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Cited by 435Muscle Physiology and DisordersGenetics and Physical PerformanceCardiac Fibrosis and Remodeling

Changes in muscle mass and phenotype and the expression of autocrine and systemic growth factors by muscle in response to stretch and overload

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GOLDSPINK, GEOFFREY·1999·Journal of Anatomy
DOI 10.1046/j.1469-7580.1999.19430323.x
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Abstract

The study of the underlying mechanisms by which cells respond to mechanical stimuli, i.e. the link between the mechanical stimulus and gene expression, represents a new and important area in the morphological sciences. Several cell types (‘mechanocytes’), e.g. osteoblasts and fibroblasts as well as smooth, cardiac and skeletal muscle cells are activated by mechanical strain and there is now mounting evidence that this involves the cytoskeleton. Muscle offers one of the best opportunities for studying this type of mechanotransduction as the mechanical activity generated by and imposed upon muscle tissue can be accurately controlled and measured in both in vitro and in vivo systems. Muscle is highly responsive to changes in functional demands. Overload leads to hypertrophy, whilst decreased load force generation and immobilisation with the muscle in the shortened position leads to atrophy. For instance it has been shown that stretch is an important mechanical signal for the production of more actin and myosin filaments and the addition of new sarcomeres in series and in parallel. This is preceded by upregulation of transcription of the appropriate genes some of which such as the myosin isoforms markedly change the muscle phenotype. Indeed, the switch in the expression induced by mechanical activity of myosin heavy chain genes which encode different molecular motors is a means via which the tissue adapts to a given type of physical activity. As far as increase in mass is concerned, our group have cloned the cDNA of a splice variant of IGF that is produced by active muscle that appears to be the factor that controls local tissue repair, maintenance and remodelling. From its sequence it can be seen that it is derived from the IGF gene by alternative splicing but it has different exons to the liver isoforms. It has a 52 base insert in the E domain which alters the reading frame of the 3′ end. Therefore, this splice variant of IGF‐1 is likely to bind to a different binding protein which exists in the interstitial tissue spaces of muscle, neuronal tissue and bone. This would be expected to localise its action as it would be unstable in the unbound form which is important as its production would not disturb the glucose homeostasis unduly. This new growth factor has been called mechano growth factor (MGF) to distinguish it from the liver IGFs which have a systemic mode of action. Although the liver is usually thought of as the source of circulating IGF, it has recently been shown that during exercise skeletal muscle not only produces much of the circulating IGF but active musculature also utilises most of the IGF produced. We have cloned both an autocrine and endocrine IGF‐1, both of which are upregulated in cardiac as well as skeletal muscle when subjected to overload. It has been shown that, in contrast to normal muscle, MGF is not detectable in dystrophic mdx muscles even when subjected to stretch and stretch combined with electrical stimulation. This is true for muscular dystrophies that are due to the lack of dystrophin (X‐linked) and due to a laminin deficiency (autosomal), thus indicating that the dystrophin cytoskeletal complex may be involved in the mechanotransduction mechanism. When this complex is defective the necessary systemic as well as autocrine IGF‐1 growth factors required for local repair are not produced and the ensuing cell death results in progressive loss of muscle mass. The discovery of the locally produced IGF‐1 appears to provide the link between the mechanical stimulus and the activation of gene expression.

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  • Mechanical tension is a sufficient stimulus to induce physiological adaptations such as increased protein turnover.

    “Boppart and Mahmassani [146] and Aguillar-Agon et al. [147] pointed out that mechanical tension was a sufficient stimulus to induce physiological adaptations such as increased protein turnover [148–152].”

    From Minimalist Training: Is Lower Dosage or Intensity Resistance Training Effective to Improve Physical Fitness? A Narrative Review (2024) · cites this paper as [149]

    The Introduction reports that stretch stimulates muscle protein synthesis and growth, supporting mechanical tension as a stimulus for physiological adaptation. It does not establish increased protein turnover overall: the passages report synthesis, not the combined processes of synthesis and breakdown. (LLM, conf=0.84)

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Research works printed but not linked: 6

  1. Peachy LD, Adrian RH, Geiger SR), pp. 593-554. Bethesda, MD : American Physiological Society.
  2. GOLDSPINK G, SCUTT A, LOUGHNA P, WELLS D, JAENICKE T, GERLACH G-F (1992) Gene expression in skeletal muscle in response to mechanical signals. American Journal of Physiology 262, R326-R363.
  3. GOLDSPINK G, YANG SY, SKARLI M, VRBOVA G (1996) Local growth regulation is associated with an isoform of IGF-1 that is expressed in normal muscle but not in dystrophic muscle when subjected to stretch. Journal of Physiology 496P, 10.
  4. INGEBAR DE (1997) Tensegrity : architectectural basis of cellular mechanotransduction. Annual Review of Physiology 59, 575-599
  5. RUDMAN DM, KUTNER MH, ROGERS CM, LUBIN MF, FLEMING GA, BAIN RP (1981) Impaired growth hormone secretion in the adult population. Journal of Clinical Investigation 67, 1361-1369
  6. SKARLI M, YANG SY, BOULOUX P, YELLON DM, GOLDSPINK G (1998) Upregulation of alternative splicing of the IGF-1 gene in the rabbit heart following a brief pressure\volume overload. Journal of Physiology 509, 192P.

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Authors
GOLDSPINK, G.
Affiliations
The Royal Free Hospital (GB)
Corresponding author
GOLDSPINK, GEOFFREY
Venue
Journal of Anatomy
Publisher
Wiley
Published
1999-04
Volume
194
Issue
3
Pages
323-334
ISSN
  • 0021-8782 (ISSN-L)
  • 1469-7580
DOI
10.1046/j.1469-7580.1999.19430323.x
OpenAlex
W2150077873
Cited by
435
References
67
Citations by year
2026: 5 · 2025: 3 · 2024: 5 · 2023: 9 · 2022: 2 · 2021: 8 · 2020: 8 · 2019: 12 · 2018: 13 · 2017: 6 · 2016: 17 · 2015: 13 · 2014: 18 · 2013: 26 · 2012: 18
FWCI
1.46
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 1355 d)
Locations
  • Journal of Anatomy (publishedVersion)
  • PubMed (publishedVersion)
Funders
Wellcome Trust
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
Keywords
mechanotransduction, muscle stretching, muscle overload, muscle hypertrophy, muscle atrophy, myosin heavy chain isoforms, mechano growth factor, autocrine growth factor, muscle phenotype, alternative splicing, gene expression regulation, cytoskeleton
MeSH terms
Adaptation, Physiological, Animals, Biomechanical Phenomena, Growth Substances, Humans, Insulin-Like Growth Factor I, Isomerism, Muscular Dystrophy, Animal, Myosins, Stress, Mechanical, Muscle, Skeletal, Autocrine Communication, Mice

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