Exercise Induces a Marked Increase in Plasma Follistatin: Evidence That Follistatin Is a Contraction-Induced Hepatokine

Abstract Follistatin is a member of the TGF-β super family and inhibits the action of myostatin to regulate skeletal muscle growth. The regulation of follistatin during physical exercise is unclear but may be important because physical activity is a major intervention to prevent age-related sarcopenia. First, healthy subjects performed either bicycle or one-legged knee extensor exercise. Arterial-venous differences were assessed during the one-legged knee extensor experiment. Next, mice performed 1 h of swimming, and the expression of follistatin was examined in various tissues using quantitative PCR. Western blotting assessed follistatin protein content in the liver. IL-6 and epinephrine were investigated as drivers of follistatin secretion. After 3 h of bicycle exercise, plasma follistatin increased 3 h into recovery with a peak of 7-fold. No net release of follistatin could be detected from the exercising limb. In mice performing a bout of swimming exercise, increases in plasma follistatin as well as follistatin mRNA and protein expression in the liver were observed. IL-6 infusion to healthy young men did not affect the follistatin concentration in the circulation. When mice were stimulated with epinephrine, no increase in the hepatic mRNA of follistatin was observed. This is the first study to demonstrate that plasma follistatin is increased during exercise and most likely originates from the liver. These data introduce new perspectives regarding muscle-liver cross talk during exercise and during recovery from exercise.

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Serum Neuregulin-1β as a Biomarker of Cardiovascular Fitness

The Open Biomarkers Journal ◽

10.2174/1875318300902010001 ◽

2009 ◽

Vol 2 (1) ◽

pp. 1-5 ◽

Cited By ~ 19

Author(s):

Vaibhav Moondra ◽

Satyam Sarma ◽

Tracy Buxton ◽

Radwan Safa ◽

Gregory Cote ◽

...

Keyword(s):

Physical Activity ◽

Skeletal Muscle ◽

Healthy Subjects ◽

Sandwich Elisa ◽

Bicycle Ergometer ◽

Cardiovascular Fitness ◽

Elisa Assay ◽

Healthy Men ◽

Sandwich Elisa Assay ◽

Cardio Respiratory Fitness

Purpose: Neuregulins (NRG) are growth factors that bind to receptors of the erbB family, and are known to mediate a number of processes involved in diverse tissues. Neuregulin-1β is expressed in skeletal muscle and is activated by exercise. We hypothesized that NRG-1β might circulate in the bloodstream and increase as a consequence of physical activity. A study was conducted in healthy subjects to determine if NRG-1β is immunodetectable in human serum, and if so whether levels relate acutely or chronically to exercise. Methods: Nine healthy men underwent three bouts of exercise of varying degrees of intensity on a bicycle ergometer over a period of three weeks. Cardio-respiratory fitness was determined by measurement of maximal oxygen uptake (VO2max). Serum was sampled prior to and immediately after each session (up to 30 minutes post) and serum NRG-1ß was quantified utilizing an indirect sandwich ELISA assay developed in our lab. Results: Across subjects, mean serum NRG-1β levels ranged from 32 ng/mL to 473 ng/mL. Individual subjects showed relatively stable levels during the study period that did not change acutely after exercise. Serum NRG-1β demonstrated a positive correlation with VO2max (r2=0.49, p =.044). Conclusions: These preliminary observations suggest that at least in healthy men, serum NRG-1β is an indicator of cardio- respiratory fitness and does not change acutely with exercise.

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Epigenetic Modifications of theα-Synuclein Gene and Relative Protein Content Are Affected by Ageing and Physical Exercise in Blood from Healthy Subjects

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/3740345 ◽

2018 ◽

Vol 2018 ◽

pp. 1-16 ◽

Cited By ~ 7

Author(s):

Simona Daniele ◽

Barbara Costa ◽

Deborah Pietrobono ◽

Chiara Giacomelli ◽

Caterina Iofrida ◽

...

Keyword(s):

Physical Activity ◽

Physical Exercise ◽

Epigenetic Regulation ◽

Healthy Subjects ◽

Dna Methyltransferase ◽

Epigenetic Modification ◽

Methylation Status ◽

Peripheral Tissues ◽

Beneficial Effects ◽

Age Related

Epigenetic regulation may contribute to the beneficial effects of physical activity against age-related neurodegeneration. For example, epigenetic alterations of the gene encoding forα-synuclein (SNCA) have been widely explored in both brain and peripheral tissues of Parkinson’s disease samples. However, no data are currently available about the effects of physical exercise onSNCAepigenetic regulation in ageing healthy subjects. The present paper explored whether, in healthy individuals, age and physical activity are related to blood intron1-SNCA(SNCAI1) methylation, as well as further parameters linked to such epigenetic modification (total, oligomericα-synuclein and DNA methyltransferase concentrations in the blood). Here, theSNCAI1methylation status increased with ageing, and consistent with this result, lowα-synuclein levels were found in the blood. The direct relationship betweenSNCAI1methylation andα-synuclein levels was observed in samples characterized by bloodα-synuclein concentrations of 76.3 ng/mg protein or lower (confidence interval (CI) = 95%). In this selected population, higher physical activity reduced the total and oligomericα-synuclein levels. Taken together, our data shed light on ageing- and physical exercise-induced changes on theSNCAmethylation status and protein levels ofα-synuclein.

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Evidence and age-related distribution of mtDNA D-loop point mutations in skeletal muscle from healthy subjects and mitochondrial patients

Journal of the Neurological Sciences ◽

10.1016/s0022-510x(02)00247-2 ◽

2002 ◽

Vol 202 (1-2) ◽

pp. 85-91 ◽

Cited By ~ 30

Author(s):

Roberto Del Bo ◽

Andreina Bordoni ◽

Filippo Martinelli Boneschi ◽

Marco Crimi ◽

Monica Sciacco ◽

...

Keyword(s):

Skeletal Muscle ◽

Healthy Subjects ◽

Point Mutations ◽

Age Related ◽

Related Distribution ◽

D Loop

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Aging, exercise, and muscle protein metabolism

Journal of Applied Physiology ◽

10.1152/japplphysiol.91551.2008 ◽

2009 ◽

Vol 106 (6) ◽

pp. 2040-2048 ◽

Cited By ~ 197

Author(s):

René Koopman ◽

Luc J. C. van Loon

Keyword(s):

Physical Activity ◽

Skeletal Muscle ◽

Protein Synthesis ◽

Food Intake ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

The Elderly ◽

Age Related

Aging is accompanied by a progressive loss of skeletal muscle mass and strength, leading to the loss of functional capacity and an increased risk of developing chronic metabolic disease. The age-related loss of skeletal muscle mass is attributed to a disruption in the regulation of skeletal muscle protein turnover, resulting in an imbalance between muscle protein synthesis and degradation. As basal (fasting) muscle protein synthesis rates do not seem to differ substantially between the young and elderly, many research groups have started to focus on the muscle protein synthetic response to the main anabolic stimuli, i.e., food intake and physical activity. Recent studies suggest that the muscle protein synthetic response to food intake is blunted in the elderly. The latter is now believed to represent a key factor responsible for the age-related decline in skeletal muscle mass. Physical activity and/or exercise stimulate postexercise muscle protein accretion in both the young and elderly. However, the latter largely depends on the timed administration of amino acids and/or protein before, during, and/or after exercise. Prolonged resistance type exercise training represents an effective therapeutic strategy to augment skeletal muscle mass and improve functional performance in the elderly. The latter shows that the ability of the muscle protein synthetic machinery to respond to anabolic stimuli is preserved up to very old age. Research is warranted to elucidate the interaction between nutrition, exercise, and the skeletal muscle adaptive response. The latter is needed to define more effective strategies that will maximize the therapeutic benefits of lifestyle intervention in the elderly.

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Age-Related Deficit in Load-Induced Skeletal Muscle Growth

The Journals of Gerontology Series A ◽

10.1093/gerona/glp026 ◽

2009 ◽

Vol 64A (6) ◽

pp. 618-628 ◽

Cited By ~ 42

Author(s):

D. T. Hwee ◽

S. C. Bodine

Keyword(s):

Skeletal Muscle ◽

Muscle Growth ◽

Skeletal Muscle Growth ◽

Age Related

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Physical activity opposes the age-related increase in skeletal muscle and plasma endothelin-1 levels and normalizes plasma endothelin-1 levels in individuals with essential hypertension

Acta Physiologica ◽

10.1111/apha.12048 ◽

2013 ◽

Vol 207 (3) ◽

pp. 524-535 ◽

Cited By ~ 36

Author(s):

M. Nyberg ◽

S. P. Mortensen ◽

Y. Hellsten

Keyword(s):

Physical Activity ◽

Skeletal Muscle ◽

Essential Hypertension ◽

Endothelin 1 ◽

Age Related ◽

Related Increase

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Myonuclear accretion is a major determinant of avian skeletal muscle growth

AJP Cell Physiology ◽

10.1152/ajpcell.1997.272.2.c565 ◽

1997 ◽

Vol 272 (2) ◽

pp. C565-C571 ◽

Cited By ~ 52

Author(s):

P. E. Mozdziak ◽

E. Schultz ◽

R. G. Cassens

Keyword(s):

Skeletal Muscle ◽

Mitotic Activity ◽

Satellite Cell ◽

Muscle Development ◽

Muscle Growth ◽

Growth Potential ◽

Unit Size ◽

Skeletal Muscle Growth ◽

Age Related ◽

Related Increase

The role of satellite cells and DNA unit size in determining skeletal muscle growth was studied after mitotic activity was inhibited in the left pectoralis thoracicus of 2-wk-old tom turkeys by means of a 25-Gy dose of irradiation. Toms were killed and muscle weights were obtained 1 (n = 5), 4 (n = 6), 7 (n = 6), and 15 (n = 4) wk after irradiation. Satellite cell mitotic activity and DNA unit size were determined using enzymatically isolated myofiber segments and image analysis. Irradiated and nonirradiated muscle weights increased (P < 0.01) between all ages examined, but irradiated muscle weights were significantly (P < 0.01) lower than nonirradiated muscle weights at 4, 7, and 15 wk after irradiation. Satellite cell mitotic activity was lower (P < 0.01) in irradiated than in nonirradiated muscles at 1 and 4 wk after irradiation and resulted in a significant reduction (P < 0.05) in the number of myofiber nuclei per millimeter at 4 and 7 wk after irradiation. Satellite cell mitotic activity was higher (P < 0.05) in irradiated than in nonirradiated muscles at 7 wk after irradiation, but at 15 wk after irradiation it had fallen to low levels in both muscles. There was no significant (P > 0.10) difference in DNA unit size between muscles at any time, but there was an age-related increase (P < 0.01) for both muscles. Irradiation reduced muscle growth through a transient reduction in myonuclear production at a critical time (3-6 wk of age) in posthatch skeletal muscle development. The age-related increase in DNA unit size was not accelerated to compensate for the reduction in myonuclear accretion. Thus it appears that muscle growth potential is governed mostly by myonuclear accretion and to a lesser extent by DNA unit size.

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The effects of osteoarthritis and age on skeletal muscle strength, Na+-K+-ATPase content, gene and isoform expression

Journal of Applied Physiology ◽

10.1152/japplphysiol.00789.2013 ◽

2013 ◽

Vol 115 (10) ◽

pp. 1443-1449 ◽

Cited By ~ 15

Author(s):

Ben D. Perry ◽

Pazit Levinger ◽

Fabio R. Serpiello ◽

Marissa K. Caldow ◽

David Cameron-Smith ◽

...

Keyword(s):

Physical Activity ◽

Older Adults ◽

Skeletal Muscle ◽

Vastus Lateralis ◽

Ion Homeostasis ◽

Knee Extensor ◽

Vastus Lateralis Muscle ◽

Knee Oa ◽

Or Gene ◽

Older Populations

Knee osteoarthritis (OA) is a debilitating disorder prevalent in older populations that is accompanied by declines in muscle mass, strength, and physical activity. In skeletal muscle, the Na+-K+ pump (NKA) is pivotal in ion homeostasis and excitability and is modulated by disuse and exercise training. This study examined the effects of OA and aging on muscle NKA in 36 older adults (range 55–81 yr), including 19 with OA (69.9 ± 6.5 yr, mean ± SD) and 17 asymptomatic controls (CON, 66.8 ± 6.4 yr). Participants completed knee extensor strength testing and a physical activity questionnaire. A vastus lateralis muscle biopsy was analyzed for NKA content ([3H]ouabain binding sites), α1–3- and β1–3-isoform protein abundance (immunoblotting), and mRNA (real-time RT-PCR). The association between age and NKA content was investigated within the OA and CON groups and in pooled data. The NKA content was also contrasted between subgroups below and above the median age of 68.5 yr. OA had lower strength (−40.8%, P = 0.005), but higher NKA α2- (∼34%, P = 0.006) and α3-protein (100%, P = 0.016) abundance than CON and performed more incidental physical activity ( P = 0.035). No differences were found between groups for NKA content, abundance of other NKA isoforms, or gene expression. There was a negative correlation between age and NKA content within OA ( r = −0.63, P = 0.03) and with both groups combined ( r = −0.47, P = 0.038). The NKA content was 25.5% lower in the older (69–81 yr) than in the younger (55–68 yr) subgroup. Hence older age, but not knee OA, was related to lowered muscle NKA content in older adults.

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