Challenges to Skeletal Muscle During Advancing Age: A Translational Approach

The purpose of this dissertation was 1) to develop noninvasive strategies to assess skeletal muscle size, architecture, and composition in young and old adults (study #1) and 2) evaluate the impact of chemotherapeutic treatment on skeletal muscle satellite cells and capillaries (study #2). For study #1 ultrasound images were obtained from the quadriceps muscles of young (8 m, 8 f) and older (7 m, 5 f) participants on two occasions, separated by 5-15 days. Images were collected while the participants were both standing and supine, and were analyzed for muscle thickness, pennation angle, and echogenicity. In addition, test-retest reliability and ICCs were evaluated for each posture and when imaging sites remained marked or were re-measured from visit #1 to visit #2. Generally, in both younger and older adults muscle thickness was greater and echogenicity was lower in the anterior quadriceps when images were collected standing versus supine. Maintaining the imaging site between visits did not influence test re-test reliability for either age group. Older adults exhibited smaller muscle thickness, lower pennation angle and increased echogenicity. Further, variability for the use of ultrasound to determine muscle thickness and pennation angle was greater in older versus younger adults. Findings from study #1 highlight several methodological considerations for US-based assessment of skeletal muscle characteristics that should be considered for improving reproducibility and generalizability of US to assess skeletal muscle characteristics and function across the aging spectrum. This is particularly relevant given the emerging use of ultrasound to assess skeletal muscle characteristics in healthy and clinical populations. In the second study, ovariectomized female Sprague-Dawley rats were randomized to receive three bi-weekly intraperitoneal injections of the chemotherapeutic drug, Doxorubicin (DOX) (4mg/kg; cumulative dose 12mg/kg) or vehicle (VEH; saline). Animals were euthanized 5d following the last injection, and the soleus (SOL) and extensor digitorum longus (EDL) muscles were dissected and prepared for immunohistochemical and RT-qPCR analyses. Relative to VEH, cross-sectional area (CSA) of the SOL and EDL muscle fibers were 26% and 33% smaller, respectively, in DOX animals (P<0.05). In the SOL satellite cell and capillary densities were 39% and 35% lower, respectively, in DOX animals (P<0.05), whereas in the EDL satellite cell and capillary densities were unaffected by DOX administration (P>0.05). In the SOL MYF5 mRNA expression was increased in DOX animals (P<0.05), while in the EDL MGF mRNA expression was reduced in DOX animals (P<0.05). Chronic DOX administration is associated with reduced fiber size in multiple skeletal muscles, however DOX appears to impact the satellite cell and capillary densities in a muscle-specific manner. These findings from study #2 highlight that therapeutic targets to protect skeletal muscle from DOX may vary across muscles. Collectively, these findings 1) improve the ability to examine muscle size and function in younger and older adults, and 2) identify promising therapeutic targets to protect skeletal muscle from the harmful effects of chemotherapy treatment.