Increased mitochondrial Ca²⁺ contributes to health decline with age and Duchene muscular dystrophy in C. elegans

Abstract

Sarcopenia is a geriatric syndrome characterized by an age-related decline in skeletal muscle mass and strength. Here, we show that suppression of mitochondrial calcium uniporter (MCU)-mediated Ca2+ influx into mitochondria in the body wall muscles of the nematode Caenorhabditis elegans improved the sarcopenic phenotypes, blunting movement and mitochondrial structural and functional decline with age. We found that normally aged muscle cells exhibited elevated resting mitochondrial Ca2+ levels and increased mitophagy to eliminate damaged mitochondria. Similar to aging muscle, we found that suppressing MCU function in muscular dystrophy improved movement via reducing elevated resting mitochondrial Ca2+ levels. Taken together, our results reveal that elevated resting mitochondrial Ca2+ levels contribute to muscle decline with age and in muscular dystrophy. Further, modulation of MCU activity may act as a potent pharmacological target in various conditions involving muscle loss.

Mitochonic Acid 5 Improves Duchenne Muscular Dystrophy and Parkinson’s Disease Model of Caenorhabditis elegans

“…Worms were age-synchronized from the eggs and allowed to grow to the designated day. The strains used in this study are as follows: wild-type N2, TG2435: vtIs1 [ dat-1p::GFP + rol-6(su1006) ] V, ATU2301: goeIs3 [ myo-3p::SL1::GCamP3.35::SL2::unc54 3’UTR + unc-119(+) ] V, acels1 [ myo-3p::mitochondrial LAR-GECO+myo-2p::RFP ] II, ATU2305: dys-1(eg33) goeIs3 [ Pmyo3::GCaMP3.35::unc-54-3’utr, unc-119(+) ], aceIs1 [ Pmyo3::mitochondrial LAR-GECO + Pmyo2::RFP ] [ 34 ], ATU3301: ccIs4251 [ (pSAK2) myo-3p::GFP::LacZ::NLS + (pSAK4)myo-3p::mitochondrialGFP+dpy-20(+) ] I, acels1 II, ATU3305:: dys-1(eg33) ccIs4251 [ Pmyo3::nucGFP-LacZ + Pmyo-3::mitochondrial GFP ], aceIs1 [ Pmyo-3::mitochondrial LAR-GECO+ Pmyo2::RFP ], SD1347: ccIs4251 [ (pSAK2) myo-3p::GFP::LacZ::NLS+ (pSAK4) myo-3p::mitochondrial GFP + dpy-20(+) ] I and ATU3307: ccIs4251 I, acels1 II, immt-1 (tm1730) X.…”

“…Mitochondrial Ca 2+ and cytoplasmic Ca 2+ in BWM cells were, respectively, observed by measuring the expression of the transgenes aceIs1 and goeIs3 as described recently from our group [ 34 ]. The Ca 2+ concentration in muscle mitochondria ([Ca 2+ ] mito ) was calculated using the following equation [ 48 ].…”

“… a ATU3301 (ccIs4251 [(pSAK2) myo-3p::GFP::LacZ::NLS + (pSAK4) myo-3p::mitochondrial GFP + dpy-20(+)] I, acels1 [myo-3p::mitochondrial LAR-GECO + myo-2p::RFP]II) in N2 wild-type background [ 34 ]. b Median life expectancy is the age at which half of the population died.…”

Mitochonic acid 5 attenuates age-related neuromuscular dysfunction associated with mitochondrial Ca2+ overload in Caenorhabditis elegans

“…Ca 2+ is essential for optimal mitochondrial function, but its overload impairs mitochondrial function, leading to decreased mitochondrial inner membrane potential (ΔΨm) and ATP production, increased ROS release, and ultimately cell death 17 . Our recent ndings indicate that both genetic (mcu-1 mutation) or pharmacological (Ru360 administration) suppression of MCU can ameliorate muscle weakness induced by C. elegans aging and dys-1 (eg33) mutation of DMD model 12 . On the other hand, MA-5 administration reduced mitochondrial Ca 2+ overload induced by aging and rotenone treatment (Fig.…”

“…1B,C,D). In addition, we recently found that the BMC's mitochondrial Ca 2+ ([Ca 2+ ] mito ) levels increases with age by using aceIs1 transgene of mitochondrial Ca 2+ sensor mtLAR-GECO 12 . The age-related increase in [Ca 2+ ] mito levels could be suppressed by the administration of MA-5 (Fig.…”