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Pharmacological Mitigation of Fibrosis in a Porcine Model of Volumetric Muscle Loss Injury

Volumetric muscle loss (VML) increases fibrotic tissue leading to deficits in function by interfering with a number of connections including neural, vascular and mechanical that complicate implementing regenerative therapeutics. In this paper, Corona et al. investigate muscle architecture and function after VML in Yorkshire Cross pigs to elucidate whether antifibrotic measures can lessen the accumulation of fibrosis and thus mitigate function deficits. Pigs (n = 10) were Randomly assigned to a sham or ~20% VML injury, then once again randomized to either nintedanib (anti-fibrotic agent) or no treatment for 30 days. In-vivo functional measurements of the anterior compartment, including maximum isometric torque, were made over the course of 30 days using Aurora’s 890A large animal apparatus in addition to tracking compartment volume and muscle stiffness. Further histological and molecular measurements of the muscle tissue were made following euthanizing of the animals. After 4-weeks following the VML injury, nontreated muscles showed a significant (23%) maximal torque deficit in contrast to sham. The affected area of the muscle was significantly stiffer (7-fold) in the VML-nontreated leg compared to the nintedanib treated legs. In addition, there was shown to be roughly 40% greater level of hydroxyproline per mg of muscle than the treated muscles. When taken together, the results show VML causes increased fibrosis and stiffness of the affected tissue. These resultant affects post VML can be lessened following antifibrotic treatment.

Optogenetic activation of muscle contraction in vivo

Optogenetics is a relatively new and exciting field of research aimed at activating excitable cells and bypassing the need for electrical stimulation both ex-vivo and in-vivo. By utilizing Channelrhodopsin-2, researchers can simply activate these cells with blue light, something that has commonly been done in neurons, but limited work has been done with direct activation of skeletal muscle. Researchers therefore aimed to determine the feasibility of using transdermal light to directly induce isometric contractions of the triceps surae in-vivo, measured with the 1300A. The authors targeted expression of ChR2 in the skeletal muscle of mice and showed that optogenetic stimulation bypassed the nerve and resulted in similar torque production to that of electrical stimulation at a frequency of 10Hz. Higher frequencies led to a larger decay in the muscle contractions, shedding light on the significance of membrane repolarization in this process. These results showed the potential for a non-invasive alternative to electrical stimulation of muscle.

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