Delineate The Molecular Mechanisms Controlling Skeletal Muscle Fitness Relevant To Exercise

Exercise is known to positively impact on lots of human chronic diseases,which including obesity,type-2 diabetes,cardiovascular diseases.On the contrary,physical inactivity is one of most important negative influences on these diseases.Furthermore,because skeletal muscle is the largest organ in human body and-80%postprandial insulin-mediated glucose disposal occurs in skeletal muscle.skeletal muscle is considered to play a critical role in exercise beneficial effects.Exercise training remodels skeletal muscle by reprograming the capacity for fuel burning,mitochondrial ATP production,and contraction.However,the molecular mechanisms of skeletal muscle adaptation to exercise training are unclear now.Pyruvate and lactate are the crucial fuel substrates in skeletal muscle exercise metabolic.Lactate dehydrogenase is the key enzyme to control the oxidation of pyruvate and lactate.Lactate dehydrogenase A(LDHA)prefers to convert pyruvate to lactate.In contrast,lactate dehydrogenase B(LDHB)tends to convert lactate to pyruvate.LDHB is widely distributed in the human body,but it mainly accumulates in the heart and skeletal muscle.Previous research indicated LDHB is a biomarker of glucose oxidation in skeletal muscle,but the physiological function of LDHB in muscle is unclear.We uncovered that the levels of LDHB were significantly increased after exercise stimulated in human muscles,which reminded that transient exercise induces the expression of the LDHB.Further studies showed the LDHB expression level was significantly higher in athlete than that in the normal human.These results suggest that LDHB may play an important role in response to exercise in skeletal muscle.We demonstrate exercise-induced PGC-la signaling can directly regulate the transcription of the LDHB gene by co-activating its promoter.To further explore the biology function of LDHB,we generate skeletal muscle specific LDHB transgenic mice(MCK-LDHB mice)and discover the increasing of LDHB can remarkable improves the mice exercise capacity by enhancing of mitochondrial oxidative function during exercise in MCK-LDHB mice.Therefore,we demonstrate a new mechanism:exercise-induced PGC-la/LDHB pathway can enhance skeletal muscle mitochondrial oxidative function in response to exercise training,and provide a therapeutic potential for chronic muscle metabolism disease.In addition,we also demonstrate that exercise can coordinately regulate the metabolic and the muscle fibers type transformation of skeletal muscle.It is not only switched the expression of MHC isoforms,but also changed mitochondrial function during exercise training.However,it is unclear how the muscle fiber types coordinately link to mitochondrial oxidative capacity in response to exercise training.We discover a novel mechanism for skeletal muscle contractile property tightly coupled to its metabolic capacity during muscle fiber type transition.First of all,our laboratory,along with others,has demonstrated that exercise can induce the expression of skeletal muscle specific miR-499 in skeletal muscle.And miR-499 is highly conservative in evolution and encoded by the introns of the oxidative fiber type Myh7b.These results suggest that miR-499 may be important in skeletal muscle during exercise.Next,we used MCK-miR-499 mice to further discover the biology function of miR-499.And overexpressing miR-499 in skeletal muscle can enhance the mitochondrial function and exercise capacity in mice.Further study showed that PGC-1? play an important role in miR-499-driven skeletal muscle mitochondrial function and exercise capacity.Finally,we identify that miR-499 directly targets the expression of AMPK inhibition factor Fnipl,and enhances the AMPK/PGC-la circuits,results in activate of mitochondrial function in skeletal muscle.So we proposal a model of muscle fiber coordinately link to mitochondrial function:oxidation type fibers can directly coupling link to the mitochondria function through the miR-499/Fnipl/AMPK circuits.This mechanism may represent a general paradigm that skeletal muscle fiber type efficiently couple cellular energy consumption with ATP production under diverse physiology and pathology.Taken together,our study had demonstrated two new mechanisms for exercise remodeling skeletal muscle function,and illuminated the molecular mechanism of exercise enhancing skeletal muscle mitochondrial function,and the coordinately link between mitochondrial function and muscle fiber types.Those findings provide new approaches for the treatment of skeletal muscle metabolism diseases.