Exercise Intolerance in Anthracycline-Treated Breast Cancer Survivors: The Role of Skeletal Muscle Bioenergetics, Oxygenation, and Composition

Abstract

Background. Peak oxygen consumption (VO 2 ) is reduced in women with a history of breast cancer (BC). We measured leg blood flow, oxygenation, bioenergetics, and muscle composition in women with BC treated with anthracycline chemotherapy (n = 16, mean age: 56 years) and age-and body mass index-matched controls (n = 16). Materials and Methods. Whole-body peak VO 2 was measured during cycle exercise. 31 Phosphorus magnetic resonance (MR) spectroscopy was used to measure muscle bioenergetics during and after incremental to maximal plantar flexion exercise (PFE). MR imaging was used to measure lower leg blood flow, venous oxygen saturation (S v O 2 ), and VO 2 during submaximal PFE, and abdominal, thigh, and lower leg intermuscular fat (IMF) and skeletal muscle (SM). Results. Whole-body peak VO 2 was significantly lower in BC survivors versus controls (23.1 AE 7.5 vs. 29.5 AE 7.7 mL/kg/minute).Muscle bioenergetics and mitochondrial oxidative capacity were not different between groups. No group differences were found during submaximal PFE for lower leg blood flow, S v O 2 , or VO 2 . The IMF-to-SM ratio was higher in the thigh and lower leg in BC survivors (0.36 AE 0.19 vs. 0.22 AE 0.07, p = .01; 0.10 AE 0.06 vs. 0.06 AE 0.02, p = .03, respectively) and were inversely related to whole-body peak VO 2 (r = −0.71, p = .002; r = −0.68, p = .003, respectively) . In the lower leg, IMF-to-SM ratio was inversely related to VO 2 and O 2 extraction during PFE. Conclusion. SM bioenergetics and oxidative capacity in response to PFE are not impaired following anthracycline treatment. Abnormal SM composition (increased thigh and lower leg IMF-to-SM ratio) may be an important contributor to reduced peak VO 2 during whole-body exercise among anthracycline-treated BC survivors. The Oncologist 2020;25:e852-e860 Implications for Practice: Peak oxygen consumption (peak VO 2 ) is reduced in breast cancer (BC) survivors and is prognostic of increased risk of cardiovascular disease-related and all-cause mortality. Results of this study demonstrated that in the presence of deficits in peak VO 2 1 year after anthracycline therapy, skeletal muscle bioenergetics and oxygenation are not impaired. Rather, body composition deterioration (e.g., increased ratio of intermuscular fat to skeletal muscle) may contribute to reduced exercise tolerance in anthracycline BC survivors. This finding points to the importance of lifestyle interventions including caloric restriction and exercise training to restore body composition and cardiovascular health in the BC survivorship setting.

Cardiovascular Consequences of Skeletal Muscle Impairments in Breast Cancer

“…Breast cancer-related treatment and lifestyle factors have been associated with impaired skeletal muscle quality, which, in turn, may contribute to exercise intolerance [ 32 ]. The most widely recognized aspect of reduced skeletal muscle quality in breast cancer is cachexia, which is characterized by intramuscular fat deposition and sarcopenia (skeletal muscle atrophy) [ 12 , 48 ].…”

“…Anthracycline-based chemotherapeutics have been linked to deleterious changes in the intramuscular fat to skeletal muscle ratio [ 49 ], yet these compositional shifts are also known to occur as a result of poor lifestyle factors, such as physical inactivity and obesity [ 50 , 51 ]. Importantly, the ratio of intramuscular fat to skeletal muscle has been inversely associated with local muscle and whole-body VO 2 in breast cancer survivors [ 32 ] and reported to explain approximately 50% of the variability in cardiorespiratory fitness in these individuals [ 32 ]. It is not fully clear how intramuscular fat is related to VO 2 , but potential mechanisms include: (i) blood flow diversion to metabolically inactive intramuscular fat via vasodilation of adipose tissue vessels, (ii) increased distance for oxygen to travel from capillaries to muscle mitochondria, and (iii) decreased overall blood flow to tissue [ 32 , 52 , 53 , 54 ].…”

“…While skeletal muscle dysfunction may be preexisting, it can also be a direct (e.g., anthracycline-mediated skeletal muscle damage) or indirect (e.g., atrophy as a result of treatment-mediated physical inactivity) consequence of traditional treatments [ 12 , 19 , 28 , 29 , 30 ]. Skeletal muscle dysfunction may be a central component linking many therapy-related toxicities and lifestyle factors with overall CVD risk, and is potentially a unique, additional contributor to CVD risk in this population [ 31 , 32 ].…”

“…Of concern, breast cancer survivors typically have a VO 2peak 20–30% less than healthy age-matched controls [ 28 , 34 , 38 ], displaying an exercise intolerance that skeletal muscle dysfunction may be driving. Breast cancer-related treatment and lifestyle factors—which may or may not be directly related to said treatment—can lead to maladaptive changes in skeletal muscle mass, quality, function, and oxidative capacity [ 32 , 39 , 40 ]. These negative changes can contribute to reduced VO 2peak and promote exercise intolerance [ 28 , 32 , 41 ].…”

“…Breast cancer-related treatment and lifestyle factors—which may or may not be directly related to said treatment—can lead to maladaptive changes in skeletal muscle mass, quality, function, and oxidative capacity [ 32 , 39 , 40 ]. These negative changes can contribute to reduced VO 2peak and promote exercise intolerance [ 28 , 32 , 41 ]. Somewhat ironically, muscular health and fitness are essential to properly engage in the very practices known to promote cardiovascular health, specifically, exercise.…”