gene program	Skeletal muscle
[[foxo3	FoxO3]]	Mitophagy, antioxidant defense (SOD2, CAT)

The ERR subfamily (estrogen-related orphan receptors) are particularly important: ERRα is sometimes described as a “partner TF” that PGC-1α constitutively coactivates, making the ERRα–PGC-1α axis a semi-constitutive mitochondrial transcription module.

TFAM is an indirect but critical output: NRF1, coactivated by PGC-1α, drives TFAM expression; TFAM packages and replicates the mitochondrial genome. The PGC-1α → NRF1 → TFAM axis is the canonical molecular link between nuclear energy-sensing and mitochondrial DNA maintenance.

PTM regulation

This is the central aging-relevant biology of PGC-1α. Activity is controlled post-translationally by three major mechanisms:

Acetylation by GCN5/KAT2A (repressive)

GCN5 (KAT2A) acetylates at least 13 lysines in PGC-1α ³, ⁴. Acetylation at these sites causes PGC-1α to redistribute to nuclear foci (associated with inactive chromatin) and reduces its transcriptional activity on target promoters. In the fed state, GCN5 activity predominates, acetylating and silencing PGC-1α. In the fasted state, SIRT1 deacetylates these sites, re-activating the protein.

Critical attribution note: GCN5/KAT2A is the experimentally identified writer for PGC-1α acetylation in the Rodgers 2005 and Lerin 2006 studies. CBP/p300 co-precipitates with PGC-1α and recruits to PGC-1α target promoters, but direct acetylation of PGC-1α by CBP/p300 has not been demonstrated in these papers. Do not propagate “CBP/p300 acetylates PGC-1α” without a primary citation establishing direct catalytic action on the protein ¹.

Acetylation site (mouse numbering in source)	Human UniProt Q9UBK2 equivalent	Writer	Effect	Source
K77	K79	GCN5/KAT2A	Repressive	Rodgers 2005 ³
K144	K146	GCN5/KAT2A	Repressive	Rodgers 2005
K183	K184	GCN5/KAT2A	Repressive	Rodgers 2005
K253	K254	GCN5/KAT2A	Repressive	Rodgers 2005
K270	K271	GCN5/KAT2A	Repressive	Rodgers 2005
K277	K278	GCN5/KAT2A	Repressive	Rodgers 2005
K320	K321	GCN5/KAT2A	Repressive	Rodgers 2005
K346	K347	GCN5/KAT2A	Repressive	Rodgers 2005
K412	K413	GCN5/KAT2A	Repressive	Rodgers 2005
K441	K442	GCN5/KAT2A	Repressive	Rodgers 2005
K450	K451	GCN5/KAT2A	Repressive	Rodgers 2005
K757	K758	GCN5/KAT2A	Repressive	Rodgers 2005
K778	K779	SIRT1 substrate (eraser known; deacetylated by SIRT1)	Repressive when acetylated	Rodgers 2005; Hubbard 2013 ⁵

Note: Rodgers 2005 identified these 13 sites by tandem mass spectrometry of mouse PGC-1α (mouse Ppargc1a sequence). Mouse numbering is used in the source paper. The “Human UniProt” column gives the corresponding residue in the canonical human isoform Q9UBK2 (798 aa), which is shifted +2 relative to mouse. Hubbard 2013 used a mouse PGC-1α K778 peptide for the SIRT1 assay, consistent with Rodgers 2005 mouse numbering.

Deacetylation by SIRT1 (activating)

SIRT1 deacetylates PGC-1α during fasting and caloric restriction in the liver, re-activating gluconeogenic and mitochondrial programs ³. The Rodgers 2005 study used adenoviral SIRT1 overexpression in mouse liver; see sirt1 for full verification details and quantitative claims. Hubbard 2013 specifically mapped K778 (K779 in current UniProt numbering) as a SIRT1 deacetylation target ⁵; see sirt1 for the Hubbard 2013 extraction.

The SIRT1–PGC-1α axis is a fasting/CR sensor: NAD+ rises as fuel availability falls → SIRT1 activity increases → PGC-1α deacetylated and activated → mitochondrial and gluconeogenic gene programs upregulated.

Hubbard 2013 used a mouse PGC-1α peptide centered on K778 (mouse sequence; equivalent to K779 in human UniProt Q9UBK2) to demonstrate SIRT1 activation by STACs. The paper explicitly labels this substrate “PGC-1α–K778” throughout; residue numbering follows the mouse sequence used in Rodgers 2005. The K778/K779 nomenclature difference is a mouse-vs-human isoform offset, not an error in either paper.

Phosphorylation by AMPK (activating)

AMPK directly phosphorylates PGC-1α at T178 and S539 (UniProt numbering; Jager 2007 uses Thr177/Ser538 in mouse sequence) in skeletal muscle ⁶. This phosphorylation activates PGC-1α and initiates a feedforward loop: AMPK → PGC-1α → PGC-1α promoter autoregulation (PGC-1α can bind and coactivate its own promoter via MEF2) → increased PGC-1α expression. This AMPK-PGC-1α-SIRT1 axis is the mechanistic basis of exercise-induced mitochondrial biogenesis:

Exercise → AMP/ATP ratio rises → AMPK activated → PGC-1α phosphorylated (T178/S539) → target genes expressed → more mitochondria → more NAD+ generation capacity → SIRT1 deacetylates PGC-1α further (activating)

Dimension	Status	Notes
Pathway conserved in humans?	yes	AMPK→PGC-1α phosphorylation demonstrated in human muscle biopsies post-exercise
Phenotype conserved in humans?	yes	Mitochondrial biogenesis in response to exercise is well-documented in humans
Replicated in humans?	yes	Multiple exercise-training studies in humans show AMPK/PGC-1α pathway activation

Phosphorylation by Akt (repressive)

In the fed state, Akt (PKB) phosphorylates PGC-1α primarily at Ser570, inhibiting its ability to coactivate gluconeogenic targets (HNF4α/FoxO1 complex) in liver ⁷. Li 2007 identified Ser570 as the major Akt phosphorylation site by in vitro kinase assay and mass spectrometry of GST-PGC-1α C-terminal fragments; mutation of S570 to Ala markedly decreased phosphorylation, while combinatorial mutation of other candidate Akt sites did not further reduce it. This provides the insulin-signaling brake on hepatic gluconeogenesis via PGC-1α: insulin → PI3K → Akt → PGC-1α(pS570) → PEPCK and G6Pase suppressed.

Note: Some earlier sources describe S265 as an additional Akt site, but Li 2007 — the primary citation on this page — demonstrates S570 as the dominant site. S265 is not reported in Li 2007. unsourced for S265 as an Akt site; a separate citation would be needed to add that claim.

Dimension	Status	Notes
Pathway conserved in humans?	yes	Insulin → Akt → gluconeogenesis suppression is conserved
Phenotype conserved in humans?	yes	Insulin resistance in T2DM involves defective Akt-mediated PGC-1α suppression
Replicated in humans?	partial	Mechanistic details established in mouse liver/cell lines (Li 2007); human studies focus on downstream phenotype rather than PGC-1α phosphorylation directly

Phosphorylation by p38 MAPK (activating, muscle-specific)

p38 MAPK phosphorylates PGC-1α at T262, S265, and T298 in response to cytokines and exercise in muscle, increasing its stability and transcriptional activity. This provides a second, AMPK-independent route to PGC-1α activation in exercising muscle. needs-replication — the specific sites and kinetic contribution relative to the AMPK route require further characterization in vivo.

Loss-of-function phenotypes

The global Pgc-1α knockout mouse (Lin 2004) is viable and fertile ⁸. Key phenotypes:

Cold intolerance: severe defect in adaptive thermogenesis; body temperature of Pgc-1α-null mice drops to ~33.5°C within 3 hr at 4°C and hypothermia becomes lethal beyond 6 hr; UCP1 induction in BAT is reduced to ~45% of wild-type level; type 2 iodothyronine deiodinase (D2) mRNA reduced ~50%
Reduced exercise capacity: impaired mitochondrial oxidative capacity in skeletal muscle; mitochondrial gene expression (ERRα, Ndufb5, Cox7a1, Atp5j) reduced 30–60% in quadriceps; AMPK constitutively activated (compensatory)
Striatal neurodegeneration: spongiform lesions found predominantly in the striatum of 3-month-old Pgc-1α-null mice (not aged mice); lesions associated with reactive astrocytes and loss of NF220-positive axons; behavioral phenotype resembles aspects of Huntington’s disease (hyperactivity + striatal lesions)
Hyperactivity: 40% increase in random movement frequency; driven by CNS/striatal pathology, not thermogenesis

Importantly, basal mitochondrial content is not abolished in Pgc-1α-null mice — compensatory mechanisms (including PGC-1β and constitutive AMPK activation) maintain some mitochondrial baseline. The null mouse also shows resistance to diet-induced obesity and improved insulin sensitivity, likely due to compensatory hyperactivity-driven energy expenditure. The null mouse reveals which programs require PGC-1α specifically rather than the broader PGC coactivator family.

Dimension	Status
Pathway conserved in humans?	yes
Phenotype conserved in humans?	partial — loss-of-function mutations in PPARGC1A in humans are rare; metabolic and neurological associations exist (Parkinson’s disease via PARIS repression of PPARGC1A)
Replicated in humans?	no — no human equivalent of germline knockout; genetic association studies support direction

Aging biology

Expression declines with age

PGC-1α mRNA and protein levels decline with age in skeletal muscle, brain, and (less consistently) liver. This decline tracks with the aging-associated reduction in mitochondrial content, OXPHOS capacity, and exercise tolerance. A primary driver appears to be declining SIRT1 activity (as NAD+ falls with age — see sirt1 and nampt) leading to net accumulation of acetylated (inactive) PGC-1α rather than a reduction in gene transcription alone.

In mouse skeletal muscle, PGC-1α is reported to be required for exercise training to prevent the age-associated decline in mitochondrial enzyme content: Ppargc1a-null mice trained from midlife do not sustain the mitochondrial enzyme levels that WT mice maintain, establishing PGC-1α as necessary (not just sufficient) for the protective effect of exercise on aging muscle ⁹. needs-human-replication no-fulltext-access — Leick 2010 is closed-access; this claim could not be verified against the primary source on this pass.

The Wenz 2009 finding — RETRACTED

Wenz et al. 2009 (PNAS 106:20405) reported that muscle-specific Pgc-1α overexpression (MCK-Pgc1a transgenic mice) extended median lifespan, prevented sarcopenia, and improved cardiac and systemic metabolic function in aged mice ¹⁰. This paper was retracted in December 2016 (retraction DOI: 10.1073/pnas.1619713114) due to concerns about data integrity. Do not propagate the lifespan or sarcopenia-prevention quantitative claims from Wenz 2009 without independent replication.

What remains valid: The general biology that PGC-1α overexpression in muscle promotes mitochondrial biogenesis and oxidative metabolism is supported by multiple independent lines of evidence and is not in dispute. The specific lifespan and sarcopenia-prevention magnitude claims from Wenz 2009 require independent replication.

needs-replication — lifespan extension from muscle-specific PGC-1α overexpression; the Wenz 2009 data have been retracted and no direct replication in aged mice has been published as of 2026-05-05.

GenAge classification

GenAge entry 256: included based on evidence that Ppargc1a knockout mice show accelerated vascular aging — telomere shortening, DNA damage accumulation, and atherosclerosis — demonstrating a direct role in mammalian aging biology. The vascular-aging phenotype is distinct from the muscle and thermogenesis phenotypes of the Lin 2004 global KO; vascular effects may reflect impaired mitochondrial function in endothelial cells and smooth muscle.

Connection to mitohormesis

Moderate reactive oxygen species (ROS) generated during exercise activate AMPK and p38 MAPK, which in turn activate PGC-1α → mitochondrial biogenesis (mitohormetic response). Ristow et al. 2009 demonstrated in a human RCT that co-supplementation with antioxidants (vitamin C + E) during exercise training blunted the exercise-induced activation of PGC-1α target genes and attenuated the insulin-sensitizing effects of training ¹¹. This supports the view that ROS act as beneficial signaling molecules upstream of PGC-1α activation, not purely as damage agents.

Dimension	Status
Pathway conserved in humans?	yes
Phenotype conserved in humans?	yes — Ristow 2009 is a human RCT
Replicated in humans?	in-progress — several follow-up trials; some partially replicate, some do not contradictory-evidence

Pharmacology and exercise

Endurance exercise

The most validated PGC-1α activator in humans. Acute endurance exercise raises the AMP:ATP ratio → AMPK → PGC-1α phosphorylation (T178/S539) and possibly p38 MAPK → PGC-1α phosphorylation (T262/S265/T298). Chronic training increases basal PGC-1α expression and mitochondrial content in skeletal muscle. This is the mechanistic basis of the exercise-mediated protection against age-related mitochondrial decline ⁹.

Resveratrol (indirect, contested)

Resveratrol was proposed to activate SIRT1 → deacetylate PGC-1α → activate mitochondrial programs. The mechanism of resveratrol→SIRT1 activation is contested (Pacholec 2010, verified on sirt1). At high doses, resveratrol can activate AMPK independently, which would also activate PGC-1α. Do not cite “resveratrol activates PGC-1α via SIRT1” as a settled mechanism. contradictory-evidence

Bezafibrate

Bezafibrate is a pan-PPAR agonist that increases Ppargc1a transcription in muscle; has been used as a pharmacological tool to probe PGC-1α biology in mouse models of mitochondrial disease. Not validated as an anti-aging intervention. needs-human-replication

ZLN005

ZLN005 is a small-molecule transcriptional inducer of PPARGC1A identified in a cell-based screen. Preclinical only as of 2026-05-05. needs-replication

Caloric restriction

Caloric restriction induces PGC-1α in liver and muscle, partly via the SIRT1 axis (NAD+ rises during CR → SIRT1 more active → PGC-1α deacetylated/activated). This is one proposed mechanism by which CR improves mitochondrial function and extends healthspan. no-mechanism — the relative contribution of SIRT1 versus AMPK versus transcriptional induction to CR-induced PGC-1α activation in different tissues is not fully resolved.

Pathway membership and cross-references

ampk — AMPK directly phosphorylates and activates PGC-1α; canonical upstream activator during exercise and energy stress
sirtuin / sirt1 — SIRT1 deacetylates and activates PGC-1α during fasting/CR; SIRT1 decline with age is a proposed mechanism of PGC-1α hypo-activity in aging
mitochondrial-biogenesis — PGC-1α is the master coactivator; NRF1/NRF2→TFAM axis is the canonical effector
mitochondrial-dysfunction — PGC-1α decline contributes to the age-related fall in mitochondrial content and OXPHOS capacity
deregulated-nutrient-sensing — fasting/CR→SIRT1→PGC-1α is a core nutrient-sensing axis; Akt-mediated repression in the fed state couples insulin signaling to mitochondrial suppression
foxo3 — co-operates with PGC-1α on mitophagy and antioxidant defense gene programs in muscle
foxo1 — PGC-1α + FoxO1 drive hepatic gluconeogenesis
gcn5 — GCN5/KAT2A is the primary acetylase writer that silences PGC-1α
tfam — indirect PGC-1α output via NRF1; TFAM packages mtDNA
nrf1 — direct TF partner; drives TFAM and OXPHOS gene expression
cbp-p300 / ep300 — recruited to PGC-1α target promoters; direct acetylation of PGC-1α by this family is not established (see PTM section)
nampt — NAD+ biosynthesis; sets SIRT1 activity ceiling; connects to PGC-1α activity
mitohormesis — PGC-1α is the effector of the mitohormetic exercise response
exercise — primary physiological activator of PGC-1α in skeletal muscle
caloric-restriction — induces PGC-1α via SIRT1 and AMPK
resveratrol — indirect; mechanism contested

Limitations and gaps

needs-human-replication — isoform-specific PGC-1α responses in human skeletal muscle (vs mouse exercise isoforms) are incompletely characterized
needs-replication — lifespan extension from muscle-specific PGC-1α overexpression (Wenz 2009 retracted; no independent replication published as of 2026-05-05)
contradictory-evidence — resveratrol→SIRT1→PGC-1α mechanism is contested; antioxidant blunting of exercise-induced PGC-1α activation (Ristow 2009) has not been uniformly replicated
no-mechanism — relative contribution of SIRT1 vs AMPK to CR-induced PGC-1α activation in liver vs muscle vs brain is unresolved
needs-human-replication — vascular aging acceleration in Ppargc1a-null mice (GenAge basis) has not been directly tested in human genetic studies
unsourced — p38 MAPK site mapping (T262/S265/T298) needs primary citation verification; present attribution is from training knowledge
no-fulltext-access — Leick 2010 (aging muscle claim) is closed-access; verification of that specific claim is pending open-access or institutional access
unsourced — S265 as a secondary Akt phosphorylation site on PGC-1α; Li 2007 identifies S570 as the primary site but does not report S265; separate primary citation needed before adding S265 back

Footnotes

CBP/p300 interacts with the PGC-1α N-terminal activation domain and co-precipitates with PGC-1α at target promoters. Direct catalytic acetylation of PGC-1α by CBP/p300 is not demonstrated in Rodgers 2005 (which names GCN5 as the writer) or other primary studies in the PGC-1α PTM literature as of 2026-05-05. This attribution gap was flagged during verification of cbp-p300 (2026-05-05). ↩ ↩²
doi:10.1016/s0092-8674(00)81410-5 · Puigserver P et al. (Spiegelman lab) · in-vitro + in-vivo (mouse BAT, C2C12 cells) · Cell 92:829 (1998) · Discovery paper: identified PGC-1α as cold-inducible PPARγ coactivator in BAT; overexpression drove thermogenic gene program · locally available in archive ↩
doi:10.1038/nature03354 · Rodgers JT, Lerin C et al. (Puigserver/Spiegelman) · in-vitro + in-vivo (mouse liver, adenoviral overexpression) · Nature 434:113 (2005) · SIRT1 deacetylates PGC-1α in liver during fasting; GCN5 identified as acetyltransferase writer · locally available in archive ↩ ↩² ↩³
doi:10.1016/j.cmet.2006.04.013 · Lerin C, Rodgers JT, Kalume DE, Kim S, Pandey A, Puigserver P · in-vitro + in-vivo (mouse liver hepatocytes, adenoviral GCN5) · Cell Metabolism 3:429 (2006) · Identifies GCN5 as the endogenous acetyltransferase in the PGC-1α protein complex; GCN5 (not p300, SRC-1, or TIP60) acetylates PGC-1α directly; GCN5 acetylation relocalizes PGC-1α to inactive nuclear foci; GCN5 represses gluconeogenic gene expression by 6-fold and reduces hepatic glucose secretion by 78%; confirms GCN5 as primary writer · locally available in archive ↩
doi:10.1126/science.1231097 · Hubbard BP, Gomes AP et al. (Sinclair) · in-vitro (biochemical) · Science 339:1216 (2013) · Maps specific SIRT1 deacetylation sites including K778 on PGC-1α; evidence for common SIRT1 activation mechanism · locally available in archive ↩ ↩²
doi:10.1073/pnas.0705070104 · Jager S, Handschin C, St-Pierre J, Spiegelman BM · in-vitro + in-vivo (primary mouse myotubes; skeletal muscle-specific Pgc-1α-KO mice; AICAR treatment) · PNAS 104:12017 (2007) · AMPK directly phosphorylates PGC-1α at Thr177+Ser538 (mouse sequence confirmed by mass spectrometry; equivalent to T178/S539 in human UniProt Q9UBK2); phosphorylation required for PGC-1α-dependent induction of PGC-1α promoter; many AMPK effects on GLUT4 and mitochondrial genes require PGC-1α protein · locally available in archive ↩
doi:10.1038/nature05861 · Li X, Monks B, Ge Q, Birnbaum MJ · in-vitro + in-vivo (mouse liver; H4IIe hepatoma cells; primary hepatocytes; Akt2-KO mice) · Nature 447:1012 (2007) · Akt phosphorylates PGC-1α at Ser570 as the primary site (identified by in vitro kinase assay + anti-pS570 antibody; S570A mutation markedly reduces phosphorylation); inhibits gluconeogenic coactivation; insulin → Akt → PGC-1α(pS570) suppression → PEPCK/G6Pase down; also inhibits fatty acid oxidation via ERRα coactivation · locally available in archive ↩
doi:10.1016/j.cell.2004.09.013 · Lin J et al. (Spiegelman) · in-vivo (global Ppargc1a-null mouse, C57Bl/6 backcross) · Cell 119:121 (2004) · Global KO: viable and fertile; cold-intolerant (BAT thermogenesis severely impaired); reduced mitochondrial gene expression in muscle (30–60%); spongiform striatal neurodegeneration in 3-month-old mice (NOT aged mice); CNS hyperactivity (+40% movement); resistant to diet-induced obesity (due to hyperactivity-driven energy expenditure) · locally available in archive ↩
doi:10.1016/j.exger.2010.01.011 · Leick L, Lyngby SS et al. (Pilegaard) · in-vivo (Ppargc1a-null and WT mice, exercise training) · Experimental Gerontology 45:336 (2010) · PGC-1α required for exercise training to prevent age-associated decline in mitochondrial enzyme content in mouse muscle · no-fulltext-access — closed-access (not_oa per a local paper archive); quantitative claims from this paper could not be verified against primary source on this pass ↩ ↩²
doi:10.1073/pnas.0911570106 · Wenz T et al. (Moraes) · RETRACTED 2016 (retraction doi:10.1073/pnas.1619713114) · Reported muscle-specific PGC-1α overexpression extends lifespan and prevents sarcopenia in aged mice · Do not cite quantitative claims from this paper. ↩
doi:10.1073/pnas.0903485106 · Ristow M, Zarse K et al. · n=40 healthy young males (20 previously untrained + 20 pretrained; each split 10/10 antioxidant vs no supplement) · two-part design: open-label pilot (n=16 part 1) then double-blind placebo-controlled (n=24 part 2); registered NCT00638560 · PNAS 106:8665 (2009) · Antioxidant supplementation (vitamin C 1000 mg/day + vitamin E 400 IU/day) during 4-week exercise training blunted PGC-1α/PGC-1β/PPARγ target gene induction and insulin sensitization (GIR, adiponectin); supports ROS-mitohormetic model · locally available in archive ↩

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