Cellular Basis for Radiation induced acceleration of sarcopenia in juvenile cancer survivors

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ABSTRACT: Although estimates indicate the 5-year survival rate of children diagnosed with a malignancy is near 80%, the vast majority of these individuals prior to the age of 40 demonstrate indices of physical limitation normally associated with the elderly population. Among the age-related phenotypes observed earlier in childhood cancer survivors is sarcopenia, the accelerated loss of lean body skeletal muscle tissue and strength with age. Sarcopenia is characterized by loss of muscle stem cells (satellite cells) and chronic low-grade inflammation, which causes atrophy of muscle fibers (myofibers). This proposal is designed to elucidate if juvenile radiation treatments lead to systemic loss of satellite cells that 1) impairs juvenile skeletal muscle maturation, and 2) accelerates sarcopenia in childhood cancer survivors. Importantly, we propose that satellite cell-specific forced expression of sprouty1 (Spry1), a receptor tyrosine kinase feedback regulator, can prevent systemic loss of satellite cells, skeletal muscle declines, and low-grade inflammation induced by juvenile irradiation. To accomplish these objectives satellite cell-specific mouse genetic models, interrogation of skeletal muscle morphology, physiology, and inflammation in response to juvenile irradiation will be conducted. We have generated preliminary data that show satellite cell activity and contribution persists after P21 (weaning age in mice) and declines ~P42 (puberty onset), suggesting that radiation could damage muscle growth up to puberty. Indeed, depletion of satellite cells, or local irradiation at juvenile stages (P28) induced loss of myonuclei and atrophy. Furthermore, the irradiation leads to persistent satellite cell loss and elevated macrophage content, a source of atrophy inducing cytokines. Consistent with a systemic effect, irradiation of one leg triggered atrophy, loss of myonuclei and satellite cells, and increased macrophage content in contralateral muscles. In addition, in satellite cells from irradiated muscle we find reduced expression of Spry1. We will solidify our preliminary findings, and assess the consequences of satellite cell depletion and irradiation on juvenile skeletal muscle maturation and sarcopenia. In addition, we will examine if satellite cell specific Spry1 forced expression can prevent juvenile radiation induced acceleration of sarcopenia. The specific aims of this proposal are: 1) To determine if satellite cell depletion at juvenile stages leads to sustained muscle decline, and low-grade inflammation, 2) To determine if juvenile radiotherapy induces systemic and persistent satellite cell loss, muscle decline, and low-grade inflammation, and 3) To determine if satellite cell-specific forced Spry1 expression prevents juvenile radiotherapy-mediated systemic loss of satellite cells, muscle decline, and low-grade inflammation. Data from this proposal should rigorously define the role of satellite cells in juvenile radiotherapy-induced sarcopenia, and elucidate if the Spry1 pathway is a potential target to prevent systemic satellite cell decline and accelerated sarcopenia induced by juvenile radiotherapy.