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PGC ‐ 1 α and fasting ‐ induced PDH regulation in mouse skeletal muscle

View Article: PubMed Central - PubMed

ABSTRACT

The purpose of the present study was to examine whether lack of skeletal muscle peroxisome proliferator‐activated receptor gamma coactivator 1 alpha (PGC‐1α) affects the switch in substrate utilization from a fed to fasted state and the fasting‐induced pyruvate dehydrogenase (PDH) regulation in skeletal muscle. Skeletal muscle‐specific PGC‐1α knockout (MKO) mice and floxed littermate controls were fed or fasted for 24 h. Fasting reduced PDHa activity, increased phosphorylation of all four known sites on PDH‐E1α and increased pyruvate dehydrogenase kinase (PDK4) and sirtuin 3 (SIRT3) protein levels, but did not alter total acetylation of PDH‐E1α. Lack of muscle PGC‐1α did not affect the switch from glucose to fat oxidation in the transition from the fed to fasted state, but was associated with lower and higher respiratory exchange ratio (RER) in the fed and fasted state, respectively. PGC‐1α MKO mice had lower skeletal muscle PDH‐E1α, PDK1, 2, 4, and pyruvate dehydrogenase phosphatase (PDP1) protein content than controls, but this did not prevent the fasting‐induced increase in PDH‐E1α phosphorylation in PGC‐1α MKO mice. However, lack of skeletal muscle PGC‐1α reduced SIRT3 protein content, increased total lysine PDH‐E1α acetylation in the fed state, and prevented a fasting‐induced increase in SIRT3 protein. In conclusion, skeletal muscle PGC‐1α is required for fasting‐induced upregulation of skeletal muscle SIRT3 and maintaining high fat oxidation in the fasted state, but is dispensable for preserving the capability to switch substrate during the transition from the fed to the fasted state and for fasting‐induced PDH regulation in skeletal muscle.

No MeSH data available.


Related in: MedlinePlus

(A) Forty‐eight hours of continuous respiratory exchange ratio (RER) and locomotor activity. (B) Average RER divided into light and dark phases of both the 24 h fed and 24 h fasting intervention. (C) Average RER in the last hour of the fed and the fasted state. (D) Average locomotor activity divided into light and dark phases of both the 24 h fed and 24 h fasting intervention. (E) Average locomotor activity in the last hour of the fed and the fasted state in skeletal muscle‐specific PGC‐1α knockout (MKO) and littermate‐floxed control (control) mice. Values are given as mean ± SE (n = 8–10). *Significantly different from FED within given genotype (P < 0.05). #Significantly different from control within given group (P < 0.05).
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phy213222-fig-0002: (A) Forty‐eight hours of continuous respiratory exchange ratio (RER) and locomotor activity. (B) Average RER divided into light and dark phases of both the 24 h fed and 24 h fasting intervention. (C) Average RER in the last hour of the fed and the fasted state. (D) Average locomotor activity divided into light and dark phases of both the 24 h fed and 24 h fasting intervention. (E) Average locomotor activity in the last hour of the fed and the fasted state in skeletal muscle‐specific PGC‐1α knockout (MKO) and littermate‐floxed control (control) mice. Values are given as mean ± SE (n = 8–10). *Significantly different from FED within given genotype (P < 0.05). #Significantly different from control within given group (P < 0.05).

Mentions: RER was overall lower (P < 0.05) and activity higher (P < 0.05) in PGC‐1α MKO than control mice at night in the fed state, while RER was overall higher (P < 0.05) and activity lower (P < 0.05) in PGC‐1α MKO than control mice at night in the fasted state (Fig. 2A and B). In the final hour of the dark, fed period (5–6 am), RER was lower (P < 0.05) and in the last hour of the dark, fasting period higher (P < 0.05) in PGC‐1α MKO than control mice (Fig. 2C).


PGC ‐ 1 α and fasting ‐ induced PDH regulation in mouse skeletal muscle
(A) Forty‐eight hours of continuous respiratory exchange ratio (RER) and locomotor activity. (B) Average RER divided into light and dark phases of both the 24 h fed and 24 h fasting intervention. (C) Average RER in the last hour of the fed and the fasted state. (D) Average locomotor activity divided into light and dark phases of both the 24 h fed and 24 h fasting intervention. (E) Average locomotor activity in the last hour of the fed and the fasted state in skeletal muscle‐specific PGC‐1α knockout (MKO) and littermate‐floxed control (control) mice. Values are given as mean ± SE (n = 8–10). *Significantly different from FED within given genotype (P < 0.05). #Significantly different from control within given group (P < 0.05).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5392513&req=5

phy213222-fig-0002: (A) Forty‐eight hours of continuous respiratory exchange ratio (RER) and locomotor activity. (B) Average RER divided into light and dark phases of both the 24 h fed and 24 h fasting intervention. (C) Average RER in the last hour of the fed and the fasted state. (D) Average locomotor activity divided into light and dark phases of both the 24 h fed and 24 h fasting intervention. (E) Average locomotor activity in the last hour of the fed and the fasted state in skeletal muscle‐specific PGC‐1α knockout (MKO) and littermate‐floxed control (control) mice. Values are given as mean ± SE (n = 8–10). *Significantly different from FED within given genotype (P < 0.05). #Significantly different from control within given group (P < 0.05).
Mentions: RER was overall lower (P < 0.05) and activity higher (P < 0.05) in PGC‐1α MKO than control mice at night in the fed state, while RER was overall higher (P < 0.05) and activity lower (P < 0.05) in PGC‐1α MKO than control mice at night in the fasted state (Fig. 2A and B). In the final hour of the dark, fed period (5–6 am), RER was lower (P < 0.05) and in the last hour of the dark, fasting period higher (P < 0.05) in PGC‐1α MKO than control mice (Fig. 2C).

View Article: PubMed Central - PubMed

ABSTRACT

The purpose of the present study was to examine whether lack of skeletal muscle peroxisome proliferator&#8208;activated receptor gamma coactivator 1 alpha (PGC&#8208;1&alpha;) affects the switch in substrate utilization from a fed to fasted state and the fasting&#8208;induced pyruvate dehydrogenase (PDH) regulation in skeletal muscle. Skeletal muscle&#8208;specific PGC&#8208;1&alpha; knockout (MKO) mice and floxed littermate controls were fed or fasted for 24&nbsp;h. Fasting reduced PDHa activity, increased phosphorylation of all four known sites on PDH&#8208;E1&alpha; and increased pyruvate dehydrogenase kinase (PDK4) and sirtuin 3 (SIRT3) protein levels, but did not alter total acetylation of PDH&#8208;E1&alpha;. Lack of muscle PGC&#8208;1&alpha; did not affect the switch from glucose to fat oxidation in the transition from the fed to fasted state, but was associated with lower and higher respiratory exchange ratio (RER) in the fed and fasted state, respectively. PGC&#8208;1&alpha; MKO mice had lower skeletal muscle PDH&#8208;E1&alpha;, PDK1, 2, 4, and pyruvate dehydrogenase phosphatase (PDP1) protein content than controls, but this did not prevent the fasting&#8208;induced increase in PDH&#8208;E1&alpha; phosphorylation in PGC&#8208;1&alpha; MKO mice. However, lack of skeletal muscle PGC&#8208;1&alpha; reduced SIRT3 protein content, increased total lysine PDH&#8208;E1&alpha; acetylation in the fed state, and prevented a fasting&#8208;induced increase in SIRT3 protein. In conclusion, skeletal muscle PGC&#8208;1&alpha; is required for fasting&#8208;induced upregulation of skeletal muscle SIRT3 and maintaining high fat oxidation in the fasted state, but is dispensable for preserving the capability to switch substrate during the transition from the fed to the fasted state and for fasting&#8208;induced PDH regulation in skeletal muscle.

No MeSH data available.


Related in: MedlinePlus