Statin Therapy Negatively Impacts Skeletal Muscle Regeneration and Cutaneous Wound Repair in Type 1 Diabetic Mice

Abstract

Those with diabetes invariably develop complications including cardiovascular disease (CVD). To reduce their CVD risk, diabetics are generally prescribed cholesterol-lowering 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors (i.e., statins). Statins inhibit cholesterol biosynthesis, but also reduce the synthesis of a number of mevalonate pathway intermediates, leading to several cholesterol-independent effects. One of the pleiotropic effects of statins is the reduction of the anti-fibrinolytic hormone plasminogen activator inhibitor-1 (PAI-1). We have previously demonstrated that a PAI-1 specific inhibitor alleviated diabetes-induced delays in skin and muscle repair. Here we tested if statin administration, through its pleiotropic effects on PAI-1, could improve skin and muscle repair in a diabetic rodent model. Six weeks after diabetes onset, adult male streptozotocin-induced diabetic (STZ), and WT mice were assigned to receive control chow or a diet enriched with 600 mg/kg Fluvastatin. Tibialis anterior muscles were injured via Cardiotoxin injection to induce skeletal muscle injury. Punch biopsies were administered on the dorsal scapular region to induce injury of skin. Twenty-four days after the onset of statin therapy (10 days post-injury), tissues were harvested and analyzed. PAI-1 levels were attenuated in statin-treated diabetic tissue when compared to control-treated tissue, however no differences were observed in non-diabetic tissue as a result of treatment. Muscle and skin repair were significantly attenuated in Fluvastatin-treated STZ-diabetic mice as demonstrated by larger wound areas, less mature granulation tissue, and an increased presence of smaller regenerating muscle fibers. Despite attenuating PAI-1 levels in diabetic tissue, Fluvastatin treatment impaired cutaneous healing and skeletal muscle repair in STZ-diabetic mice.

Mechanic-Driven Biodegradable Polyglycolic Acid/Silk Fibroin Nanofibrous Scaffolds Containing Deferoxamine Accelerate Diabetic Wound Healing

“…The excisional wound model was established based on a previous method [ 48 ]. Before the operation, the mice were anesthetized by intraperitoneal injection of 10% chloral hydrate solution (Sinopharm Chemical Reagent Co., Ltd., Shanghai, China).…”

Impaired muscle stem cell function and abnormal myogenesis in acquired myopathies

“…In addition, statins can directly impair MuSC function and myogenesis. In vivo , treatment of diabetic mice with Fluvastatin decreases the regenerative capacity after cardiotoxin injury, resulting in smaller newly formed myofibers [ 197 ]. Similarly, simvastatin decreases the proliferation and differentiation of myogenic cells through the activation of several cellular pathways [ 198 ].…”