Skeletal muscle biopsy and exercise rehabilitation in children with end-stage liver disease pre- and post-liver transplantation
Creators: Hager, Amber R
Publisher: name: University of Alberta Library
Year: 2024

<p>Background &amp; Aims: Sarcopenia, or muscle wasting (myopenia) with deficits in muscle strength/muscle function, is a common condition occurring in children awaiting liver transplantation (LTx). Changes in skeletal muscle structural and biological characteristics (fibre types, size, and presence of myocellular lipids) identified through muscle biopsies may be informative of the underlying physiological determinants of sarcopenia in liver disease and rehabilitation therapies that should be considered to treat this condition. Resistance training may positively influence muscle function and tissue regeneration/synthesis and may be an important therapy to treat sarcopenia in children after LTx. The aims of this thesis were to describe skeletal muscle biology in children at time of LTx and to study the effects of a 12-week resistance training program on skeletal muscle mass and function in children after LTx. In study 1, we microscopically describe characteristics of the rectus abdominus muscle in children with myopenia and ESLD at time of LTx. In study 2, we designed a 12-week resistance training program to improve muscle mass and function in children post-LTx.<br>
Methods: Study 1: A prospective cohort study involving characterization of muscle using histology (fibre types and size, location of nuclei) and gas chromatography (triacylglycerol content) from muscle biopsies of the rectus abdominus at time of LTx. Myopenia and high muscle adiposity were radiologically determined (MRI/CT at time of LTx assessment) based on cut-offs (-2SD) developed using healthy control data. Muscle mass and muscle characteristics were related to clinical outcomes including surgical complications, infection risk, and hospitalization. Study 2: A non-randomized controlled pilot study was conducted over 12 weeks. Children 6-18 years post-LTx and healthy age-sex matched controls were invited to participate. At baseline and 12-weeks, muscle and adipose tissue indices (abdomen and thigh) were determined by MRI and muscle strength/function was assessed using handgrip (HG), sit-to-stand (STS), push-up (PU), timed-up and down stairs test (TUDS), 6-minute walk tests (6MWT). <br>
Results: In study 1, Myopenia was present in 43% of children. Children also had a high prevalence of high muscle adiposity (25%) and high muscle adiposity+myopenia (11%). Children with myopenia were older (7yrs vs 1 yrs) and had smaller total (median 619 vs. 844µm/m2; p=0.05) and hybrid IIA/X (525±266 vs. 993±340 µm/m2; p=0.04) muscle fibre size index, higher proportion of type IIA/X hybrid (median 6 vs. 0%; p=0.04) and lower % type I fibres (median 52 vs. 64%; p=0.01). Lower IIA/X fibre size and higher proportion of centralized nuclei were associated with worse post-operative outcomes (longer LOS in hospital, ICU, days intubated, and higher number of post-Tx complications) (p&lt;0.05). In study 2, Ten children post-LTx (11.9±3.5 yrs) and 13 HC (11.7±3.9yrs) participated in the RT program. LTx children experienced significant increases in abdominal SMM index (+4.6% LTx vs a -2.7%  controls; p=0.01) and decreases in visceral adipose tissue index (-18% LTx vs -0.8% controls; p=0.04). Significant increases in 6MWT distance (LTx only; p=0.04) number of PU (both groups; p=0.04), and greater reduction in time for the TUDS test (-10.6% vs. +1.7%; p=0.05) occurred after 12-weeks of RT. Higher abdominal adiposity and inter- and intramuscular fat in the thigh was associated with worse STS test performance.<br>
Conclusions: Children with myopenia were older and had reduced skeletal muscle fibre size indices and alterations in proportions of type I and IIA/X fibres. A 12-week RT program shows promising effects in improving muscle mass and function. Future research should focus on understanding the effect of exercise on skeletal muscle in children within the context of rehabilitation and sarcopenia treatment. Early identification and treatment of sarcopenia in pediatric Tx recipients would enable better overall outcomes, quality of life, and participation daily activities and sports that all children and youth value and enjoy. </p>