January 17, 2017
Tumor suppressor key in maintaining stem cell status in muscle
WEST LAFAYETTE, Ind. – A gene known to suppress tumor formation in a broad range of tissues plays a key role in keeping stem cells in muscles dormant until needed, a finding that may have implications for both human health and animal production, according to a Purdue University study.
Shihuan Kuang, professor of animal sciences, and Feng Yue, a postdoctoral researcher in Kuang’s lab, reported their findings in two papers published in the journals Cell Reports and Nature Communications. The results suggest modifying expression of the PTEN gene could one day play a role in increasing muscle mass in agricultural animals and improve therapies for muscle injuries in humans.
Muscle stem cells, called satellite cells, normally sit in a quiescent, or dormant, state until called upon to build muscle or repair a damaged muscle. Inability to maintain the quiescence would lead to a loss of satellite cells. As humans age, the number of satellite cells gradually declines and the remaining cells become less effective in regenerating muscles, resulting in muscle loss – a condition called sarcopenia.
Kuang and Yue, in the Nature Communications paper, explored the role tumor-suppressor gene PTEN plays in satellite cells. The PTEN gene encodes a protein that suppresses the growth signaling, thereby, limiting the growth of fast-growing tumor cells. Mutation of the PTEN gene is associated with many types of cancers, but how the gene functions in muscle stem cells is unknown.
To understand the function of a gene, the authors first wanted to know how the gene is expressed.
“This gene is highly expressed in the satellite cells when the cells are in the quiescent state. When they become differentiated, the PTEN level reduces,” Yue said.
By knocking out the PTEN gene in resting satellite cells, the researchers found that satellite cells quickly differentiate and become muscle cells. So PTEN plays an essential role in keeping satellite cells in their quiescent state.
“You no longer have the stem cells once you knock out the gene,” Kuang said.
In their Cell Reports paper, Kuang and Yue took a step further to examine PTEN function in proliferating stem cells. This time, they knocked out PTEN in embryonic progenitor cells, those that will later become muscle in the mouse. They found that as the mouse grew, muscle mass increased significantly — by as much as 40 percent in some muscles — over that of a normal mouse.
“That would be significant in an animal production point of view,” Kuang said.
The increased muscle came with a cost, however. Besides creating muscle, those progenitor cells create satellite cells. Without PTEN, not only fewer satellite cells were created, but the resulting satellite cells cannot maintain dormancy, leading to an accelerated rate of depletion during aging.
The faster depletion of satellite cells during aging wouldn’t matter much in an animal production scenario, Kuang said. Beef cattle, for example, are harvested before they age. The increase in muscle mass, however, would be a significant advantage in production efficiency.
The findings may lead to improvement in human health, the authors said. The ability to control the expression of PTEN could lead to therapies for quicker healing of muscle injuries.
“If you want to quickly boost up the stem cells to repair something, you need to suppress PTEN,” Kuang said. “After that, you’d need to increase PTEN to return the cells back to quiescent state. If we could do that, you would suspect that the muscle would repair more quickly.”
Knowing that PTEN also suppresses tumors in many types of tissues, the authors noted that the elimination of the gene did not cause tumor formation in the muscle cells they studied. That suggests regulation of PTEN could be a feasible method for improving human health and animal agriculture.
The National Institutes of Health, the Purdue University Center for Cancer Research and other Purdue resources funded the research.
Writer: Brian Wallheimer, 765-532-0233, firstname.lastname@example.org
Sources: Shihuan Kuang, 765-494-8283, email@example.com
Feng Yue, 765-496-6274, firstname.lastname@example.org
Pten is necessary for the quiescence and maintenance of adult muscle stem cells
Feng Yue1, Pengpeng Bi1 , Chao Wang1 , Tizhong Shan1 , Yaohui Nie1,2, Timothy L. Ratliff3,4, Timothy P. Gavin2 & Shihuan Kuang1,3
1 Department of Animal Sciences, Purdue University, 901W State Street, West Lafayette, Indiana
2 Department of Health and Kinesiology, Purdue University, 800W. Stadium Ave, West Lafayette, Indiana
3 Center for Cancer Research, Purdue University, 201S University Street, West Lafayette, Indiana.
4 Department of Comparative Pathobiology, Purdue University, 625 Harrison St, West Lafayette, Indiana
Satellite cells (SCs) are myogenic stem cells required for regeneration of adult skeletal muscles. A proper balance among quiescence, activation and differentiation is essential for long-term maintenance of SCs and their regenerative function. Here we show a function of Pten (phosphatase and tensin homologue) in quiescent SCs (QSCs). Deletion of Pten in QSCs leads to their spontaneous activation and premature differentiation without proliferation, resulting in depletion of SC pool and regenerative failure. However, prior to depletion, Pten-null activated SCs can transiently proliferate upon injury and regenerate injured muscles, but continually decline during regeneration, suggesting an inability to return to quiescence. Mechanistically, Pten deletion increases Akt phosphorylation, which induces cytoplasmic translocation of FoxO1 and suppression of Notch signaling. Accordingly, constitutive activation of Notch1 prevents SC depletion despite Pten deletion. Our findings delineate a critical function of Pten in maintaining SC quiescence and reveal an interaction between Pten and Notch signaling.
Loss of Pten in Myogenic Progenitors Leads to Postnatal Skeletal Muscle Hypertrophy but Age-Dependent Exhaustion of Satellite Cells
Feng Yue, Pengpeng Bi, Chao Wang, Jie Li, Xiaoqi Liu, Shihuan Kuang
Skeletal muscle stem cells (satellite cells [SCs]) are normally maintained in a quiescent (G0) state. Muscle injury not only activates SCs locally, but also alerts SCs in distant uninjured muscles via circulating factors. The resulting GAlert SCs are adapted to regenerative cues and regenerate injured muscles more efficiently, but whether they provide any long-term benefits to SCs is unknown. Here, we report that embryonic myogenic progenitors lacking the phosphatase and tensin homolog (Pten) exhibit enhanced proliferation and differentiation, resulting in muscle hypertrophy but fewer SCs in adult muscles. Interestingly, Pten null SCs are predominantly in the GAlert state, even in the absence of an injury. The GAlert SCs are deficient in self-renewal and subjected to accelerated depletion during regeneration and aging and fail to repair muscle injury in old mice. Our findings demonstrate a key requirement of Pten in G0 entry of SCs and provide functional evidence that prolonged GAlert leads to stem cell depletion and regenerative failure.