Search

Aging-related loss of adult stem cell function contributes to impaired tissue regeneration. Mice deficient in zinc metalloproteinase STE24 (Zmpste24−/−) exhibit premature age-related musculoskeletal pathologies similar to those observed in children with Hutchinson-Gilford progeria syndrome (HGPS). We have reported that muscle-derived stem/progenitor cells (MDSPCs) isolated from Zmpste24−/− mice are defective in their proliferation and differentiation capabilities in culture and during tissue regeneration. The mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth, and inhibition of the mTORC1 pathway extends the lifespan of several animal species. We therefore hypothesized that inhibition of mTORC1 signaling would rescue the differentiation defects observed in progeroid MDSPCs. MDSPCs were isolated from Zmpste24−/− mice, and the effects of mTORC1 on MDSPC differentiation and function were examined. We found that mTORC1 signaling was increased in senescent Zmpste24−/− MDSPCs, along with impaired chondrogenic, osteogenic, and myogenic differentiation capacity versus wild-type MDSPCs. Interestingly, we observed that mTORC1 inhibition with rapamycin improved myogenic and chondrogenic differentiation and reduced levels of apoptosis and senescence in Zmpste24−/− MDSPCs. Our results demonstrate that age-related adult stem/progenitor cell dysfunction contributes to impaired regenerative capacities and that mTORC1 inhibition may represent a potential therapeutic strategy for improving differentiation capacities of senescent stem and muscle progenitor cells.

The primary risk factor for most musculoskeletal diseases, including osteoarthritis, osteoporosis and sarcopenia, is aging. To treat the diverse types of musculoskeletal diseases and pathologies, targeting their root cause, the aging process itself, has the potential to slow or prevent multiple age-related musculoskeletal conditions simultaneously. However, the development of approaches to delay onset of age related diseases, including musculoskeletal pathologies, has been slowed by the relatively long lifespan of rodent models of aging. Thus, to expedite the development of therapeutic approaches for age-related musculoskeletal disease, the implementation of mouse models of accelerated musculoskeletal aging are of great utility. Currently there are multiple genetically diverse mouse models that mirror certain aspects of normal human and mouse aging. Here, we provide a review of some of the most relevant murine models of accelerated aging that mimic many aspects of natural musculoskeletal aging, highlighting their relative strengths and weaknesses. Importantly, these murine models of accelerated aging recapitulate phenotypes of musculoskeletal age-related decline observed in humans.

Aging affects bones, cartilage, muscles, and other connective tissue in the musculoskeletal system, leading to numerous age-related pathologies including osteoporosis, osteoarthritis, and sarcopenia. Understanding healthy aging may therefore open new therapeutic targets, thereby leading to the development of novel approaches to prevent several age-related orthopaedic diseases. It is well recognized that aging-related stem cell depletion and dysfunction leads to reduced regenerative capacity in various musculoskeletal tissues. However, more recent evidence suggests that dysregulated autophagy and cellular senescence might be fundamental mechanisms associated with aging-related musculoskeletal decline. The mammalian/mechanical target of Rapamycin (mTOR) is known to be an essential negative regulator of autophagy, and its inhibition has been demonstrated to promote longevity in numerous species. Besides, several reports demonstrate that selective elimination of senescent cells and their cognate Senescence-Associated Secretory Phenotype (SASP) can mitigate musculoskeletal tissue decline. Therefore, senolytic drugs/agents that can specifically target senescent cells, may offer a novel therapeutic strategy to treat a litany of age-related orthopaedic conditions. This chapter focuses on osteoarthritis and osteoporosis, very common debilitating orthopaedic conditions, and reviews current concepts highlighting new therapeutic strategies, including the mTOR inhibitors, senolytic agents, and mesenchymal stem cell (MSC)-based therapies.

Hutchinson–Gilford progeria syndrome (HGPS) is caused by the accumulation of mutant prelamin A (progerin) in the nuclear lamina, resulting in increased nuclear stiffness and abnormal nuclear architecture. Nuclear mechanics are tightly coupled to cytoskeletal mechanics via lamin A/C. However, the role of cytoskeletal/nuclear mechanical properties in mediating cellular senescence and the relationship between cytoskeletal stiffness, nuclear abnormalities, and senescent phenotypes remain largely unknown. Here, using muscle‐derived mesenchymal stromal/stem cells (MSCs) from the Zmpste24 −/− (Z24 −/−) mouse (a model for HGPS) and human HGPS fibroblasts, we investigated the mechanical mechanism of progerin‐induced cellular senescence, involving the role and interaction of mechanical sensors RhoA and Sun1/2 in regulating F‐actin cytoskeleton stiffness, nuclear blebbing, micronuclei formation, and the innate immune response. We observed that increased cytoskeletal stiffness and RhoA activation in progeria cells were directly coupled with increased nuclear blebbing, Sun2 expression, and micronuclei‐induced cGAS‐Sting activation, part of the innate immune response. Expression of constitutively active RhoA promoted, while the inhibition of RhoA/ROCK reduced cytoskeletal stiffness, Sun2 expression, the innate immune response, and cellular senescence. Silencing of Sun2 expression by siRNA also repressed RhoA activation, cytoskeletal stiffness and cellular senescence. Treatment of Zmpste24− / − mice with a RhoA inhibitor repressed cellular senescence and improved muscle regeneration. These results reveal novel mechanical roles and correlation of cytoskeletal/nuclear stiffness, RhoA, Sun2, and the innate immune response in promoting aging and cellular senescence in HGPS progeria., There is increased RhoA activation and cytoskeleton stiffness in progeria cells, which mediates increased nuclear blebbing, micronuclei formation, innate immune response, and cellular senescence. RhoA activation is coupled with elevated Sun2 expression, but not Sun1, especially in nucleus with blebbing and micronuclei. Repression of RhoA and Sun2 activation was able to reduce cytoskeleton stiffness, nuclear blebbing, and micronuclei formation and delay the progression of cellular senescence.

Skeletal muscle is a highly interactive connective tissue that makes up a large portion of an adult's body mass. Muscles are integrated with tendons as well as other specialized structures to support physiologic and homeostatic functions. In the state of injury, muscles have the ability to innately repair themselves through various phases of tightly regulated healing that can result in fibrotic tissue development. However, during aging, these homeostatic processes are disrupted leading to sarcopenia and reduced muscle regeneration capacity. Several cell-based therapies and biologic therapies have been investigated to regenerate skeletal muscle tissue and reduce fibrosis following injury or during aging. These include platelet-rich plasma (PRP) and an acellular portion of blood known as platelet-poor plasma (PPP). However, current clinical practice recommendations for the utilization of different PRP preparations vs PPP are unclear. Recent efforts have strove to improve the understanding of the role of senescent cells and profiles in the presence of early to late stage skeletal muscle injury and fibrosis, yet targeted interventions to remove senescent cells and attenuate the secretory environment to improve muscle regeneration are still forthcoming. Therefore, the purpose of this article is to review the basic principles of skeletal muscle repair, the role of senescence in attenuated muscle regeneration, and discuss current standards and literature supporting PRP and PPP treatment for skeletal muscle repair. This review concludes with future directions to improve biologic therapies and ongoing initiatives to customize PRP and PPP preparations using Food and Drug Administration-approved medications.