Obestatin controls skeletal muscle fiber-type determination

Abstract

Obestatin/GPR39 signaling stimulates skeletal muscle growth and repair by inducing both G-protein-dependent and -independent mechanisms linking the activated GPR39 receptor with distinct sets of accessory and effector proteins. In this work, we describe a new level of activity where obestatin signaling plays a role in the formation, contractile properties and metabolic profile of skeletal muscle through determination of oxidative fiber type. Our data indicate that obestatin regulates Mef2 activity and PGC-1α expression. Both mechanisms result in a shift in muscle metabolism and function. The increase in Mef2 and PGC-1α signaling activates oxidative capacity, whereas Akt/mTOR signaling positively regulates myofiber growth. Taken together, these data indicate that the obestatin signaling acts on muscle fiber-type program in skeletal muscle.

Improvement of Duchenne muscular dystrophy phenotype following obestatin treatment

“…The age‐related changes prompted us to examine the effects of exogenous obestatin in 8‐week‐old mdx mice. Obestatin treatment was performed via intramuscular injection into the TA muscles every 72 h during 30 days [500 nmol/kg body weight ( n = 5); referred as obestatin group; Figure B] with sampling at 12 weeks the age, as previously described . Results from this group were compared with control vehicle‐treated mdx mice (PBS; n = 5; now referred as control group) under the same conditions.…”

“…This improvement correlates with improved muscle function because obestatin‐treated mice show a significant increase in muscle strength, as determined by generation of specific force. Because obestatin controls the fibre type determination, some of this gain‐of‐function may be linked to a conversion of fast‐twitch to slow‐twitch fibres, which are more resistant to degeneration. The slow and oxidative myofibre identity is governed by the balance between positive and negative signalling by Mef2 and class II HDACs, respectively .…”

“…The experimental protocol used in the present work was previously described . Animals, 8‐week‐old male mdx mice, were assigned to one of the following experimental groups ( n = 5 per group): (i) control group {[vehicle administration: phosphate‐buffered saline (PBS)]; n = 5} and (ii) obestatin‐treated group ( n = 5).…”

“…Muscle force was measured in a living animal as previously described . Briefly, TA muscle contractile performance was measured in vivo in anaesthetized mice using 1305A Whole Animal System (Aurora Scientific, Inc., ON, Canada).…”

“…The obestatin‐associated mitogenic action is determined by G protein‐dependent activation defining the intricate pathways related to the ERK1/2 and JunD axis, and the transactivation of epidermal growth factor receptor through the β‐arrestin signal complex determines the cell cycle exit and the development and progression of differentiation through a kinase hierarchy determined by the Akt, Ca 2+ /calmodulin‐dependent protein kinase II (CaMKII), c‐Jun, and p38 axes. In addition to its well‐established role in the control of muscle regeneration, obestatin participates in the specification of muscle fibre identity by inducing skeletal muscle remodelling toward an oxidative phenotype more resistant to damage and enhanced in muscle strength . Obestatin acts through both class II histone deacetylases (HDAC)/myocyte enhancer factor‐2 (Mef2) and peroxisome proliferator‐activated receptor‐gamma coactivator 1α (PGC1α) mechanisms, thereby controlling the establishment of oxidative muscle fibres.…”