A PGC-1α isoform induced by resistance training regulates skeletal muscle hypertrophy
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PGC-1α is a transcriptional coactivator induced by exercise that gives muscle many of the best known adaptations to endurance-type exercise but has no effects on muscle strength or hypertrophy. We have identified a form of PGC-1α (PGC-1α4) that results from alternative promoter usage and splicing of the primary transcript. PGC-1α4 is highly expressed in exercised muscle but does not regulate most known PGC-1α targets such as the mitochondrial OXPHOS genes. Rather, it specifically induces IGF1 and represses myostatin, and expression of PGC-1α4 in vitro and in vivo induces robust skeletal muscle hypertrophy. Importantly, mice with skeletal muscle-specific transgenic expression of PGC-1α4 show increased muscle mass and strength and dramatic resistance to the muscle wasting of cancer cachexia. Expression of PGC-1α4 is preferentially induced in mouse and human muscle during resistance exercise. These studies identify a PGC-1α protein that regulates and coordinates factors involved in skeletal muscle hypertrophy.
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PGC-1α4 is abundantly expressed in skeletal muscle and appears to play a role in the adaptive response to exercise, particularly in the setting of resistance training.
“PGC-1α4, a transcript from the PGC-1 α gene, is abundantly expressed in skeletal muscle and appears to play a role in the adaptive response to exercise, particularly in the setting of resistance training (Ruas et al., 2012;White et al., 2014).”
From Concurrent exercise training: do opposites distract? (2017) · cites this paper as Ruas et al., 2012
After training consisting of either endurance exercise, resistance exercise, or a combination of both endurance and resistance exercise, increases in PGC-1α4 are confined to resistance-only and combined exercise training programmes, with no changes in this transcript after endurance-only training.
“In this regard, Ruas and co-workers (Ruas et al., 2012) have shown that after training consisting of either endurance exercise, resistance exercise, or a combination of both endurance and resistance exercise, increases in PGC-1α4 are confined to resistance-only and combined exercise training programmes, with no changes in this transcript after endurance-only training (Ruas et al., 2012).”
From Concurrent exercise training: do opposites distract? (2017) · cites this paper as Ruas et al., 2012
Exercise promotes the upregulation of mitochondrial peroxisome proliferator-activated receptor gamma coactivator 1-alpha in muscle cells.
“Exercise promotes the upregulation of mitochondrial peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha, a principal regulator of mitochondrial biogenesis, within muscle cells [21].”
From Aerobic exercise improves astrocyte mitochondrial quality and transfer to neurons in a mouse model of Alzheimer's disease (2025) · cites this paper as [21]
CT increased pgc1α4.
“The CT-induced increase in pgc1α4 is also consistent with its ability to stimulate skeletal muscle hypertrophy (15).”
From Combined Training Enhances Skeletal Muscle Mitochondrial Oxidative Capacity Independent of Age (2015) · cites this paper as [15]
The mRNA abundance for pgc1α1 increased.
“Moreover, the observation of the increase in the mRNA abundance for pgc1α1, which is an isoform of PGC1α that promotes an oxidative phenotype in skeletal muscle (15), further supports this PCG-1–related mechanism for muscular adaptation to exercise training.”
From Combined Training Enhances Skeletal Muscle Mitochondrial Oxidative Capacity Independent of Age (2015) · cites this paper as [15]
PGC1α transgenic mice do not show muscle growth and do not display enhancement of protein synthesis, but the splicing isoform PGC1α4 promotes muscle hypertrophy.
“However, despite the fact that PGC1α transgenic mice do not show muscle growth and do not display an enhancement of protein synthesis, the splicing isoform 4 (PGC1α4) was found to promote muscle hypertrophy32.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [32]
PGC-1α splice variants PGC-1α2, PGC-1α3, and PGC-1α4 stimulate protein synthesis and attenuate UPS activity in cultured myotubes and mouse skeletal muscle.
“PGC-1α2, PGC-1α3, and PGC-1α4, have been shown to stimulate protein synthesis and attenuate UPS activity in cultured myotubes and mouse skeletal muscle (87, 119).”
From Mitochondria initiate and regulate sarcopenia (2017) · cites this paper as [119]
PGC-1α4 is highly expressed in exercising skeletal muscle, increases IGF1 expression, and induces skeletal muscle hypertrophy.
“PGC-1α4 has been found to be highly expressed in exercising skeletal muscle, which increases IGF1 expression, and induces skeletal muscle hypertrophy [14].”
From Apigenin Enhances Skeletal Muscle Hypertrophy and Myoblast Differentiation by Regulating Prmt7 (2017) · cites this paper as [14]
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- Authors
- Ruas, J. L., White, J. P., Rao, R. R., Kleiner, S., Brannan, K. T., Harrison, B. C., Greene, N. P., Wu, J., Estall, J. L., Irving, B. A., Lanza, I. R., Rasbach, K. A., Okutsu, M., Nair, K. S., Yan, Z., Leinwand, L. A., & Spiegelman, B. M.
- Affiliations
- Harvard University (US)
- University of Colorado Boulder (US)
- University of Virginia (US)
- Mayo Clinic (US)
- Corresponding author
- Ruas, Jorge L.
- Spiegelman, Bruce M.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-12
- Volume
- 151
- Issue
- 6
- Pages
- 1319-1331
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3520615
- OpenAlex
- W1964739304
- Cited by
- 677
- References
- 44
- Citations by year
- 2026: 22 · 2025: 40 · 2024: 49 · 2023: 55 · 2022: 41 · 2021: 49 · 2020: 44 · 2019: 41 · 2018: 62 · 2017: 52 · 2016: 44 · 2015: 59 · 2014: 59 · 2013: 46 · 2012: 2
- FWCI
- 21.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Civil War Book Review (submittedVersion)
- Funders
- Novo Nordisk Fonden (NNF12OC1016062)
- National Institute on Aging (AG-09531, R01AG009531)
- National Heart, Lung, and Blood Institute (R01HL119937, T32HL007284, T-32 HL07284)
- National Institute of General Medical Sciences (GM 29090, R01GM029090)
- National Institute of Diabetes and Digestive and Kidney Diseases (R56DK054477, DK061562, K01DK094824, R01DK061562)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (5K01AR55676-2, R01AR050429, K01AR055676, AR 050429)
- National Center for Research Resources (KL2RR024151, RR024151)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
- Keywords
- PGC-1α, alternative splicing, alternative promoters, resistance training, skeletal muscle hypertrophy, insulin-like growth factor I, myostatin, cancer cachexia, muscle atrophy, muscle strength, exercise-induced gene expression, transcriptional coactivator
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Glucose, Heat-Shock Proteins, Humans, Hypertrophy, Insulin-Like Growth Factor I, Mice, Transgenic, Molecular Sequence Data, Physical Conditioning, Animal, Transcription Factors, Trans-Activators, Muscle, Skeletal, Muscle Fibers, Skeletal, Protein Isoforms, Adiposity, Mice, Resistance Training, Myostatin
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