After the chemotherapy: potential mechanisms for chemotherapy-induced delayed skeletal muscle dysfunction in survivors of acute lymphoblastic leukaemia in childhood

Abstract

There is evidence that survivors of childhood cancers, such as acute lymphoblastic leukemia (ALL), have increased rates of long-term skeletal muscle dysfunction. This places them at higher risk of physical restriction and functional impairment as well as potentially contributing to observed increases in cardiovascular disease and insulin resistance in later life. The mechanisms underlying these changes in skeletal muscle are unknown but chemotherapy drugs used in treatment for ALL are strongly implicated. Normal skeletal muscle growth, development, and function are dependent on correctly functioning muscle satellite cells, muscle motor neurons, and muscle mitochondria. Each of these key components is potentially susceptible to damage by chemotherapy in childhood, particularly prolonged courses including repeated administration of combination chemotherapy. If this chemotherapy-induced damage is not fully reversible, impairment of satellite cells, muscle motor innervation, and mitochondria could, either singly or together, lead to the emergence of delayed or persistent skeletal muscle dysfunction many years later. The known effects of individual drugs used in the treatment of ALL are outlined and the need for specific targeted studies to investigate the mechanisms underlying persistent muscle dysfunction in survivors of ALL and other childhood cancers is highlighted.

Skeletal muscle loss after total gastrectomy, exacerbated by adjuvant chemotherapy

“…Another anticancer agent, doxorubicin, has recently been shown to cause a catabolic response in skeletal muscle through oxidative stress by elevating the serum levels of inflammatory cytokines, especially tumor necrosis factor (TNF), resulting in a loss of skeletal muscle mass leading to weakness and fatigue [28]. One study reported delayed skeletal muscle dysfunction in survivors of childhood acute lymphoblastic leukemia, in which repeated administration of combination chemotherapy drugs (e.g., vincristine, glucocorticoids, doxorubicin, methotrexate, asparaginase) was strongly implicated [29]. These findings suggest that chemotherapy could affect skeletal muscle loss.…”

BGP-15 Protects against Oxaliplatin-Induced Skeletal Myopathy and Mitochondrial Reactive Oxygen Species Production in Mice

“…However, due to its non-specific and systemic mode of action, chemotherapy also elicits effects on healthy tissues causing the classic side-effects attributable to anti-cancer therapy including nausea, vomiting, cardio-toxicity, immune disorders, peripheral and axial neuropathy, hair and weight loss and debilitative fatigue (Greene et al, 1993; Zitvogel et al, 2008; Gilliam and St Clair, 2011; National Cancer Institute, 2012; Ariaans et al, 2015). These side-effects often limit treatment tolerability, efficacy and therapeutic options, sometimes leading to the cessation of treatment all together and ultimately reducing patient quality of life and prognosis due to the development of co-morbidities (Gilliam and St Clair, 2011; Scheede-Bergdahl and Jagoe, 2013; Argilés et al, 2015; Cheregi et al, 2015). Emerging evidence suggests that the skeletal muscle is also a target of chemotherapy-induced atrophy (Pfeiffer et al, 1997), weakness and fatigue (Gilliam and St Clair, 2011), dysfunction (Scheede-Bergdahl and Jagoe, 2013; Bredahl et al, 2016) and insulin resistance (Ariaans et al, 2015).…”

“…These side-effects often limit treatment tolerability, efficacy and therapeutic options, sometimes leading to the cessation of treatment all together and ultimately reducing patient quality of life and prognosis due to the development of co-morbidities (Gilliam and St Clair, 2011; Scheede-Bergdahl and Jagoe, 2013; Argilés et al, 2015; Cheregi et al, 2015). Emerging evidence suggests that the skeletal muscle is also a target of chemotherapy-induced atrophy (Pfeiffer et al, 1997), weakness and fatigue (Gilliam and St Clair, 2011), dysfunction (Scheede-Bergdahl and Jagoe, 2013; Bredahl et al, 2016) and insulin resistance (Ariaans et al, 2015). These effects appear to be more pronounced when chemotherapy is administered in childhood, due to the hyperplastic and hypertrophic nature of skeletal muscle at this early stage of life and persist well into adulthood (Ness et al, 2007; Scheede-Bergdahl and Jagoe, 2013; Ariaans et al, 2015).…”

“…Emerging evidence suggests that the skeletal muscle is also a target of chemotherapy-induced atrophy (Pfeiffer et al, 1997), weakness and fatigue (Gilliam and St Clair, 2011), dysfunction (Scheede-Bergdahl and Jagoe, 2013; Bredahl et al, 2016) and insulin resistance (Ariaans et al, 2015). These effects appear to be more pronounced when chemotherapy is administered in childhood, due to the hyperplastic and hypertrophic nature of skeletal muscle at this early stage of life and persist well into adulthood (Ness et al, 2007; Scheede-Bergdahl and Jagoe, 2013; Ariaans et al, 2015). Since skeletal muscle has a high energy requirement, and thus a high mitochondrial density, emerging data suggests that skeletal muscle pathology may be underpinned by damage induced to the mitochondrial by chemotherapy administration (Davies and Doroshow, 1986; Doroshow and Davies, 1986; Sarosiek et al, 2013; Tabassum et al, 2015).…”

A Review of Cardiorespiratory Fitness in Adolescent and Young Adult Survivors of Childhood Cancer: Factors that Affect its Decline and Opportunities for Intervention

“…27 Though data on muscular changes among survivors of childhood cancer are sparse, Scheede-Bergdahl et al have reviewed potential mechanisms of chemotherapy-induced skeletal muscle dysfunction in survivors of childhood ALL, noting impairments in muscle satellite cells, motor neurons, and muscle mitochondrial function that all contribute to reduced mobility and oxidative function. 50 …”