WO2019099717A1 - Methods for measuring reducing equivalent production by tissues to determine metabolic rates and methods of use - Google Patents
Methods for measuring reducing equivalent production by tissues to determine metabolic rates and methods of use Download PDFInfo
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- WO2019099717A1 WO2019099717A1 PCT/US2018/061349 US2018061349W WO2019099717A1 WO 2019099717 A1 WO2019099717 A1 WO 2019099717A1 US 2018061349 W US2018061349 W US 2018061349W WO 2019099717 A1 WO2019099717 A1 WO 2019099717A1
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- Prior art keywords
- animal
- metabolic rate
- production
- reducing equivalent
- animals
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Classifications
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K50/00—Feeding-stuffs specially adapted for particular animals
- A23K50/10—Feeding-stuffs specially adapted for particular animals for ruminants
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K50/00—Feeding-stuffs specially adapted for particular animals
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/008—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions for determining co-enzymes or co-factors, e.g. NAD, ATP
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5082—Supracellular entities, e.g. tissue, organisms
- G01N33/5088—Supracellular entities, e.g. tissue, organisms of vertebrates
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/52—Use of compounds or compositions for colorimetric, spectrophotometric or fluorometric investigation, e.g. use of reagent paper and including single- and multilayer analytical elements
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
- G01N33/582—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with fluorescent label
-
- G—PHYSICS
- G06—COMPUTING; CALCULATING OR COUNTING
- G06Q—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES; SYSTEMS OR METHODS SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL OR SUPERVISORY PURPOSES, NOT OTHERWISE PROVIDED FOR
- G06Q50/00—Information and communication technology [ICT] specially adapted for implementation of business processes of specific business sectors, e.g. utilities or tourism
- G06Q50/02—Agriculture; Fishing; Forestry; Mining
Definitions
- the present invention relates to the use of measuring reducing equivalents, such as NADH, FADH 2 , NADP(H), and/or Coenzyme Q, to measure tissue metabolic rate in animals and humans.
- the methods of measuring reducing equivalents provide a high throughput means of determining metabolic rates of animals or humans.
- the methods may be used for a variety of purposes, for example assessing feed efficiency, assessing productivity of animals, determining a likelihood of developing obesity, sorting animals, etc.
- Basal metabolic rate may be estimated by housing animals in metabolic chambers, but the use of metabolic chambers is difficult due to practical and economic challenges.
- neither of these measures have the sensitivity associated with the accumulation of signal noted with this invention, and both are subject to exchange of gases between the media and the air.
- the technique described herein was previously used to assess ceil viability, not metabolic rate. Thus, it was surprising to discover that measuring reducing equivalents in tissues of an animal (or human) could be used as a proxy for measuring the metabolic rate of the animal (or human). An additional leap was made when it was discovered that tissue metabolic rate could be applied to assess an individual’s feed efficiency or a tissue’s production potential.
- the methods of the present invention feature measuring reducing equivalents (e.g., NADH, FADH 2 , NADP(H), Coenzyme Q, etc.), which are used to determine the metabolic rate of the animal or human (e.g., tissue-specific metabolic rate).
- the present invention provides a high throughput means of determining metabolic rate of an animal or human.
- the technology of the present invention is advantageous because it provides a fast, high-throughput, scalable and easy means of assessing metabolic rate of tissues (via ceil viability assays, e.g., measuring reducing equivalents), while allowing the user to associate that metabolic rate to parameters such as feed efficiency and tissue-specific production formation.
- ceil viability assays e.g., measuring reducing equivalents
- the technology of the present invention is advantageous because it provides a fast, high-throughput, scalable and easy means of assessing metabolic rate of tissues (via ceil viability assays, e.g., measuring reducing equivalents), while allowing the user to associate that metabolic rate to parameters such as feed efficiency and tissue-specific production formation.
- ceil viability assays e.g., measuring reducing equivalents
- the term“animal” may refer to any appropriate animal or human, e.g., cattle (e.g., dairy cattle, beef cattle), goats, sheep, swine, mice, dogs, cats, humans, non-human primates, chickens, fish, moliusks, etc.
- cattle e.g., dairy cattle, beef cattle
- goats, sheep, swine mice
- dogs, cats humans
- non-human primates chickens
- fish moliusks
- the methods of the present invention may be used to determine a likelihood of obesity.
- the methods and systems of the present invention are not limited to the animals disclosed herein.
- a lower tissue-specific metabolic rate can be indicative of a lower whole animal basal metabolic rate (energy expended to maintain proper tissue function without a change in tissue mass) if that tissue mass is large relative to whole body mass (e.g. skeletal muscle).
- a lower basal metabolic rate allows for less of the dietary energy to go toward body maintenance energy requirements and more to go toward growth or product (e.g., milk, eggs, meat, etc.) formation.
- a low skeletal muscle metabolic rate in slow/non- growing adult animals is indicative of the potential for good feed efficiency (product mass/feed mass), and a high potential for product (e.g., milk, meat) production, etc.
- the present invention provides methods of identifying animals with a particular feed efficiency, e.g., a high feed efficiency.
- feed efficiency refers to the amount of weight gained per unit of feed or product produced per unit feed.
- the present invention also features methods of stratifying animals based on feed efficiency.
- the present invention also features method of selection (e.g., methods of grouping, sequestering, etc.) of animals with a particular feed efficiency, e.g., a high feed efficiency.
- feed efficiency determined by the methods herein may be used to calculate an expected progeny difference.
- the aforementioned methods may comprise determining the reducing equivalent production (e.g., an amount, a change in, etc.) in a tissue sample (e.g., skeletal muscle tissue sample) from the animal, wherein the reducing equivalent production (e.g., an amount, a change in, etc.) in the tissue sample is inversely related to feed efficiency.
- determining the reducing equivalent production e.g., an amount, a change in, etc.
- a tissue sample e.g., skeletal muscle tissue sample
- the predetermined threshold may be an average of reducing equivalent production for a breed, herd, or species of the animal.
- the predetermined threshold may be determined by the user, e.g., based on a desired stringency of selection for feed efficiency.
- the predetermined threshold may be a percentile level (e.g., 5 th percentile, 10 th percentile, 25 th percentile, 50 th percentile, etc.).
- the predetermined threshold may be determined using a cohort of animals with a known reducing equivalent production (e.g., an amount, a change in, etc.) and known feed efficiencies.
- the predetermined threshold may stratify animals by feed efficiency.
- the reducing equivalent is NADH. In some embodiments, the reducing equivalent is NADP(H). In some embodiments, the reducing equivalent is FADH 2 . In some embodiments, the reducing equivalent is Coenzyme Q. In some embodiments, the reducing equivalent is NADH or FADH 2 . In some embodiments, the reducing equivalent is NADH or Coenzyme Q. In some embodiments, the reducing equivalent is FADH 2 or Coenzyme Q. In some embodiments, the reducing equivalent is NADH or NADP(H). In some embodiments, the reducing equivalent is NADP(H) or CoEnzyme Q. In some embodiments, the reducing equivalent is NADP(H) or FADH 2 .
- the reducing equivalent is one or more of: NADH, FADH 2 , NADP(H), and Coenzyme Q. In some embodiments, the reducing equivalent is NADH, FADH 2 , or Coenzyme Q. In some embodiments, the reducing equivalent is NADH, FADH 2 , NADP(H), or Coenzyme Q.
- the animal from which the mammary tissue sample was obtained has a high milk production potential compared to animals having a reducing equivalent production (e.g., an amount, a change in, etc.) below the predetermined threshold.
- Determining the reducing equivalent production in the tissue sample may comprise introducing a reducing equivalent indicator to the tissue sample and measuring an amount of or a change in reducing equivalent indicator (which is indicative of metabolic activity).
- the predetermined threshold may be an average of reducing equivalent production for a breed, herd, or species of the animal.
- the predetermined threshold may be determined by the user, e.g., based on a desired stringency of selection for milk production potential.
- the predetermined threshold may be a percentile level (e.g., 5 th percentile, 10 th percentile, 25 ni percentile, 50 th percentile, etc.).
- the predetermined threshold may be determined using a cohort of animals with a known reducing equivalent production (e.g., an amount, a change in, etc.) and known milk production.
- the predetermined threshold may stratify animals by milk production potential.
- the reducing equivalent is NADH. In some embodiments, the reducing equivalent is NADP(H). In some embodiments, the reducing equivalent is FADH 2 . In some embodiments, the reducing equivalent is Coenzyme Q. In some embodiments, the reducing equivalent is NADH or FADH 2 . In some embodiments, the reducing equivalent is NADH or Coenzyme Q. In some embodiments, the reducing equivalent is FADH 2 or Coenzyme Q. In some embodiments, the reducing equivalent is NADH or NADP(H). In some embodiments, the reducing equivalent is NADP(H) or CoEnzyme Q. In some embodiments, the reducing equivalent is NADP(H) or FADH 2 .
- the reducing equivalent is one or more of: NADH, FADH 2 , NADP(H), and Coenzyme Q.
- the reducing equivalent Is NADH, FADH 2 , or Coenzyme Q.
- the reducing equivalent is NADH, FADH 2 , NADP(H), or Coenzyme Q.
- the present invention also features methods of favoring or skewing a genetic makeup of an animal population (e.g., a newborn animal population) towards having high milk production.
- the method comprises determining a metabolic rate of a tissue sample (e.g , mammary tissue) from the animals (as described herein).
- the method further comprises selecting the animals with the best milk production for breeding a newborn animal population with a particular predicted milk production.
- the present invention also features methods for detecting an effect of a drug, dietary supplement, diet, or other composition on feed efficiency of an animal.
- the method comprises determining a baseline tissue-specific metabolic rate for the animal by measuring reducing equivalent production (e.g., an amount, a change in, etc.) in a first tissue sample (e.g., skeletal muscle) from the animal; administering the drug, dietary suppiement, diet, or other composition to the animal; then determining the reducing equivalent production in a second tissue sample of the tissue of the animal (a second tissue-specific metabolic rate).
- reducing equivalent production e.g., an amount, a change in, etc.
- the drug, dietary suppiement, diet, or other composition does not affect feed efficiency of the animal. In some embodiments, if the second tissue-specific metabolic rate is less than the baseline tissue-specific metabolic then the drug, dietary supplement, diet, or other composition has a positive effect on feed efficiency of the animal. In some embodiments, if the second tissue-specific metabolic rate is greater than the baseline tissue-specific metabolic then the drug, dietary supplement, diet, or other composition has a negative effect on feed efficiency of the animal.
- the method comprises administering the drug, dietary supplement, diet, or composition to the animal; and determining a metabolic rate for the animal by determining reducing equivalent production (e.g., an amount, a change in, etc.) in a tissue (e.g., skeletal muscle) of the animal.
- reducing equivalent production e.g., an amount, a change in, etc.
- a tissue e.g., skeletal muscle
- the control metabolic rate being a metabolic rate of one or a group animals not administered the drug, dietary supplement, diet, or other composition
- the drug, dietary supplement, diet, or other composition does not affect feed efficiency of the animal.
- the metabolic rate of the animal is less than a control metabolic rate, the control metabolic rate being a metabolic rate of one or a group animals not administered the drug, dietary supplement, diet, or other composition, then the drug, dietary supplement, diet, or other composition has a positive affect on feed efficiency of the animal.
- the metabolic rate of the animal is greater than a control metabolic rate, the control metabolic rate being a metabolic rate of one or a group animals not administered the drug, dietary supplement, diet, or other composition, then the drug, dietary supplement, diet, or other composition has a negative effect on feed efficiency of the animal.
- the drug, dietary supplement, diet, or other composition does not affect milk production of the animal. In some embodiments, if the second tissue-specific metabolic rate is less than the baseline tissue-specific metabolic then the drug, dietary supplement, diet, or other composition has a negative effect on milk production of the animal. In some embodiments, if the second tissue-specific metabolic rate is greater than the baseline tissue-specific metabolic then the drug, dietary supplement, diet, or other composition has a positive effect on milk production of the animal.
- tissue-specific metabolic rate of the animal is less than a control tissue- specific metabolic rate, the control tissue-specific metabolic rate being a metabolic rate of one or a group animals not administered the drug, dietary supplement, diet, or other composition, then the drug, dietary supplement, diet, or other composition has a positive affect on milk production of the animal.
- the tissue-specific metabolic rate of the animal is greater than a control tissue-specific metabolic rate, the control tissue-specific metabolic rate being a metabolic rate of one or a group animals not administered the drug, dietary supplement, diet, or other composition, then the drug, dietary supplement, diet, or other composition has a negative effect on milk production of the animal.
- the present invention also features methods of testing a drug, dietary supplement, diet, or composition ex vivo.
- the method may feature obtaining samples from the animal and treating the samples with the drug, dietary supplement, diet, or composition in culture to determined wither or not there is an affect of the drug, dietary supplement, diet, or composition on the production of reducing equivalents (e.g., metabolic rate)
- the term “baseline,” referring to metabolic rate or other parameter, may refer to an amount predetermined by the industry or by the user.
- the baseline may be predetermined by the user by testing the animal’s metabolic rate (or milk production) prior to administration of the drug or composition.
- the baseline is predetermined by other individuals, e.g., national averages, breed averages, etc.
- the present invention also features methods for treating animals to improve feed efficiency.
- the method may comprise determining an amount of a drug, dietary supplement, diet, or other composition to administer to achieve a particular feed efficiency (e.g., using the methods or a combination of methods described herein), and administering the dose of the drug, dietary supplement, diet, or other composition to achieve the desired feed efficiency.
- the terms percentile, percentile level, threshold, threshold level, and/or baseline may refer to a predetermined amount or level that is determined by the user or by the industry.
- the threshold level or percentile level is an industry average.
- the threshold level or percentile level is set by the user.
- the threshold level may be unique to a particular breed or herd.
- the threshold level or percentile level may depend on the desired feed efficiency, milk production, etc.
- the threshold or percentile is the 50 th percentile or average.
- the threshold or percentile is the 5 th percentile.
- the threshold or percentile is the 1Q !h percentile.
- the threshold or percentile is the 70 ih percentile. In some embodiments, the threshold or percentile is the 75 ih percentile. In some embodiments, the threshold or percentile is the 80 th percentile. In some embodiments, the threshold or percentile is the 85 th percentile. In some embodiments, the threshold or percentile is the 90 !h percentile. In some embodiments, the threshold or percentile is the 95 th percentile. In some embodiments, the threshold or percentile is the 5 Ih percentile. In some embodiments, the threshold or percentile is the 99 th percentile. In some embodiments, the threshold or percentile is the 5 ih percentile.
- the present invention is not limited to the aforementioned thresholds or percentiles.
- the present invention is not limited to the aforementioned means of determining the thresholds or percentiles.
- features and advantages of the methods of the present invention include, but are not limited to: (a) the ability to test tissue-specific metabolic rate; (b) the ability to test for genetic, nutrition, endocrine, and physiological effects on tissue-specific metabolic rate; (c) the ability to test for effects either in vivo or ex vivo (d) the ability to test the effect on metabolic rate of any water or DMSG soluble compound; (e) the ease of application and measurement (includes fluorescence change or color change, which can be measured from a photograph); (f) the use of a cumulative signal, which is more sensitive that a simple measure of oxygen consumption and allows for differentiation of small differences between animals; (g) the simplicity, including only the mixture of a few solutions; and (h) the ability to scale this up for simultaneous measure of 1000s of samples.
- FIG. 1C shows the 4h metabolic rate from figures 5A and 5B (fluorescence change/ng DNA). Metabolic rate of skeletal muscle biopsies is decreased by fasting (16b), but fasting did not affect liver biopsy metabolic rate. This establishes that the assay can be applied to assess the effect of nutritional state on tissue specific metabolic rate.
- FIG. 1 D shows glucose (1 mM) in the media increases skeletal muscle biopsy metabolic rate measured as relative change in fluorescence/mg tissue. This establishes that the assay can be applied to assess the effect of nutrients on tissue specific metabolic rate.
- FIG. 1 E shows Isoproterenol, a beta-adrenergic receptor agonist, increases skeletal muscle metabolic rate at high glucose concentrations (2 mM). This establishes that the assay can be applied to assess the effect of drugs on tissue specific metabolic rate.
- F!G. 1 F shows metabolic rates (expressed as fluorescence change/mg tissue) of tissue biopsies (e.g., brown adipose tissue (BAT), white adipose tissue (WAT), white skeletal muscle, red skeletal muscle, heart, kidney, and liver) differ across tissues and with age of the mouse (1 month, 3 months).
- tissue biopsies e.g., brown adipose tissue (BAT), white adipose tissue (WAT), white skeletal muscle, red skeletal muscle, heart, kidney, and liver
- BAT brown adipose tissue
- WAT white adipose tissue
- red skeletal muscle red skeletal muscle
- FIG. 2 shows metabolic rates (as changes in fluorescence over time) of many tissues (e.g., brown adipose tissue (BAT), white adipose tissue (WAT), white skeletal muscle, red skeletal muscle, heart, kidney, and liver) in fed and fasted mice.
- tissues e.g., brown adipose tissue (BAT), white adipose tissue (WAT), white skeletal muscle, red skeletal muscle, heart, kidney, and liver
- FIG. 3 shows that mammary gland biopsy metabolic rate may be used to predict milk production.
- Ex vivo mammary gland metabolic rate (top panel), as measured using the assay described in this patent, predicts ex vivo mammary gland lactose production (bottom panel) in response to heat stress (days 13-19 of pregnancy 35°C/50% humidity), maintenance at room temperature (RT; 22 ⁇ 24°C/50% humidity) with ad libitum access to feed, or maintenance at room temperature (22-24°C/50% humidity) with feed restricted to that consumed ad libitum by heat stressed animals (pair-fed; PF).
- skeletal muscle metabolic rate There was no breed difference in skeletal muscle metabolic rate between Hereford and Angus cattle.
- intrabreed animal-to-animal variability in skeletal muscle metabolic rate FC/4b is extensive in Hereford and Angus cattle. This variability may be important for improving genetics for efficiency.
- resazurin assays for measuring NADH H + production
- a biopsy is collected from an animal and immediately put into a well of a 96-weli plate containing Duibecco’s Modified Eagle Medium (DMEM) with Pen/Strep and put into a 37°C incubator with 95% 0 2 5% CO2. After 1 h equilibration, biopsies are moved into a well filled with 300 ul DMEM supplemented with 0.1 % DMSO, Pen/Strep and 0.16% 10X resazurin.
- DMEM Modified Eagle Medium
- FIG. 1A, FIG. 1 B, FIG. 1C, FIG. 1 D, FIG. 1 E, and FIG. 1 F show the application of the resazurin-based assay to homeothermic tissue collected from mice.
- FIG. 1A shows skeletal muscle metabolic rate linearly increases with time to 4 hours and is sensitive to fasting.
- FIG. 1 B shows liver metabolic rate (linearly increases with time and is not sensitive to fasting.
- FIG. 1 C shows metabolic rate (expressed as fluorescence change/ng DNA) is decreased by fasting in skeletal muscle.
- FIG. 1 D shows glucose in the media increases skeletal muscle metabolic rate (sensitive to ex vivo nutrient application).
- FIG. 1A shows skeletal muscle metabolic rate linearly increases with time to 4 hours and is sensitive to fasting.
- FIG. 1 B shows liver metabolic rate (linearly increases with time and is not sensitive to fasting.
- FIG. 1 C shows metabolic rate (expressed as fluorescence change/ng DNA) is decreased by fasting in skeletal muscle.
- FIG. 1 E shows Isoproterenol, a beta-adrenergic receptor agonist, increases skeletal muscle metabolic rate at high glucose concentrations (sensitive to drug application).
- FIG. 1 F shows metabolic rates of tissues differ across tissues and with age of the mouse (1 month, 3 months).
- FIG. 2 shows the metabolic rates of various tissues, e.g., brown adipose tissue (BAT), white adipose tissue (WAT), white skeletal muscle, red skeletal muscle, heart, kidney, and liver in fed and fasted mice, showing the effect of a physiological change (fasting) on metabolic rate (as measured by the 4br fluorescence change/mg tissue).
- BAT brown adipose tissue
- WAT white adipose tissue
- FIG. 2 shows the metabolic rates of various tissues, e.g., brown adipose tissue (BAT), white adipose tissue (WAT), white skeletal muscle, red skeletal muscle, heart, kidney, and liver in
- White adipose tissue and liver were the two tissues that were affected by fasting when measured as the 4hr fluorescence change per mg tissue. Skeletal muscle tissues were unaffected. Without wishing to limit the present invention to any theory or mechanism, DNA may be a preferred correction factor.
- the present invention is not limited to the aforementioned methods and compositions for measuring reducing equivalents.
- a tissue from an animal e.g., skeletal muscle
- determines the metabolic rate by determining reducing equivalent production (e.g., an amount, a change in, etc.).
- the animal or tissue from the animal e.g., skeletal muscle
- a reducing equivalent indicator is evaluated by assessing the change in fluorescence, absorbance (570-800 nM when using resazurin), or by color.
- the resulting metabolic rate is then compared to the range of known changes in
- mammary gland metabolic rate may be used to predict milk production.
- FIG. 3 shows that ex vivo mammary gland metabolic rate (top panel) predicts ex vivo mammary gland lactose production (bottom panel) in response to heat stress (days 13-19 of pregnancy 35°C/50% humidity), maintenance at room temperature (RT; 22-24°C/50% humidity) with ad libitum access to feed, or maintenance at room temperature (22-24°C/50% humidity) with feed restricted to that consumed ad libitum by heat stressed animals (pair-fed; PF).
- the present invention also features methods for selection of broodstock, e.g., selecting broodstock with high feed efficiency, selecting broodstock with high productivity, etc.
- the broodstock selection may feature testing a mother's or father’s tissue-specific metabolic rate (e.g., skeletal muscle, etc ), which can be indicative of the feed efficiency and/or productivity of the progeny.
- the present invention also provides methods for determining an effect of genetics, environmental stimuli, a drug treatment (e.g., antibiotics), physiological treatment (e.g., exercise), a dietary supplement, a diet, or nutritional treatment on the metabolic rates (e.g., basal metabolic rate, tissue-specific metabolic rate) of animals of interest, and thus the effect on feed efficiency, productivity, etc.
- a drug treatment e.g., antibiotics
- physiological treatment e.g., exercise
- a dietary supplement e.g., a diet
- nutritional treatment e.g., basal metabolic rate, tissue-specific metabolic rate
- the present invention features high-throughput methods for assessing energy expenditure for selection to improve efficiency.
- the methods below describe a muscle biopsy technique for stratifying cattle by skeletal muscle nicotinamide adenine dinucleotide reduction rate for assessing the metabolic rate of skeletal muscle biopsies in cattle.
- the technique may be applied to allow for genetic selection for growth or feed efficiency across species.
- the present invention is not limited to the methods, assays, and compositions described herein.
- Tissue biopsy metabolic activity assessed using the oxidation-reduction indicator Resazurin, may serve as a proxy to assess energy expenditure associated with maintenance in non-growing animals or growth rate in growing animals. These methods may evaluate the repeatability, practicality, and sensitivity of a Resazurin-based assay for ranking bovine skeletal muscle biopsies based on metabolic activity.
- Six yearling Holstein heifers (BW 330 ⁇ 11 3 kg) were fed 4 dietary treatments consisting of high or low rumen degradable starch and fiber arranged factor!ally in a partially replicated Latin Square design.
- this method can rank individual animals based on metabolic activity and detect differences in metabolic activity associated with dietary changes.
- diets also contained soybean meal (HS-HF 9.3, % DM; HS-LF 17.1 , % DM; LS-HF 9.95, % DM; LS-LF 15.3, % DM), blood meal (HS-HF 3.78, % DM; HS-LF 0.00, % DM; LS-HF 4.37, % DM; LS-LF 0.040, % DM), and corn gluten feed (HS-HF 3.26, % DM; HS-LF 0.00, % DM; LS-HF 1.65, % DM; LS-LF 7.22, % DM) to make them isonitrogenous.
- soybean meal HS-HF 9.3, % DM; HS-LF 17.1 , % DM; LS-HF 9.95, % DM; LS-LF 15.3, % DM
- blood meal HS-HF 3.78, % DM; HS-LF 0.00, % DM; LS-HF 4.37, % DM
- a 10 cm wide area 5 cm to 35 cm ventral to the point of the ischium was shaved and scrubbed three times with betadine and isopropano!.
- 10 ml of iidocaine was administered subcutaneously in 5 to 6 locations radially arrayed 2 cm externally to the biopsy site.
- the target biopsy site was 20 cm ventral to the point of the ischium.
- Muscle tissue samples were collected by making a 1 cm incision through the skin with a #20 scalpel blade, inserting a 20 gauge biopsy needle (Bard® Mission® Disposable Core Biopsy Instrument) to a 4 cm depth, and depressing the needle collection sheath to obtain a sample.
- sample mass sample mass, collection site within the muscle, and other unknown factors
- sample mass sample mass, collection site within the muscle, and other unknown factors
- sample mass sample mass, collection site within the muscle, and other unknown factors
- Samples were not weighed after collection because an analytical balance was not available at the farm.
- the incision site was sealed using monofilament #2 suture wire, cleaned with isopropanol, and sprayed with adhesive bandage.
- the right semitendinosus was sampled in periods 1 and 3 and the left semitendinosus was sampled in periods 2 and 4.
- the structurally intact core samples were placed in individual wells of a 96 well plate filled with a pre-test solution.
- the pre-test solution and contained 30 ml DMEM (Fisher Science 21-041-025), 7.5 mg Fungizone (Fisher Science 15-290-026), 0.12 mg Chloramphenicol (Fisher Science BP904-100), and 0.03 mg Ampicillin (Fisher Science AAJ6097714). After ail samples were collected, they were transferred from the pre-test solution into individual wells of a 96 well plate filled with resazurin test assay solution.
- test solution was identical to the pre-test solution with 1.6% AiamarBiue® (resazurin-based reagent, Thermo Scientific Y00-10Q) added. Solutions were mixed immediately prior to biopsy collection, filtered using a sterile 0.22 pM filter, and warmed to 37 " C before use.
- AiamarBiue® resazurin-based reagent, Thermo Scientific Y00-10Q
- the live muscle tissue samples were transported to the lab in the pre-test solution, transferred to the test solution, and analyzed. Analysis was initiated within one hour of tissue collection to ensure tissue viability.
- the test solution plate was incubated in the plate reader (Spectramax M5; Molecular Devices, LLC, San Jose, CA) at 37°C Fluorescence was read at time 0 and every 15 minutes for 2 hours using excitation and emission wavelengths of 530 and 590 nm, respectively.
- Soft Max Pro 8.1 (Molecular Devices, LLC, San Jose, CA) was used to quantify resulting emissions, and relative fluorescence (standardized to time 0) was calculated at each time point for each sample.
- VFA contribution to muscle is dependent upon individual VFA metabolism. Less than 30% of acetate, 40-55% of propionate, and minimal butyrate is available to the periphery.
- Glucose contribution to skeletal muscle in ruminants is due to gluconeogenesis. Hepatic uptake of propionate, valerate, and isobutyrate allows for increased gluconeogenic substrate. If the different starch sources contributed to different profiles of absorbed VFA, it is possible that the absorbed VFA profiles contributed to the effect of ruminaliy degradable starch on skeletal muscle metabolic activity. Independent of the mechanism driving this dietary effect, the results suggest the assay can be applied to understand the metabolic effects of ration changes.
- the metabolic activity of a ruminant is a function of body mass and metabolic flux during an inactive, tbermoneutra! environment. These differences in metabolic flux contribute to variability in feed efficiency.
- the individual metabolic flux can be influenced by genetic potential, activity and behavior, environment, and heifer rearing practices. Referring to FIG 7, the average skeletal muscle metabolic activity (expressed as relative fluorescence) of each individual was paired with dry matter intake (DMI), average daily gain (ADG), and calculated feed to grain ratio (F:G).
- a rancher owns a population of cattle and is interested in choosing the animals with the highest feed efficiency for breeding purposes. For each adult animal, she obtains a skeletal muscle tissue sample and measures the metabolic rate by measuring reducing equivalents.
- the metabolic rate of the skeletal muscle tissue is inversely related to the feed efficiency, so the farmer chooses to breed the animals with the metabolic rates that are in the lowest 25%, which would have the highest feed efficiency. For example, for a group of 100 animals, the rancher chooses the 25 animals with the lowest skeletal muscle metabolic rate. Those animals in the 25 th percentile are selected for breeding purposes. The remaining 75% of the animals are not used for breeding
- a farmer owns a population of cattle and is interested in choosing the animals with the highest milk production for breeding purposes. For each animal, he obtains a mammary tissue sample and measures the metabolic rate by measuring reducing equivalents.
- the metabolic rate of the mammary tissue is directly related to the potential milk production.
- the farmer has previously done studies to determine the amount of milk produced per day (gallons per day) based on a particular metabolic rate of mammary tissue. For example, a metabolic rate of 1000 (fluorescence change per mg tissue) or more predicts the animal will produce at least 6 gallons of milk per day. A metabolic rate of 2000 (fluorescence change per mg tissue) or more predicts the animal will produce at least 9 gallons of milk per day. A metabolic rate of 3000 (fluorescence change per mg tissue) predicts the animal will produce at least 12 gallons per day.
- a rancher owns 40 cattle and is interested in determining how Drug A will affect the feed efficiency of the cattle. For each animal, she obtains a skeletal muscle tissue sample and measures the metabolic rate by measuring reducing equivalents. She calculates the average metabolic rate for the group of animals.
- the rancher calculates that treatment with Drug A lowered the average metabolic rate of the animals by 20%. This correlates with a 20% change in average feed efficiency of the animals as well.
- a farmer owns 100 cows and is interested in determining how Drug B will affect milk production of the animals. For each animal, he obtains a mammary tissue sample and measures the metabolic rate by measuring reducing equivalents. He calculates the average metabolic rate for the group of animals.
- descriptions of the inventions described herein using the phrase“comprising” includes embodiments that could be described as “consisting of”, and as such the written description requirement for claiming one or more embodiments of the present invention using the phrase“consisting of is met.
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EP18878766.7A EP3709818A4 (en) | 2017-11-15 | 2018-11-15 | Methods for measuring reducing equivalent production by tissues to determine metabolic rates and methods of use |
AU2018370021A AU2018370021B2 (en) | 2017-11-15 | 2018-11-15 | Methods for measuring reducing equivalent production by tissues to determine metabolic rates and methods of use |
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