Insulin and exercise improved muscle function in rats with severe burns and hindlimb unloading

Abstract

Prior work established that exercise alleviates muscle function loss in a clinically relevant rodent model mimicking the clinical sequelae of severely burned patients. On the basis of these data, we posit that pharmacologic treatment with insulin combined with exercise further mitigates loss of muscle function following severe burn with immobilization. Twenty‐four Sprague–Dawley rats were assessed and trained to complete a climbing exercise. All rats followed a standardized protocol to mimic severe burn patients (40% total body surface area scald burn); all rats were immediately placed into a hindlimb unloading apparatus to simulate bedrest. The rats were then randomly assigned to four treatment groups: saline vehicle injection without exercise (VEH/NEX), insulin (5 U/kg) injection without exercise (INS/NEX), saline vehicle with daily exercise (VEH/EX), and insulin with daily exercise (INS/EX). The animals were assessed for 14 days following injury. The groups were compared for multiple variables. Isometric tetanic (Po) and twitch (Pt) forces were significantly elevated in the plantaris and soleus muscles of the INS/EX rats ( P < 0.05). Genomic analysis revealed mechanistic causes with specific candidate changes. Molecular analysis of INS/EX rats revealed Akt phosphorylated by PDPK1 was increased with this treatment, and it further activated downstream signals mTOR, eEF2, and GSK3‐ β ( P < 0.05). Furthermore, muscle RING‐finger protein‐1 (MuRF‐1), an E3 ubiquitin ligase, was reduced in the INS/EX group ( P < 0.05). Insulin and resistance exercise have a positive combined effect on the muscle function recovery in this clinically relevant rodent model of severe burn. Both treatments altered signaling pathways of increasing protein synthesis and decreasing protein degradation.

Metformin prevents the pathological browning of subcutaneous white adipose tissue

“…Therefore, the extent of muscle catabolism and atrophy in the murine model does not mimic the human experience, and we propose that maintenance of skeletal muscle glucose uptake via GLUT4 underlies the absence of hyperglycemia in murine studies despite the elevated glucose levels and insulin resistance observed in burn patients [38]. This may be corrected with a hindlimb unloading model, which more accurately captures the magnitude of muscle atrophy post-burn [39].…”

MuRF1/TRIM63, Master Regulator of Muscle Mass

“…Such a down-regulation was also observed using other reversible rodent atrophy models like nerve injury [ 39 , 40 ] or tetrodotoxin injection [ 41 ]. Accordingly, anabolic effectors like leucine [ 42 , 43 , 44 ], insulin, or IGF-1 [ 45 , 46 , 47 , 48 ] are able to blunt the expression of MuRF1 in parallel to muscle sparing during different catabolic situations (dexamethasone, unloading, burns). However, IGF-1 is not able to repress Angiotensin II-induced [ 49 ] or LPS-induced [ 50 ] muscle atrophy, suggesting that the prevalence of anabolic and catabolic stimuli depends on the nature of the stimuli.…”

Burn-induced hypermetabolism and skeletal muscle dysfunction

“…They also noted the insulin-induced activation of 3-phosphoinositide-dependent protein kinase-1 (PDK1) with downstream phosphorylation of Akt mediating survival signals and conferring resistance to apoptosis. Moreover, there was an increase in eukaryotic elongation factor 2 promoting protein synthesis and decrease in MuRF-1, which regulates degradation, further supporting insulin's benefits for protein homeostasis in muscle (122). Despite these benefits, exogenous insulin is also associated with episodes of hypoglycemia, which increase mortality ninefold in patients with burns (123).…”