Article

A PGC-1α Isoform Induced by Resistance Training Regulates Skeletal Muscle Hypertrophy.

Department of Cell Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address: .
Cell (Impact Factor: 33.12). 12/2012; 151(6):1319-31. DOI: 10.1016/j.cell.2012.10.050
Source: PubMed

ABSTRACT 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.

4 Followers
 · 
367 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: PGC1α, a transcriptional coactivator, interacts with PPARs and others to regulate skeletal muscle metabolism. PGC1α undergoes splicing to produce several mRNA variants, with the NTPGC1α variant having a similar biological function to the full length PGC1α (FLPGC1α). CVD is associated with obesity and T2D and a lower percentage of type 1 oxidative fibers and impaired mitochondrial function in skeletal muscle, characteristics determined by PGC1α expression. PGC1α expression is epigenetically regulated in skeletal muscle to determine mitochondrial adaptations, and epigenetic modifications may regulate mRNA splicing. We report in this paper that skeletal muscle PGC1α -1 nucleosome (-1N) position is associated with splice variant NTPGC1α but not FLPGC1α expression. Division of participants based on the -1N position revealed that those individuals with a -1N phased further upstream from the transcriptional start site (UP) expressed lower levels of NTPGC1α than those with the -1N more proximal to TSS (DN). UP showed an increase in body fat percentage and serum total and LDL cholesterol. These findings suggest that the -1N may be a potential epigenetic regulator of NTPGC1α splice variant expression, and -1N position and NTPGC1α variant expression in skeletal muscle are linked to CVD risk. This trial is registered with clinicaltrials.gov, identifier NCT00458133.
    PPAR Research 12/2014; 2014:895734. DOI:10.1155/2014/895734 · 1.64 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Irisin is a recently identified exercise-induced hormone that increases energy expenditure, at least in rodents. The main purpose of this study was to test the hypothesis that Irisin increases acutely in blood after singular sessions of intense endurance exercise (END) and heavy strength training (STR). Secondary, we wanted to explore the relationship between body composition and exercise-induced effects on irisin, and the effect of END and STR on muscular expression of the irisin gene FNDC5. Nine moderately trained healthy subjects performed three test days using a randomized and standardized crossover design: one day with 60 minutes of END, one day with 60 minutes of STR, and one day without exercise (CON). Venous blood was sampled over a period of 24h on the exercise days. Both END and STR led to transient increases in irisin concentrations in blood, peaking immediately after END and one hour after STR, before gradually returning to baseline. Irisin responses to STR, but not END, showed a consistently strong negative correlation with proportions of lean body mass. Neither END nor STR affected expression of FNDC5, measured 4h after training sessions, though both protocols led to pronounced increases in PGC-1α expression, which is involved in transcriptional control of FNDC5. The results strongly suggest that single sessions of intense endurance exercise and heavy strength training lead to transient increases in irisin concentrations in blood. This was not accompanied by increased FNDC5 expression, measured 4h post-exercise. The results suggest that irisin responses to resistance exercise are higher in individuals with lower proportions of lean body mass.
    PLoS ONE 10(3):e0121367. DOI:10.1371/journal.pone.0121367 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Muscle atrophy contributes to the poor prognosis of many pathophysiological conditions, but pharmacological therapies are still limited. Muscle activity leads to major swings in mitochondrial [Ca(2+)], which control aerobic metabolism, cell death, and survival pathways. We investigated in vivo the effects of mitochondrial Ca(2+) homeostasis in skeletal muscle function and trophism by overexpressing or silencing the mitochondrial calcium uniporter (MCU). The results demonstrate that in both developing and adult muscles, MCU-dependent mitochondrial Ca(2+) uptake has a marked trophic effect that does not depend on aerobic control but impinges on two major hypertrophic pathways of skeletal muscle, PGC-1α4 and IGF1-Akt/PKB. In addition, MCU overexpression protects from denervation-induced atrophy. These data reveal a novel Ca(2+)-dependent organelle-to-nucleus signaling route that links mitochondrial function to the control of muscle mass and may represent a possible pharmacological target in conditions of muscle loss. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.