Life science
Medical & healthcare

New insights into the mechanism underlying
muscle hypertrophy during resistance training
Laboratory of Stem Cell Regeneration and Adaptation, Graduate School of Pharmaceutical Sciences
Professor So-ichiro Fukada
https://researchmap.jp/mdx?lang=en

Life science

Abstract
Skeletal muscle is mainly composed of multinucleated cells
called myofibers. It has been established that skeletal muscle
hypertrophy by resistance training requires an increased numberof myonuclei provided by muscle satellite cells (MuSCs). Nevertheless, the mechanisms governing how MuSCs respond to
the increased mechanical load during resistance training longremained elusive. Our research has unveiled that stromal cells inskeletal muscle (mesenchymal progenitors) perceive the increased
mechanical load and subsequently secrete factors inducing MuSCproliferation.

atrophy conditions. If the responses of mesenchymal progenitors
observed during muscle training can be safely replicated throughpharmaceutical interventions, our findings hold the promise of pioneering innovative anti-muscle atrophy medications.

▍ Background & Results
Skeletal muscle consists of multinucleated cells called myofibers.
Prolonged periods of disuse, such as being bedridden or immobilized in a cast induce muscle atrophy. Aging also causes skeletal
muscle atrophy, increasing the risk of fractures resulting from falls,
reducing overall activity levels, and ultimately decreasing healthy
life expectancy. Skeletal muscle atrophy is thus a pressing global
research concern that demands therapeutic approaches.
Conversely, skeletal muscles possess the ability to increase
their size (hypertrophy) by training. Understanding the mechanism
underlying skeletal muscle hypertrophy is a highly active area of
research within the field of musculoskeletal studies, as it is likely tolead to the development of preventive and therapeutic methods for
atrophy and innovative drugs to extend healthy life expectancy.
One of the mechanisms identified for muscle hypertrophy induced by muscle training is the increase in the number of myonuclei. It is well-established that MuSCs, which are stem cells specificto skeletal muscle, play a pivotal role in this increase of myonuclei
number. However, the manner in which MuSCs proliferate in response to the physical forces generated during muscle training
had remained elusive. While it had generally been assumed thatMuSC proliferation is triggered by the breakdown of myofibers during muscle training, our previous study has revealed that MuSCs
can proliferate independently death of myofibers. In the present
study, our research group focused on mesenchymal progenitorsand discovered that these cells secrete molecules necessary forthe proliferation of MuSCs in response to the physical force exerted
by muscle training.

Figure 1 When YAP/TAZ, which migrate to the nucleus in a mechanical load-dependent manner, is eliminated in mesenchymal progenitors, myofiber size does
not increase with mechanical load compared to controls. The increased numberof myonuclei observed in Cont is also almost nonexistent in cKO.

▍ Significance of the research and Future perspective
In recent years, stromal cells (fibroblasts) in various organs havegarnered significant attention. It is becoming increasingly evident
that stromal cells in different tissues possess unique characteristics. The stromal cells in skeletal muscle (mesenchymal progenitors) are highly differentiated into adipocytes, which cause scar formation. Intriguingly, mesenchymal progenitors also play a crucialrole in maintaining skeletal muscle homeostasis and facilitating regeneration. Consequently, they have emerged as potential targets
for addressing skeletal muscle diseases through pharmacologicalinterventions. Our current study not only unveils novel insights
into the biology of skeletal muscle mesenchymal progenitors but
also underscores their relevance as therapeutic targets for muscle

Figure 2 Increased mechanical load causes nuclear translocation of YAP/TAZ in
mesenchymal progenitors, and then mesenchymal progenitors secrete thrombospondin 1. Satellite cells that have lost calcitonin receptor expression recognize
the presence of thrombospondin 1 using CD47 and proliferate. The proliferating
satellite cells eventually fuse with myofibers, becoming the nuclei of new myofibers and contributing the increase in muscle mass.

P a t e n t
Tr e a t i s e

Kaneshige, Akihiro; Kaji, Takayuki; Zhang, Lidan et al. Relayed signaling between mesenchymal progenitors and muscle stem cells ensures adaptive stemcell response to increased mechanical load. Cell Stem Cell. 2022, 29(2):265-280.e6. doi: 10.1016/j.stem.2021.11.003
Fukuda, Sumiaki; Kaneshige, Akihiro; Kaji, Takayuki et al. Sustained expression of HeyL is critical for the proliferation of muscle stem cells in overloaded
muscle. Elife. 2019, 8:e48284. doi: 10.7554/eLife.48284

URLK e y w o r d resistance training, mesenchymal progenitors, muscle satellite cells