Physiactisome: A New Nanovesicle Drug Containing Heat Shock Protein 60 for Treating Muscle Wasting and Cachexia

Abstract

Currently, no commercially available drugs have the ability to reverse cachexia or counteract muscle wasting and the loss of lean mass. Here, we report the methodology used to develop Physiactisome—a conditioned medium released by heat shock protein 60 (Hsp60)—overexpressing C2C12 cell lines enriched with small and large extracellular vesicles. We also present evidence supporting its use in the treatment of cachexia. Briefly, we obtain a nanovesicle-based secretion by genetically modifying C2C12 cell lines with an Hsp60-overexpressing plasmid. The secretion is used to treat naïve C2C12 cell lines. Physiactisome activates the expression of PGC-1α isoform 1, which is directly involved in mitochondrial biogenesis and muscle atrophy suppression, in naïve C2C12 cell lines. Proteomic analyses show Hsp60 localisation inside isolated nanovesicles and the localisation of several apocrine and merocrine molecules, with potential benefits for severe forms of muscle atrophy. Considering that Physiactisome can be easily obtained following tissue biopsy and can be applied to autologous muscle stem cells, we propose a potential nanovesicle-based anti-cachexia drug that could mimic the beneficial effects of exercise. Thus, Physiactisome may improve patient survival and quality of life. Furthermore, the method used to add Hsp60 into nanovesicles can be used to deliver other drugs or active proteins to vesicles.

Extracellular vesicles in cancer cachexia: deciphering pathogenic roles and exploring therapeutic horizons

“…Additionally, engineering EVs to display specific targeting ligands on their surface would allow them to selectively bind to receptors on CC-related cells. An example of this is Physiactisome, a nanovesicle incorporating Hsp60, which mimics the beneficial effects of exercise training in combating muscle atrophy and cachexia [ 242 ]. Further, by manipulating the cargo of EVs, the adverse impacts of cancer-derived EVs on cachexia might be lessened.…”

The role of extracellular vesicles in skeletal muscle wasting

“…As IL‐6 is a significant mediator of skeletal muscle loss, 60–63,65 the inhibition of IL‐6 through IL‐6ST decoy receptor loaded by EVs demonstrates great therapeutic potential. Besides the IL‐6 decoy receptor, another promising drug named physiactisome for treating muscle wasting has been proposed recently 66 . The functional molecules are actually Hsp60 contained by EVs derived from Hsp60‐overexpressing C2C12 cell lines.…”

“…The functional molecules are actually Hsp60 contained by EVs derived from Hsp60‐overexpressing C2C12 cell lines. Treatment with Hsp60 containing EVs could induce the expression of PGC‐1α in naïve C2C12 cells, thus promoting mitochondria biogenesis and counteracting muscle wasting 66 . It was said that physiactisome is the first and only patented EV‐based drug for the treatment of muscle wasting 66 .…”

“…Besides the IL‐6 decoy receptor, another promising drug named physiactisome for treating muscle wasting has been proposed recently. 66 The functional molecules are actually Hsp60 contained by EVs derived from Hsp60‐overexpressing C2C12 cell lines. Treatment with Hsp60 containing EVs could induce the expression of PGC‐1α in naïve C2C12 cells, thus promoting mitochondria biogenesis and counteracting muscle wasting.…”

“…Treatment with Hsp60 containing EVs could induce the expression of PGC‐1α in naïve C2C12 cells, thus promoting mitochondria biogenesis and counteracting muscle wasting. 66 It was said that physiactisome is the first and only patented EV‐based drug for the treatment of muscle wasting. 66 In addition to EV‐encapsulated proteins, proteins loaded on the surface of EVs can also present therapeutic potential.…”